TY - JOUR AB - BACKGROUND: Childhood asthma has been linked to distinct metabolomic profiles. OBJECTIVE: To identify phenotypes (metabotypes) in children with moderate-to-severe asthma through integrative fecal and serum metabolome analysis. METHODS: Children from the Systems Pharmacology Approach to Uncontrolled Pediatric Asthma cohort with Global Initiative for Asthma treatment step ≥3 were recruited. Asthma control was defined by the Asthma Control Test and annual exacerbation history. Targeted metabolomics profiling of feces and serum was performed using liquid chromatography and flow injection electrospray ionization-triple quadrupole mass spectrometry. Similarity Network Fusion integrated fecal and serum metabolome profiles, followed by spectral clustering. Clusters were analyzed for differences in asthma characteristics, food diaries, fecal microbiota composition, and levels of serum inflammatory markers and blood cells. RESULTS: Integrative fecal and serum metabolome analysis of 92 children with moderate-to-severe asthma (median age: 11.5 years, 34% female) revealed three metabotypes. Metabotype1 had the lowest percentage of allergic rhinitis, with elevated serum ceramides and triglycerides. Metabotype2 had higher odds of asthma control, the highest percentage of children with ≥4 months of breastfeeding, reduced sugar intake, lowest levels of blood neutrophils and serum inflammatory markers, and with elevated serum acylcarnitines and ω-3 fatty acids. Metabotype3 included the highest percentage of uncontrolled asthma patients, with decreased serum cholesteryl esters, phosphatidylcholines, and sphingomyelins, elevated fecal amino acids, and reduced fecal microbiota diversity. CONCLUSIONS: Metabotypes in children with moderate-to-severe asthma are linked to asthma control, distinct fecal microbiota and systemic inflammatory patterns. The findings suggest that metabotyping can be valuable in precision medicine approaches for asthma. AU - Abdel-Aziz, M.I.* AU - Hashimoto, S.* AU - Neerincx, A.H.* AU - Haarman, E.G.* AU - Cecil, A. AU - Lintelmann, J. AU - Witting, M. AU - Hauck, S.M. AU - Kerssemakers, N.* AU - Verster, J.C.* AU - Bang, C.* AU - Franke, A.* AU - Dierdorp, B.S.* AU - Dekker, T.J.* AU - Metwally, N.K.A.* AU - Duitman, J.W.* AU - Lutter, R.* AU - Gorenjak, M.* AU - Toncheva, A.A.* AU - Kheiroddin, P.* AU - Harner, S.* AU - Brandstetter, S.* AU - Wolff, C.* AU - Corcuera-Elosegui, P.* AU - López-Fernández, L.* AU - Perez-Garcia, J.* AU - Almeida, M.M.* AU - Sardón-Prado, O.* AU - Pino-Yanes, M.* AU - Potocnik, U.* AU - Kabesch, M.* AU - Vijverberg, S.J.H.* AU - Kraneveld, A.D.* AU - Maitland-van der Zee, A.H.* C1 - 74207 C2 - 57369 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa TI - Metabotypes are linked to uncontrolled childhood asthma, gut microbiota, and systemic inflammation. JO - J. Allergy Clin. Immunol. VL - 156 IS - 2 PB - Mosby-elsevier PY - 2025 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Eczema herpeticum (EH) is a potentially life-threatening disseminated skin infection caused by herpes simplex virus (HSV) in a subset of atopic dermatitis (AD) patients. The occurrence of EH in a subset of AD patients and its frequent recurrence imply the importance of genetic factors in its pathogenesis. OBJECTIVE: We aimed to identify novel genetic risk factors for EH and to study their impact on HSV-1 infection. METHODS: Using whole exome sequencing we identified a heterozygous single nucleotide polymorphism (SNP) in the COL23A1 gene (encoding Collagen type XXIII alpha 1 chain or COL23A1) that was associated with EH and validated it by PCR in a larger cohort. We studied the effect of upregulated COL23A1 expression on HSV-1 infection in primary keratinocytes and HaCaT cells and performed bulk RNA sequencing to address the underlying mechanism. RESULTS: EH-patient-derived primary keratinocytes carrying this heterozygous SNP rs2973744 had elevated COL23A1 mRNA and protein levels as well as an increased susceptibility to HSV-1. Increasing the COL23A1 levels experimentally enhanced HSV-1 infection in human keratinocytes. COL23A1 overexpression elevated syndecan-1 and nectin-1 levels on the cell surface, which are HSV-1 attachment and entry factors, respectively, and downregulated genes involved in antiviral responses such as IL1R1, IL32, TLR4, IRF1, S100A9, C3, and CFH. CONCLUSION: The SNP rs2973744 enhances COL23A1 expression in ADEH+-derived keratinocytes. Upregulation of COL23A1 promotes HSV-1 infection presumably by upregulating the HSV-1 attachment and entry factors syndecan-1 and nectin-1 on the cell surface and attenuating antiviral responses of keratinocytes. AU - Chopra, S.* AU - Zeitvogel, J.* AU - Traidl, S.* AU - Klug, I.* AU - Rodriguez, E. AU - Harder, I.* AU - Lieb, W.* AU - Weidinger, S.* AU - Schulz, T.F.* AU - Sodeik, B.* AU - Döhner, K.* AU - Roesner, L.M.* AU - Werfel, T.* C1 - 75032 C2 - 57704 TI - Collagen XXIII (COL23A1): A novel risk factor for eczema herpeticum. JO - J. Allergy Clin. Immunol. PY - 2025 SN - 0091-6749 ER - TY - JOUR AB - With the prevalence of pediatric asthma and allergy rising substantially since last mid-century, birth cohort studies starting in pregnancy have been pivotal in identifying prenatal and early life environmental factors that influence risk of these diseases. With these findings, researchers have been able to identify biological mechanisms at play with the eventual goal of engineering tailored interventions to optimize immune system development and decrease the risk of allergic disorders. In this review, we describe the critical role birth cohort studies have played in starting to disentangle the environmental epidemiology and etiology of childhood-onset asthma and other allergic diseases, and how these studies have guided ongoing clinical trials for asthma and allergy prevention. Lastly, we highlight important questions that remain unanswered and potential approaches to help fill these gaps in knowledge. AU - Eapen, A.A.* AU - Shankhwar, S. AU - von Mutius, E. AU - Johnson, C.C.* C1 - 75145 C2 - 57792 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 535-545 TI - Environmental risk factors and asthma primary prevention: From birth cohort studies to clinical trials. JO - J. Allergy Clin. Immunol. VL - 156 IS - 3 PB - Mosby-elsevier PY - 2025 SN - 0091-6749 ER - TY - JOUR AU - Ege, M.J. C1 - 75078 C2 - 57737 TI - Neighborhoods - opportunity or harm? JO - J. Allergy Clin. Immunol. PY - 2025 SN - 0091-6749 ER - TY - JOUR AB - RATIONALE: Preschool wheeze is a heterogenous and poorly understood clinical syndrome. As a result, current treatments are insufficient, and prevention is not possible. OBJECTIVES: To increase understanding of the genetic susceptibility and underlying disease mechanisms of wheeze phenotypes in early childhood through large-scale genome-wide association study (GWAS) analyses. METHODS: We performed meta-analyses of GWAS on early-onset wheeze, defined as recurrent wheeze or asthma in the first 3 years of life, and subtypes hereof, including early transient and persistent wheeze, defined by asthma/wheeze at age 3 and subsequent remission or persistence at age 6 respectively. The discovery analyses included data on more than 13,000 children from 15 cohorts and replication was sought through meta-analyses of data from 7 additional cohorts including up to 5,000 children. Genetic variants associated with asthma-related traits in adulthood (adult asthma, atopy, eosinophils and lung function) were used to quantify the degree to which genetic risk influencing asthma-related adult traits also influences genetic risk of preschool wheeze. RESULTS: Variants near the GSDMB gene in the 17q-region showed genome-wide significant association with early onset (rs2305480, OR = 1.26 (1.17 - 1.33), P = 2.30E-16), and persistent (rs11078926, OR = 1.43 (1.30 - 1.578), P = 2.14E-11), but not with early transient wheeze (rs1054609, OR = 1.08 (0.98 - 1.18), P = 0.094). Other known asthma loci were associated with early onset wheeze, particularly CDHR3. Additionally, increased genetic risk to early onset wheeze was associated with genetic risk for asthma at older ages, atopy, eosinophil count and lower adult lung function. This was driven by persistent wheeze while transient early wheeze was only associated with low lung function. CONCLUSIONS: Preschool wheeze phenotypes displayed distinct patterns of single SNP associations and genetic enrichment with asthma related traits. These results indicate distinct etiologies of wheeze phenotypes, which could inform studies in optimization of prevention and treatment strategies. AU - Fischer-Rasmussen, K.* AU - Granell, R.* AU - Eliasen, A.U.* AU - Kreiner, E.* AU - Tingskov Pedersen, C.E.* AU - Luo, Y.* AU - Chawes, B.* AU - Stokholm, J.* AU - Malby Schoos, A.M.* AU - Kumar, A.* AU - Nybo Andersen, A.M.* AU - Feenstra, B.* AU - Geller, F.* AU - Siroux, V.* AU - Demenais, F.* AU - Bouzigon, E.* AU - Jaddoe, V.* AU - van der Valk, R.J.* AU - Duijts, L.* AU - Sunyer, J.* AU - Guxens, M.* AU - Marinelli, M.* AU - Bustamante, M.* AU - Heinrich, J.* AU - Standl, M. AU - Curtin, J.* AU - Simpson, A.* AU - Murray, C.* AU - Jacobsson, B.* AU - Myhre, R.* AU - Pennell, C.E.* AU - Daley, D.* AU - Ober, C.* AU - Gern, J.E.* AU - Jackson, D.J.* AU - Boomsma, D.I.* AU - Hottenga, J.J.* AU - Abdellaoui, A.* AU - Holloway, J.W.* AU - Collins, S.* AU - Turner, S.* AU - Arshad, S.H.* AU - Ullah, A.* AU - Melén, E.* AU - Henderson, J.* AU - Bisgaard, H.* AU - Pedersen, A.G.* AU - Custovic, A.* AU - Vonk, J.M.* AU - Koppelman, G.H.* AU - Kabesch, M.* AU - Bønnelykke, K.* C1 - 75320 C2 - 57947 TI - Genetic characterization of preschool wheeze phenotypes. JO - J. Allergy Clin. Immunol. PY - 2025 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: TNFα is an important proinflammatory cytokine, but its neutralization in the management of inflammatory skin disorders like psoriasis may trigger eczematous skin lesions as an adverse reaction. OBJECTIVES: This study aimed to elucidate whether TNF-α may protect from skin inflammation and to identify in detail the underlying mechanisms. METHODS: Wildtype, TNF-α-deficient, TSLPR-deficient, mast cell (MC)-deficient, TNF-α-TSLPR-double-deficient and TNF-α-MC-double-deficient mice were subjected to a skin inflammation model and inspected by physical, clinical, histological, immunohistochemical and bioanalytical techniques. RESULTS: TNFα deficiency promoted skin inflammation. This was accompanied by MC hyperplasia and potent TSLP production in lesional skin and serum of TNFα deficient mice. Specifically, MCs were found to be responsible for inducing high levels of TSLP in the epidermis, compromising barrier function and initiating inflammation. In contrast, the production of immunoglobulins, including IgE, was reduced in mice lacking TNFα. CONCLUSIONS: TNFα restrains MC-dependent TSLP production and the onset of eczema. AU - Redhu, D.* AU - Kumari, V. AU - Franke, K.* AU - Hartmann, K.* AU - Worm, M.* AU - Babina, M.* C1 - 73997 C2 - 57296 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 150-158 TI - TNFα counters skin inflammation by restraining mast cell-dependent TSLP production. JO - J. Allergy Clin. Immunol. VL - 156 IS - 1 PB - Mosby-elsevier PY - 2025 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: NSAID-exacerbated respiratory disease (N-ERD) is characterized by chronic asthma, nasal polyposis and intolerance to nonsteroidal anti-inflammatory drugs. We have recently described aberrant macrophage activation and lipid metabolism in N-ERD, however local drivers of nasal inflammation in N-ERD are incompletely understood. OBJECTIVE: To study how apolipoprotein E deficiency in the N-ERD nasal mucosa affects the crosstalk and inflammatory activation of macrophages and epithelial cells. METHODS: We combined transcriptional and mediator analysis of N-ERD patient samples and primary human cell culture to study ApoE in epithelial and myeloid cells. RESULTS: N-ERD nasal scrapings exhibited decreased APOE expression in comparison to healthy nasal mucosa, but APOE was inherently low in epithelial cells. Instead, myeloid cells expressed highly abundant APOE, which was reduced in monocyte-derived macrophages from N-ERD patients. siRNA-mediated knockdown of APOE in monocyte-derived macrophages resulted in increased CXCL7 expression, an inflammatory chemokine implicated in N-ERD. In addition, highly oxidized arachidonyl-phosphatidylethanolamine accumulated in APOE-knockdown macrophages and ApoE protected macrophages from ferroptotic cell death. CONCLUSION: Our results suggest a role for myeloid ApoE in regulating the crosstalk between macrophages and epithelial cells as well as ferroptosis during type 2 airway inflammation. ApoE deficiency may thus contribute to chronic type 2 inflammation in N-ERD, and its restoration could help reestablish normal epithelial barrier integrity and macrophage effector functions. AU - Schmiz, G. AU - Haimerl, P. AU - Ram, I.* AU - Kulagin, M.* AU - Spitzlberger, B. AU - Henkel, F. AU - Hartung, F. AU - Schindela, S. AU - Rao, Z.* AU - Koeberle, A.* AU - Schmidt-Weber, C.B. AU - Chaker, A. AU - Lechner, A. AU - Esser-von Bieren, J. C1 - 74994 C2 - 57682 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 1095-1102.e4 TI - Loss of apolipoprotein E contributes to inflammatory macrophage activation and ferroptosis in NSAID-exacerbated respiratory disease. JO - J. Allergy Clin. Immunol. VL - 156 IS - 4 PB - Mosby-elsevier PY - 2025 SN - 0091-6749 ER - TY - JOUR AB - Inflammatory skin diseases, like atopic eczema (atopic dermatitis, AD), affect children and adults globally. In AD, the skin barrier is impaired on multiple levels. Underlying factors include genetic, chemical, immunological, and microbial components. Increased skin pH in AD is part of the altered microbial microenvironment that promotes overgrowth of the skin microbiome with Staphylococcus aureus (S. aureus). The secretion of virulence factors, like toxins and proteases, by S. aureus further aggravates the skin barrier deficiency and additionally off-balances the already skewed immune response. Skin commensal bacteria, however, can inhibit the growth and pathogenicity of S. aureus through quorum sensing systems. Therefore, restoring a healthy skin microbiome could contribute to remission induction in AD. This review discusses direct and indirect approaches to targeting the skin microbiome through modulation of the skin pH, UV treatment, and pre-, pro-, and postbiotics. Furthermore, exploratory techniques like skin microbiome transplantation, ozone therapy, and phage therapy are discussed. Finally, we summarize the latest findings on disease and microbiome modification through targeted immunomodulatory, systemic treatments and biologicals. We believe that targeting the skin microbiome should be considered a crucial component of successful AD treatment in the future. AU - Hülpüsch, C. AU - Rohayem, R.* AU - Reiger, M. AU - Traidl-Hoffmann, C. C1 - 70702 C2 - 55720 TI - Exploring the skin microbiome in atopic dermatitis pathogenesis and disease modification. JO - J. Allergy Clin. Immunol. PY - 2024 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: T helper 2 (Th2) cells crucially contribute to the pathogenesis of atopic dermatitis (AD) by secreting high levels of IL-13 and IL-22. Yet, the upstream regulators that activate Th2 cells in AD skin remain unclear. IL-18 is a putative upstream regulator of Th2 cells as it is implicated in AD pathogenesis and has the capacity to activate T cells. OBJECTIVE: To decipher the role of IL-18 in Th2 responses in blood and skin of AD patients. METHODS: PBMCs and skin biopsies from AD patients and healthy donors were used. Functional assays were performed ex vivo using stimulation or blocking experiments. Analysis was performed using flow cytometry, bead-based multiplex assays, RT-qPCR, RNA-seq, western blotting, and spatial sequencing. RESULTS: IL-18Rα+ Th2 cells were enriched in blood and lesional skin of AD patients. Of all the cytokines for which Th2 cells express the receptor, only IL-9 was able to induce IL-18R via an IL-9R-JAK1/JAK3-STAT1 signaling pathway. Functionally, stimulation of circulating Th2 cells with IL-18 induced secretion of IL-13 and IL-22, an effect that was enhanced by co-stimulation with IL-9. Mechanistically, IL-18 induced Th2 cytokines via activation of IRAK4, NF-κB, and AP-1 signaling in Th2 cells, and neutralization of IL-18 inhibited these cytokines in cultured explants of AD skin lesions. Finally, IL-18 protein levels correlated positively with disease severity in lesional AD skin. CONCLUSION: Our data identify a novel IL-9-IL-18 axis that contributes to Th2 responses in AD. Our findings suggest that both IL-9 and IL-18 could represent upstream targets for future treatment of AD. AU - Schärli, S.* AU - Luther, F.* AU - Di Domizio, J.* AU - Hillig, C. AU - Radonjic-Hoesli, S.* AU - Thormann, K.* AU - Simon, D.* AU - Møller Rønnstad, A.T.* AU - Ruge, I.F.* AU - Fritz, B.G.* AU - Bjarnsholt, T.* AU - Vallone, A.* AU - Kezic, S.* AU - Menden, M.P. AU - Roesner, L.M.* AU - Werfel, T.* AU - Thyssen, J.P.* AU - Eyerich, S. AU - Gilliet, M.* AU - Bertschi, N.L.* AU - Schlapbach, C.* C1 - 72311 C2 - 56582 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa TI - IL-9 sensitizes human Th2 cells to pro-inflammatory IL-18 signals in atopic dermatitis. JO - J. Allergy Clin. Immunol. VL - 155 IS - 2 PB - Mosby-elsevier PY - 2024 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Nummular eczema (NE) is a common chronic inflammatory skin disease characterized by multiple, pruritic, discoid-shaped lesions. Since the underlying immune mechanisms are not fully understood, it is unclear whether NE should be regarded as variant of atopic dermatitis (AD) or a distinct disease. OBJECTIVE: We compared the clinical, histopathologic, and molecular signatures of NE with that of type 2 and type 3 skin diseases. METHODS: We performed bulk RNA sequencing as well as histologic and clinical studies in lesional and nonlesional skin biopsy specimens from NE (n = 50), AD (n = 47), and psoriasis (n = 90) patients. RESULTS: NE displayed typical hallmarks of AD, such as an impaired epidermal barrier, microbial colonization, spongiosis, and eosinophil infiltration, but also aspects of psoriasis, including increased epidermal thickness, number of Ki-67+ cells, and neutrophilic infiltration. At the gene expression level, neutrophil-attracting cytokines (IL19, CXCL8, CXCL5) were upregulated, whereas TH2-related cytokines (IL13, CCL17, CCL18, CCL26, CCL27) were similarly expressed in NE compared to AD. Principal component analysis of transcriptome data from lesional skin showed that AD and NE cluster together distinct of psoriasis. In line with this, an established molecular classifier identified NE as AD rather than psoriasis. Finally, we demonstrated clinical and molecular efficacy of dupilumab treatment in NE. CONCLUSION: NE shows overlapping type 2 and type 3 immune signatures, while type 2 immunity predominates and should be the primary target of specific therapeutic interventions. This supports the view of NE as a variant of AD. AU - Böhner, A.* AU - Jargosch, M. AU - Müller, N.S. AU - Garzorz-Stark, N.* AU - Pilz, A.C. AU - Lauffer, F.* AU - Wang, R.* AU - Roenneberg, S.* AU - Zink, A.* AU - Thomas, J.* AU - Theis, F.J. AU - Biedermann, T.* AU - Eyerich, S. AU - Eyerich, K.* C1 - 67783 C2 - 54261 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 408-419 TI - The neglected twin: Nummular eczema is a variant of atopic dermatitis with codominant TH2/TH17 immune response. JO - J. Allergy Clin. Immunol. VL - 152 IS - 2 PB - Mosby-elsevier PY - 2023 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Toll-like receptors (TLRs) mediate functions for host defense and inflammatory responses. TLR4 recognizes LPS, a component of gram-negative bacteria as well as host-derived endogenous ligands such as S100A8 and S100A9 proteins. OBJECTIVE: We sought to report phenotype and cellular function of individuals with complete TLR4 deficiency. METHODS: We performed genome sequencing and investigated exome and genome sequencing databases. Cellular responses were studied on primary monocytes, macrophages, and neutrophils, as well as cell lines using flow cytometry, reporter, and cytokine assays. RESULTS: We identified 2 individuals in a family of Qatari origin carrying a homozygous stop codon variant p.Q188X in TLR4 presenting with a variable phenotype (asymptomatic and inflammatory bowel disease consistent with severe perianal Crohn disease). A third individual with homozygous p.Y794X was identified in a population database. In contrast to hypomorphic polymorphisms p.D299G and p.T399I, the variants p.Q188X and p.Y794X completely abrogated LPS-induced cytokine responses whereas TLR2 response was normal. TLR4 deficiency causes a neutrophil CD62L shedding defect, whereas antimicrobial activity toward intracellular Salmonella was intact. CONCLUSIONS: Biallelic TLR4 deficiency in humans causes an inborn error of immunity in responding to LPS. This complements the spectrum of known primary immunodeficiencies, in particular myeloid differentiation primary response 88 (MYD88) or the IL-1 receptor-associated kinase 4 (IRAK4) deficiency that are downstream of TLR4 and TLR2 signaling. AU - Capitani, M.* AU - Al-Shaibi, A.A.* AU - Pandey, S.* AU - Gartner, L.* AU - Taylor, H.A.* AU - Hubrack, S.Z.* AU - Agrebi, N.* AU - Al-Mohannadi, M.J.* AU - Al Kaabi, S.* AU - Vogl, T.* AU - Roth, J.* AU - Kotlarz, D.M. AU - Klein, C.* AU - Charles, A.K.* AU - Vijayakumar, V.* AU - Karim, M.Y.* AU - George, B.* AU - Travis, S.P.* AU - Elawad, M.* AU - Lo, B.* AU - Uhlig, H.H.* C1 - 66838 C2 - 53311 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 783-790.e5 TI - Biallelic TLR4 deficiency in humans. JO - J. Allergy Clin. Immunol. VL - 151 IS - 3 PB - Mosby-elsevier PY - 2023 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Studies have linked daily pollen counts to respiratory allergic health outcomes but few have considered allergen levels. OBJECTIVE: This study assessed associations of grass pollen counts and allergen levels (Phl p 5) with 1) respiratory allergic health symptoms in a panel of 93 adults with moderate-severe allergic rhinitis and 2) daily asthma hospital admissions in London, UK. METHODS: Daily symptom and medication scores were collected from adult participants in an allergy clinical trial. Daily counts of asthma hospital admissions in the London general population were obtained from Hospital Episode Statistics data. Daily grass pollen counts were measured using a volumetric air sampler, and novel Phl p 5 levels, using a Chemvol high-volume cascade impactor and ELISA analyses (May-August). Associations between the two pollen variables and daily health scores (dichotomized based on within-person 75th percentiles) were assessed using generalized estimating equation logistic models, and with asthma hospital admissions using Poisson regression models. RESULTS: Daily pollen counts and Phl p 5 levels were each positively associated with reporting a high combined symptom and medication health score in separate models. However, in mutually adjusted models including terms for both pollen counts and Phl p 5 levels, associations remained for Phl p 5 levels (odds ratio [95% confidence intervals]: 1.18 [1.12, 1.24]) but were heavily attenuated for pollen counts (1.00 [0.93, 1.07]). Similar trends were not observed for asthma hospital admissions in London. CONCLUSION: Grass allergen (Phl p 5) levels are more consistently associated with allergic respiratory symptoms than grass pollen counts. AU - Fuertes, E.* AU - Jarvis, D.* AU - Lam, H.* AU - Davies, B.* AU - Fecht, D.* AU - Candeias, J. AU - Schmidt-Weber, C.B. AU - Douiri, A.* AU - Slovick, A.* AU - Scala, E.* AU - Smith, T.E.* AU - Shamji, M.* AU - Buters, J.T.M. AU - Cecchi, L.* AU - Till, S.J.* C1 - 68910 C2 - 53762 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 844-851 TI - Phl p 5 levels more strongly associated than grass pollen counts with allergic respiratory health. JO - J. Allergy Clin. Immunol. VL - 153 IS - 3 PB - Mosby-elsevier PY - 2023 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: The Asthma Severity Scoring System (ASSESS) quantifies asthma severity in adolescents and adults. Scale performance in children < 12 years is unknown. OBJECTIVE: To validate the ASSESS score in the All Age Asthma Cohort (ALLIANCE) and explore its use in children <12 years. METHODS: Scale properties, responsiveness, and known-group validity were assessed in 247 children (median age 11 years, IQR: 8-13 years) and 206 adults (median age 52 years, IQR: 43-63 years). RESULTS: Overall, measures of internal test consistency and test-retest reliability were similar to the original data of the Severe Asthma Research Program (SARP). Cronbach's α was 0.59 in children 12-18 years and 0.73 in adults, reflecting the inclusion of multiple and not always congruent dimensions to the ASSESS score especially in children. Analysis of known-group validity confirmed the discriminatory power, as the ASSESS score was significantly worse in patients with poor asthma control, exacerbations and increased salbutamol use. In children between 6-11 years test reliability was inferior compared to adults and adolescents (Cronbach's α 0.27) mostly due to a less lung function impairment in asthmatic children of this age group. Known-group validity however confirmed good discriminative power regarding severity-associated variables similar to adolescents and adults. CONCLUSION: Test reliability and validity of the ASSESS score was confirmed in the ALLIANCE cohort. In children aged 6-11 years internal consistency was inferior compared to older asthma patients, however test validity was good and encourages age-spanning usage of the ASSESS score in all asthma patients ≥ 6 years. AU - Grychtol, R.* AU - Riemann, L.* AU - Gaedcke, S.* AU - Liu, B.* AU - Deluca, D.* AU - Forster, R.* AU - Maison, N. AU - Thiele, D.* AU - Jakobs, N.* AU - Bahmer, T.* AU - Meyer, M.* AU - Foth, S.* AU - Weber, S.* AU - Rietschel, E.* AU - Rabe, K.F.* AU - Kopp, M.V.* AU - von Mutius, E. AU - Dittrich, A.M.* AU - Hansen, G.* AU - ALLIANCE Study Group (Illi, S. AU - Marzi, C. AU - Zissler, U.M. AU - Schmidt-Weber, C.B.) C1 - 67457 C2 - 54114 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 1525-1535.e4 TI - Validation of the Asthma Severity Scoring System (ASSESS) in the ALLIANCE cohort. JO - J. Allergy Clin. Immunol. VL - 151 IS - 6 PB - Mosby-elsevier PY - 2023 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Alpha-gal (Galα1-3Galβ1-4GlcNAc) is a carbohydrate with the potential to elicit fatal allergic reactions to mammalian meat and drugs of mammalian origin. This type of allergy is induced by tick bites and therapeutic options for this skin-driven food allergy are limited to the avoidance of the allergen and treatment of symptoms. Thus, a better understanding of the immune mechanisms resulting in sensitization through the skin is crucial, especially in the case of a carbohydrate allergen for which underlying immune responses are poorly understood. OBJECTIVE: We aimed to establish a mouse model of alpha-gal allergy for in-depth immunological analyses. METHODS: GGTA1-deficient mice devoid of alpha-gal glycosylations were sensitized with the alpha-gal-carrying self-protein mouse serum albumin via repetitive intracutaneous injections in combination with the adjuvant aluminum hydroxide. The role of basophils and IL-4 in sensitization was investigated by using antibody-mediated depletion. RESULTS: Alpha-gal-sensitized mice displayed increased levels of alpha-gal-specific IgE and IgG1 and developed systemic anaphylaxis upon challenge with both alpha-gal-containing glycoproteins and glycolipids. In accordance with alpha-gal-allergic patients, we detected elevated numbers of basophils at the site of sensitization as well as increased numbers of alpha-gal-specific B cells, germinal center B cells and B cells of IgE and IgG1 isotypes in skin-draining lymph nodes. By depleting IL-4 during sensitization, we demonstrated for the first time that sensitization and elicitation of allergy to alpha-gal and correspondingly to a carbohydrate allergen is dependent on IL-4. CONCLUSION: These findings establish IL-4 as a potential target to interfere with alpha-gal allergy elicited by tick bites. AU - Hils, M.* AU - Hoffard, N.* AU - Iuliano, C.* AU - Kreft, L. AU - Chakrapani, N.* AU - Swiontek, K.* AU - Fischer, K.* AU - Eberlein, B.* AU - Köberle, M.* AU - Fischer, J.* AU - Hilger, C.* AU - Ohnmacht, C. AU - Kaesler, S.* AU - Wölbing, F.* AU - Biedermann, T.* C1 - 69042 C2 - 53824 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 1050-1062.e6 TI - IgE and anaphylaxis specific to the carbohydrate alpha-gal depend on interleukin-4. JO - J. Allergy Clin. Immunol. VL - 153 IS - 4 PB - Mosby-elsevier PY - 2023 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Toll-like receptors (TLRs) are important pattern recognition receptors that sense microbes and control host defense. Myeloid differentiation protein 2 (MD2) is the indispensable coreceptor for TLR4, facilitating the binding to the gram-negative bacterial cell wall component LPS and activation of downstream signaling. OBJECTIVE: We sought to provide phenotypic and mechanistic insights into human MD2 deficiency. METHODS: To elucidate the genetic cause in a patient with very early onset inflammatory bowel disease, we performed whole-exome sequencing and studied the functional consequences of the identified mutation in LY96 (encoding for MD2) in genetically engineered induced pluripotent stem cell-derived macrophages with knockout of MD2 or knockin of the patient-specific mutation, including TLR4-mediated signaling, cytokine production, and bacterial handling. RESULTS: Whole-exome sequencing identified a homozygous in-frame deletion in the LY96 gene (c.347_349delCAA; p.Thr116del) in a patient with very early onset inflammatory bowel disease and a sibling presenting with pneumonia and otitis media. Induced pluripotent stem cell-derived macrophages with knockout of MD2 or expression of the Thr116del mutation showed impaired activation of nuclear factor kappa B and mitogen-activated protein kinase signaling as well as TLR4 endocytosis on challenge with LPS or bacteria. In addition, MD2-deficient macrophages showed decreased cytokine expression (eg, IL-6, TNF, and IL-10) in response to LPS or gram-negative but not gram-positive bacteria. CONCLUSIONS: Human MD2 deficiency causes defective TLR4 signaling in response to LPS or gram-negative bacteria. The clinical manifestations and expressivity might be variable due to unknown secondary risk factors. Because TLR4 represents a therapeutic target for multiple inflammatory conditions, our study may provide insights into potential side effects of pharmacological TLR4 targeting. AU - Li, Y.* AU - Yu, Z.* AU - Schenk, M.* AU - Lagovsky, I.* AU - Illig, D.* AU - Walz, C.* AU - Rohlfs, M.* AU - Conca, R.* AU - Muise, A.M.* AU - Snapper, S.B.* AU - Uhlig, H.H.* AU - Garty, B.Z.* AU - Klein, C.* AU - Kotlarz, D.M. C1 - 66837 C2 - 53310 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 791-796.e7 TI - Human MD2 deficiency-an inborn error of immunity with pleiotropic features. JO - J. Allergy Clin. Immunol. VL - 151 IS - 3 PB - Mosby-elsevier PY - 2023 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Growing up on traditional European or US Amish dairy farms in close contact with cows and hay protects children against asthma, and airway administration of extracts from dust collected from cowsheds of those farms prevents allergic asthma in mice. OBJECTIVES: This study sought to begin identifying farm-derived asthma-protective agents. METHODS: Our work unfolded along 2 unbiased and independent but complementary discovery paths. Dust extracts (DEs) from protective and nonprotective farms (European and Amish cowsheds vs European sheep sheds) were analyzed by comparative nuclear magnetic resonance profiling and differential proteomics. Bioactivity-guided size fractionation focused on protective Amish cowshed DEs. Multiple in vitro and in vivo functional assays were used in both paths. Some of the proteins thus identified were characterized by in-solution and in-gel sodium dodecyl sulfate-polyacrylamide gel electrophoresis enzymatic digestion/peptide mapping followed by liquid chromatography/mass spectrometry. The cargo carried by these proteins was analyzed by untargeted liquid chromatography-high-resolution mass spectrometry. RESULTS: Twelve carrier proteins of animal and plant origin, including the bovine lipocalins Bos d 2 and odorant binding protein, were enriched in DEs from protective European cowsheds. A potent asthma-protective fraction of Amish cowshed DEs (≈0.5% of the total carbon content of unfractionated extracts) contained 7 animal and plant proteins, including Bos d 2 and odorant binding protein loaded with fatty acid metabolites from plants, bacteria, and fungi. CONCLUSIONS: Animals and plants from traditional farms produce proteins that transport hydrophobic microbial and plant metabolites. When delivered to mucosal surfaces, these agents might regulate airway responses. AU - Marques Dos Santos, M.* AU - Pivniouk, V.* AU - Rankl, B. AU - Walker, A. AU - Pagani, G. AU - Hertkorn, N. AU - Schmitt-Kopplin, P. AU - Müller, C.* AU - Bracher, F.* AU - Merl-Pham, J. AU - Hauck, S.M. AU - Schloter, M. AU - Michael, A.N.* AU - Anderson, D.* AU - Honeker, L.* AU - Gozdz, J.* AU - Pivniouk, O.* AU - Ober, C.* AU - Holbreich, M.* AU - Martinez, F.D.* AU - Snyder, S.A.* AU - von Mutius, E. AU - Vercelli, D.* C1 - 67857 C2 - 54335 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 610-621 TI - Asthma-protective agents in dust from traditional farm environments. JO - J. Allergy Clin. Immunol. VL - 152 IS - 3 PB - Mosby-elsevier PY - 2023 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: The α-Gal syndrome is associated with the presence of IgE directed to the carbohydrate galactose-α-1,3-galactose (α-Gal) and is characterized by a delayed allergic reaction occurring 2 to 6 hours after ingestion of mammalian meat. On the basis of their slow digestion and processing kinetics, α-Gal-carrying glycolipids have been proposed as the main trigger of the delayed reaction. OBJECTIVE: We analyzed and compared the in vitro allergenicity of α-Gal-carrying glycoproteins and glycolipids from natural food sources. METHODS: Proteins and lipids were extracted from pork kidney (PK), beef, and chicken. Glycolipids were purified from rabbit erythrocytes. The presence of α-Gal and IgE binding of α-Gal-allergic patient sera (n = 39) was assessed by thin-layer chromatography as well as by direct and inhibition enzyme-linked immunosorbent assay. The in vitro allergenicity of glycoproteins and glycolipids from different meat extracts was determined by basophil activation test. Glycoprotein stability was evaluated by simulated gastric and intestinal digestion assays. RESULTS: α-Gal was detected on glycolipids of PK and beef. Patient IgE antibodies recognized α-Gal bound to glycoproteins and glycolipids, although binding to glycoproteins was more potent. Rabbit glycolipids were able to strongly activate patient basophils, whereas lipid extracts from PK and beef were also found to trigger basophil activation, but at a lower capacity compared to the respective protein extracts. Simulated gastric digestion assays of PK showed a high stability of α-Gal-carrying proteins in PK. CONCLUSION: Both α-Gal-carrying glycoproteins and glycolipids are able to strongly activate patient basophils. In PK and beef, α-Gal epitopes seem to be less abundant on glycolipids than on glycoproteins, suggesting a major role of glycoproteins in delayed anaphylaxis upon consumption of these food sources. AU - Chakrapani, N.* AU - Fischer, J.* AU - Swiontek, K.* AU - Codreanu-Morel, F.* AU - Hannachi, F.* AU - Morisset, M.* AU - Mugemana, C.* AU - Bulaev, D.* AU - Blank, S. AU - Bindslev-Jensen, C.* AU - Biedermann, T.* AU - Ollert, M.* AU - Hilger, C.* C1 - 64874 C2 - 51977 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 396-405.e11 TI - α-Gal present on both glycolipids and glycoproteins contributes to immune response in meat-allergic patients. JO - J. Allergy Clin. Immunol. VL - 150 IS - 2 PB - Mosby-elsevier PY - 2022 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Infectious agents can reprogram or "train" macrophages and their progenitors to respond more readily to subsequent insults. However, whether such an inflammatory memory exists in type-2 inflammatory conditions such as allergic asthma was not known. OBJECTIVE: To decipher macrophage trained immunity in allergic asthma. METHODS: We used a combination of clinical sampling of house dust mite (HDM)-allergic patients, HDM-induced allergic airway inflammation (AAI) in mice and an in vitro training set-up to analyze persistent changes in macrophage eicosanoid-, cytokine- and chemokine production as well as underlying metabolic and epigenetic mechanisms. Transcriptional and metabolic profiles of patient-derived and in vitro trained macrophages were assessed by RNA sequencing or Seahorse and LC-MS/MS analysis, respectively. RESULTS: We found that macrophages differentiated from bone marrow- or blood monocyte- progenitors of HDM-allergic mice or asthma patients show inflammatory transcriptional reprogramming and excessive mediator (TNF-α, CCL17, leukotriene, PGE2, IL-6) responses upon stimulation. Macrophages from HDM-allergic mice initially exhibited a type-2 imprint, which shifted towards a classical inflammatory training over time. HDM-induced AAI elicited a metabolically activated macrophage phenotype, producing high amounts of 2-hydroxyglutarate (2-HG). HDM-induced macrophage training in vitro was mediated by a formyl-peptide receptor 2 (FPR2)-TNF-2-HG-PGE2/EP2-axis, resulting in an M2-like macrophage phenotype with high CCL17 production. TNF blockade by etanercept or genetic ablation of Tnf in myeloid cells prevented the inflammatory imprinting of bone marrow-derived macrophages from HDM-allergic mice. CONCLUSION: Allergen-triggered inflammation drives a TNF-dependent innate memory, which may perpetuate and exacerbate chronic type-2 airway inflammation and thus represents a target for asthma therapy. AU - Lechner, A. AU - Henkel, F. AU - Hartung, F. AU - Bohnacker, S. AU - Alessandrini, F. AU - Gubernatorova, E.O.* AU - Drutskaya, M.S.* AU - Angioni, C.* AU - Schreiber, Y.* AU - Haimerl, P. AU - Ge, Y.* AU - Thomas, D.* AU - Kabat, A.M.* AU - Pearce, E.J.* AU - Ohnmacht, C. AU - Nedospasov, S.A.* AU - Murray, P.J.* AU - Chaker, A. AU - Schmidt-Weber, C.B. AU - Esser-von Bieren, J. C1 - 64020 C2 - 51652 SP - 2078-2090 TI - Macrophages acquire a TNF-dependent inflammatory memory in allergic asthma. JO - J. Allergy Clin. Immunol. VL - 149 IS - 6 PY - 2022 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Growing up on a farm is associated with a reduced prevalence of respiratory allergies in childhood. It is unknown whether this protective effect remains into adulthood. OBJECTIVES: We aimed to prospectively investigate the relationship between farm exposure and prevalence of allergic rhinitis and wheeze from childhood to early adulthood. METHODS: Participants from phase 2 of the GABRIEL (Multidisciplinary Study to Identify the Genetic and Environmental Causes of Asthma in the European Community) study living in southern Germany (aged 6-11 years at baseline; 20-25 at follow-up) were invited to complete a questionnaire on sociodemographic data, farm contact, respiratory symptoms, and potential confounders. Odds ratios (OR) with 95% confidence intervals (95% CI) were modelled using generalized estimating equations (GEE). RESULTS: Of the 2,276 phase 2 participants, 1,501 (66%) answered the follow-up questionnaire of which 1,333 could be included in the analyses. Living on a farm was associated with reduced prevalence of allergic rhinitis (persistent farm living OR 0.4; 95% CI 0.2-0.6; only baseline farm living 0.4; 0.2-0.8). The odds ratio for developing symptoms from baseline to follow-up was almost three (OR 2.7; 95% CI 2.1-3.3), irrespective of farm living. For symptoms of wheeze, no statistically significant association with farm living was observed. CONCLUSIONS: The protective effect of farm living on allergic rhinitis persists from childhood to early adulthood. Continuing exposure over puberty does not add to the effect. This confirms that the window of opportunity for a protective effect might be found in childhood. AU - Strieker, S.* AU - Weinmann, T.* AU - Gerlich, J.* AU - von Mutius, E. AU - Nowak, D.* AU - Radon, K.* AU - Wengenroth, L.* C1 - 65671 C2 - 52882 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 1209-1215.e2 TI - Farm living and allergic rhinitis from childhood to young adulthood - prospective results of the GABRIEL study. JO - J. Allergy Clin. Immunol. VL - 150 IS - 5 PB - Mosby-elsevier PY - 2022 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Hereditary angioedema (HAE) is a potentially fatal disorder resulting in recurrent attacks of severe swelling. It may be associated with a genetic deficiency of functional C1 inhibitor (C1-INH) or with normal C1-INH (HAEnCI). In families with HAEnCI, HAE-linked mutations in the F12, PLG, KNG1, ANGPT1, or MYOF genes have been identified. In many families with HAEnCI the genetic cause of the disease is currently unknown. OBJECTIVE: The aim of this study was to identify a novel disease-linked mutation for HAEnCI. METHODS: Methods comprised whole exome sequencing (WES), Sanger sequencing analysis, pedigree analysis, bioinformatical analysis of the mutation, and biochemical analysis of parameters of the kallikrein-kinin (contact) system. RESULTS: By performing WES on a multi-generation family with HAEnCI we identified the HS3ST6 mutation c.430A>T (p.Thr144Ser) in all three affected family members that were sequenced. This gene encodes the heparan sulfate glucosamine 3-O-sulfotransferase 6 (3-OST-6) which is involved in the last step of heparan sulfate biosynthesis. The p.Thr144Ser mutation is likely to affect the interaction between two beta sheets stabilizing the active center of the 3-OST-6 protein. CONCLUSIONS: We conclude that mutant 3-OST-6 fails to transfer sulfo groups to the 3-OH position of heparan sulfate, resulting in incomplete heparan sulfate biosynthesis. This is likely to affect cell surface interactions of key players in angioedema formation and is a novel mechanism for disease development. AU - Bork, K.* AU - Wulff, K.* AU - Möhl, B.S. AU - Steinmüller-Magin, L.* AU - Witzke, G.* AU - Hardt, J.* AU - Meinke, P.* C1 - 61203 C2 - 50088 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 1041-1048 TI - Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation. JO - J. Allergy Clin. Immunol. VL - 148 IS - 4 PB - Mosby-elsevier PY - 2021 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Markedly elevated levels of pro-inflammatory cytokines and defective type-I interferon responses were reported in COVID-19 patients. OBJECTIVE: This study aimed to determine whether particular cytokine profiles are associated with COVID-19 severity and mortality. METHODS: Cytokine concentrations and SARS-CoV-2 antigen were measured at hospital admission in serum of symptomatic COVID-19 patients (N=115), classified at hospitalization into three respiratory severity groups: no need for mechanical ventilatory support (No-MVS), intermediate severity requiring mechanical ventilatory support (MVS) and critical severity requiring extracorporeal membrane oxygenation (ECMO). Principal component analysis was used to characterize cytokine profiles associated with severity and mortality. The results were thereafter confirmed in an independent validation cohort (N=86). RESULTS: At time of hospitalization, ECMO patients presented a dominant pro-inflammatory response with elevated levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-8 and IL-10. In contrast, an elevated type-I interferon response involving IFN-α and IFN-β was characteristic of No-MVS patients, whereas MVS patients exhibited both profiles. Mortality at one month was associated with higher levels of pro-inflammatory cytokines in ECMO patients, higher levels of type-I interferons in No-MVS patients and their combination in MVS patients, resulting in a combined mortality prediction accuracy of 88.5% (Risk Ratio 24.3, p<0.0001). SARS-CoV-2 antigen levels correlated with type-I interferon levels and were associated with mortality, but not with pro-inflammatory response or severity. CONCLUSION: Distinct cytokine profiles are observed in association with COVID-19 severity and are differentially predictive of mortality according to oxygen support modalities. These results warrant personalized treatment of COVID-19 patients based on cytokine profiling. AU - Dorgham, K.* AU - Quentric, P.* AU - Gökkaya, M. AU - Marot, S.* AU - Parizot, C.* AU - Sauce, D.* AU - Guihot, A.* AU - Luyt, C.E.* AU - Schmidt, M.* AU - Mayaux, J.* AU - Beurton, A.* AU - Le Guennec, L.* AU - Demeret, S.* AU - Ben Salah, E.* AU - Mathian, A.* AU - Yssel, H.* AU - Combadiere, B.* AU - Combadière, C.* AU - Traidl-Hoffmann, C. AU - Burrel, S.* AU - Marcelin, A.G.* AU - Amoura, Z.* AU - Voiriot, G.* AU - Neumann, A.U. AU - Gorochov, G.* C1 - 61881 C2 - 50498 SP - 2098-2107 TI - Distinct cytokine profiles associated with COVID-19 severity and mortality. JO - J. Allergy Clin. Immunol. VL - 147 IS - 6 PY - 2021 SN - 0091-6749 ER - TY - JOUR AU - Kutukculer, N.* AU - Seeholzer, T. AU - O'Neill, T.J. AU - Grass, C. AU - Aykut, A.* AU - Karaca, N.E.* AU - Durmaz, A.* AU - Cogulu, O.* AU - Aksu, G.* AU - Gehring, T. AU - Gewies, A. AU - Krappmann, D. C1 - 60164 C2 - 49575 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 775-778.e8 TI - Human immune disorder associated with homozygous hypomorphic mutation affecting MALT1B splice variant. JO - J. Allergy Clin. Immunol. VL - 147 IS - 2 PB - Mosby-elsevier PY - 2021 SN - 0091-6749 ER - TY - JOUR AB - Background: Human milk oligosaccharides (HMO) are a diverse range of sugars secreted in breast milk that have direct and indirect effects on immunity. The profiles of HMOs produced differ between mothers. Objective: We sought to determine the relationship between maternal HMO profiles and offspring allergic diseases up to age 18 years. Methods: Colostrum and early lactation milk samples were collected from 285 mothers enrolled in a high-allergy-risk birth cohort, the Melbourne Atopy Cohort Study. Nineteen HMOs were measured. Profiles/patterns of maternal HMOs were determined using LCA. Details of allergic disease outcomes including sensitization, wheeze, asthma, and eczema were collected at multiple follow-ups up to age 18 years. Adjusted logistic regression analyses and generalized estimating equations were used to determine the relationship between HMO profiles and allergy. Results: The levels of several HMOs were highly correlated with each other. LCA determined 7 distinct maternal milk profiles with memberships of 10% and 20%. Compared with offspring exposed to the neutral Lewis HMO profile, exposure to acidic Lewis HMOs was associated with a higher risk of allergic disease and asthma over childhood (odds ratio asthma at 18 years, 5.82; 95% CI, 1.59-21.23), whereas exposure to the acidic-predominant profile was associated with a reduced risk of food sensitization (OR at 12 years, 0.08; 95% CI, 0.01-0.67). Conclusions: In this high-allergy-risk birth cohort, some profiles of HMOs were associated with increased and some with decreased allergic disease risks over childhood. Further studies are needed to confirm these findings and realize the potential for intervention. AU - Lodge, C.J.* AU - Lowe, A.J.* AU - Milanzi, E.* AU - Bowatte, G.* AU - Abramson, M.J.* AU - Tsimiklis, H.* AU - Axelrad, C.* AU - Robertson, B.* AU - Darling, A.E.* AU - Svanes, C.* AU - Wjst, M. AU - Dharmage, S.C.* AU - Bode, L.* C1 - 59892 C2 - 49102 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 1041-1048 TI - Human milk oligosaccharide profiles and allergic disease up to 18 years. JO - J. Allergy Clin. Immunol. VL - 147 IS - 3 PB - Mosby-elsevier PY - 2021 SN - 0091-6749 ER - TY - JOUR AU - Mazein, A.* AU - Ivanova, O.* AU - Balaur, I.* AU - Ostaszewski, M.* AU - Berzhitskaya, V.* AU - Serebriyskaya, T.* AU - Ligon, T.* AU - Hasenauer, J. AU - De Meulder, B.* AU - Overall, R.W.* AU - Roy, L.* AU - Knowles, R.G.* AU - Wheelock, C.E.* AU - Dahlen, S.E.* AU - Chung, K.F.* AU - Adcock, I.M.* AU - Roberts, G.* AU - Djukanovic, R.* AU - Pellet, J.* AU - Gawron, P.* AU - Balling, R.* AU - Maitland-van der Zee, A.H.* AU - Schneider, R.* AU - Sterk, P.J.* AU - Auffray, C.* C1 - 61108 C2 - 49838 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 853-856 TI - AsthmaMap: An interactive knowledge repository for mechanisms of asthma. JO - J. Allergy Clin. Immunol. VL - 147 IS - 3 PB - Mosby-elsevier PY - 2021 SN - 0091-6749 ER - TY - JOUR AB - Background: Whether long-term exposure air to pollution has effects on allergic sensitization is controversial. Objective: Our aim was to investigate associations of air pollution exposure at birth and at the time of later biosampling with IgE sensitization against common food and inhalant allergens, or specific allergen molecules, in children aged up to 16 years. Methods: A total of 6163 children from 4 European birth cohorts participating in the Mechanisms of the Development of ALLergy [MeDALL] consortium were included in this meta-analysis of the following studies: Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) (Sweden), Influences of Lifestyle-Related Factors on the Human Immune System and Development of Allergies in Childhood (LISA)/German Infant Study on the Influence of Nutrition Intervention PLUS Environmental and Genetic Influences on Allergy Development (GINIplus) (Germany), and Prevention and Incidence of Asthma and Mite Allergy (PIAMA) (The Netherlands). The following indicators were modeled by land use regression: individual residential outdoor levels of particulate matter with aerodynamic diameters less than 2.5 μm, less than 10 μm, and between 2.5 and 10 μm; PM2.5 absorbance (a measurement of the blackness of PM2.5 filters); and nitrogen oxides levels. Blood samples drawn at ages 4 to 6 (n = 5989), 8 to 10 (n = 6603), and 15 to 16 (n = 5825) years were analyzed for IgE sensitization to allergen extracts by ImmunoCAP. Additionally, IgE against 132 allergen molecules was measured by using the MedALL microarray chip (n = 1021). Results: Air pollution was not consistently associated with IgE sensitization to any common allergen extract up to age 16 years. However, allergen-specific analyses suggested increased risks of sensitization to birch (odds ratio [OR] = 1.12 [95% CI = 1.01-1.25] per 10-μg/m3 increase in NO2 exposure). In a subpopulation with microarray data, IgE to the major timothy grass allergen Phleum pratense 1 (Phl p 1) and the cat allergen Felis domesticus 1 (Fel d 1) greater than 3.5 Immuno Solid-phase Allergen Chip standardized units for detection of IgE antibodies were related to PM2.5 exposure at birth (OR = 3.33 [95% CI = 1.40-7.94] and OR = 4.98 [95% CI = 1.59-15.60], respectively, per 5-μg/m3 increase in exposure). Conclusion: Air pollution exposure does not seem to increase the overall risk of allergic sensitization; however, sensitization to birch as well as grass pollen Phl p 1 and cat Fel d 1 allergen molecules may be related to specific pollutants. AU - Melén, E.* AU - Standl, M. AU - Gehring, U.* AU - Altug, H.* AU - Antó, J.M.* AU - Berdel, D.* AU - Bergström, A.* AU - Bousquet, J.* AU - Heinrich, J. AU - Koppelman, G.H.* AU - Kull, I.* AU - Lupinek, C.* AU - Markevych, I. AU - Schikowski, T.* AU - Thiering, E. AU - Valenta, R.* AU - van Hage, M.* AU - von Berg, A.* AU - Vonk, J.M.* AU - Wickman, M.* AU - Wijga, A.* AU - Gruzieva, O.* C1 - 60318 C2 - 49382 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 713-722 TI - Air pollution and IgE sensitization in 4 European birth cohorts—the MeDALL project. JO - J. Allergy Clin. Immunol. VL - 147 IS - 2 PB - Mosby-elsevier PY - 2021 SN - 0091-6749 ER - TY - JOUR AB - Around 20% of all children worldwide suffer from Atopic Dermatitis (AD). Therefore, eczematous skin lesions and elevated serum Immunglobulin E (IgE) levels are common findings. Inborn Errors of Immunity (IEI) may be missed in the context of AD, and management and prognosis of these conditions can be substantially different. Children suffering from IEIs such as Hyper-IgE-Syndromes (HIES), Wiskott-Aldrich-syndrome (WAS), Immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, Omenn syndrome, the atypical complete DiGeorge syndrome and skin barrier disorders like Comèl-Netherton-syndrome and Severe-dermatitis-multiple-allergies-and-metabolic-wasting (SAM) syndrome may present with additional "red flags", which should raise a clinical suspicion for an underlying IEI. These "red flags" may include eczematous skin lesion manifesting prior to two month of life, disseminated or recurrent viral, bacterial or fungal infections, mucocutaneous candidiasis, purpura, chronic diarrhea, or abnormalities in development or of connective tissue. A differential blood count, as well as a lymphocyte subset analysis, total immunoglobulin levels and vaccination titers can help the clinician to decide whether a patient with eczematous skin lesions and elevated serum IgE should be referred to a clinical immunologist for a full immunologic work-up and broad genetic analysis. AU - Stadler, P.C.* AU - Renner, E.D. AU - Milner, J.* AU - Wollenberg, A.* C1 - 61338 C2 - 50129 CY - Radarweg 29, 1043 Nx Amsterdam, Netherlands SP - 1501-1507 TI - Inborn error of immunity or atopic dermatitis: When to be concerned and how to investigate. JO - J. Allergy Clin. Immunol. VL - 9 IS - 4 PB - Elsevier PY - 2021 SN - 0091-6749 ER - TY - JOUR AU - Blank, S. AU - Pehlivanli, S.* AU - Methe, H.* AU - Schmidt-Weber, C.B. AU - Biedermann, T.* AU - Horny, H.P.* AU - Kristensen, T.* AU - Amar, Y.* AU - Köberle, M.* AU - Brockow, K.* AU - Stömmer, P.E.* C1 - 56547 C2 - 47097 CY - Radarweg 29, 1043 Nx Amsterdam, Netherlands SP - 401-403.e2 TI - Fatal anaphylaxis following a hornet sting in a yellow jacket venom-sensitized patient with undetected monoclonal mast cell activation syndrome and without previous history of a systemic sting reaction. JO - J. Allergy Clin. Immunol. VL - 8 IS - 1 PB - Elsevier PY - 2020 SN - 0091-6749 ER - TY - JOUR AU - Fuertes, E.* AU - Heinrich, J. C1 - 57541 C2 - 47823 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 100-102 TI - Does traffic proximity at home and school influence asthma exacerbations? JO - J. Allergy Clin. Immunol. VL - 145 IS - 1 PB - Mosby-elsevier PY - 2020 SN - 0091-6749 ER - TY - JOUR AB - Background: Pollen exposure induces local and systemic allergic immune responses in sensitized individuals, but nonsensitized individuals also are exposed to pollen. The kinetics of symptom expression under natural pollen exposure have never been systematically studied, especially in subjects without allergy.Objective: We monitored the humoral immune response under natural pollen exposure to potentially uncover nasal biomarkers for in-season symptom severity and identify protective factors.Methods: We compared humoral immune response kinetics in a panel study of subjects with seasonal allergic rhinitis (SAR) and subjects without allergy and tested for cross-sectional and interseasonal differences in levels of serum and nasal, total, and Betula verrucosa 1-specific immunoglobulin isotypes; immunoglobulin free light chains; cytokines; and chemokines. Nonsupervised principal component analysis was performed for all nasal immune variables, and single immune variables were correlated with in-season symptom severity by Spearman test.Results: Symptoms followed airborne pollen concentrations in subjects with SAR, with a time lag between 0 and 13 days depending on the pollen type. Of the 7 subjects with nonallergy, 4 also exhibited in-season symptoms whereas 3 did not. Cumulative symptoms in those without allergy were lower than in those with SAR but followed the pollen exposure with similar kinetics. Nasal eotaxin-2, CCL22/MDC, and monocyte chemoattactant protein-1 (MCP-1) levels were higher in subjects with SAR, whereas IL-8 levels were higher in subjects without allergy. Principal component analysis and Spearman correlations identified nasal levels of IL-8, IL-33, and Betula verrucosa 1-specific IgG 4 (sIgG 4) and Betula verrucosa 1-specific IgE (sIgE) antibodies as predictive for seasonal symptom severity.Conclusions: Nasal pollen-specific IgA and IgG isotypes are potentially protective within the humoral compartment. Nasal levels of IL-8, IL-33, sIgG 4 and sIgE could be predictive biomarkers for pollen-specific symptom expression, irrespective of atopy. AU - Gökkaya, M. AU - Damialis, A. AU - Nussbaumer, T. AU - Beck, I. AU - Bounas-Pyrros, N. AU - Bezold, S. AU - Amisi, M. AU - Kolek, F. AU - Todorova, A. AU - Chaker, A.* AU - Aglas, L.* AU - Ferreira, F.* AU - Redegeld, F.A.* AU - Brunner, J.O.* AU - Neumann, A.U. AU - Traidl-Hoffmann, C. AU - Gilles, S. C1 - 59194 C2 - 48721 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 583-594.e6 TI - Defining biomarkers to predict symptoms in subjects with and without allergy under natural pollen exposure. JO - J. Allergy Clin. Immunol. VL - 146 IS - 3 PB - Mosby-elsevier PY - 2020 SN - 0091-6749 ER - TY - JOUR AB - Background: Nonsteroidal anti-inflammatory drug–exacerbated respiratory disease (N-ERD) is a chronic inflammatory condition, which is driven by an aberrant arachidonic acid metabolism. Macrophages are major producers of arachidonic acid metabolites and subject to metabolic reprogramming, but they have been neglected in N-ERD. Objective: This study sought to elucidate a potential metabolic and epigenetic macrophage reprogramming in N-ERD. Methods: Transcriptional, metabolic, and lipid mediator profiles in macrophages from patients with N-ERD and healthy controls were assessed by RNA sequencing, Seahorse assays, and LC-MS/MS. Metabolites in nasal lining fluid, sputum, and plasma from patients with N-ERD (n = 15) and healthy individuals (n = 10) were quantified by targeted metabolomics analyses. Genome-wide methylomics were deployed to define epigenetic mechanisms of macrophage reprogramming in N-ERD. Results: This study shows that N-ERD monocytes/macrophages exhibit an overall reduction in DNA methylation, aberrant metabolic profiles, and an increased expression of chemokines, indicative of a persistent proinflammatory activation. Differentially methylated regions in N-ERD macrophages included genes involved in chemokine signaling and acylcarnitine metabolism. Acylcarnitines were increased in macrophages, sputum, nasal lining fluid, and plasma of patients with N-ERD. On inflammatory challenge, N-ERD macrophages produced increased levels of acylcarnitines, proinflammatory arachidonic acid metabolites, cytokines, and chemokines as compared to healthy macrophages. Conclusions: Together, these findings decipher a proinflammatory metabolic and epigenetic reprogramming of macrophages in N-ERD. AU - Haimerl, P. AU - Bernhardt, U. AU - Schindela, S. AU - Henkel, F. AU - Lechner, A. AU - Zissler, U.M. AU - Pastor, X. AU - Thomas, D.* AU - Cecil, A. AU - Ge, Y.* AU - Haid, M. AU - Prehn, C. AU - Tokarz, J. AU - Heinig, M. AU - Adamski, J. AU - Schmidt-Weber, C.B. AU - Chaker, A. AU - Esser-von Bieren, J. C1 - 59595 C2 - 48861 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 587-599 TI - Inflammatory macrophage memory in nonsteroidal anti-inflammatory drug–exacerbated respiratory disease. JO - J. Allergy Clin. Immunol. VL - 147 IS - 2 PB - Mosby-elsevier PY - 2020 SN - 0091-6749 ER - TY - JOUR AB - Background: Coronavirus disease 2019 (COVID-19) can manifest as a viral-induced hyperinflammation with multiorgan involvement. Such patients often experience rapid deterioration and need for mechanical ventilation. Currently, no prospectively validated biomarker of impending respiratory failure is available.Objective: We aimed to identify and prospectively validate biomarkers that allow the identification of patients in need of impending mechanical ventilation.Methods: Patients with COVID-19 who were hospitalized from February 29 to April 9, 2020, were analyzed for baseline clinical and laboratory findings at admission and during the disease. Data from 89 evaluable patients were available for the purpose of analysis comprising an initial evaluation cohort (n = 40) followed by a temporally separated validation cohort (n = 49).Results: We identified markers of inflammation, lactate dehydrogenase, and creatinine as the variables most predictive of respiratory failure in the evaluation cohort. Maximal IL-6 level before intubation showed the strongest association with the need for mechanical ventilation, followed by maximal CRP level. The respective AUC values for IL-6 and CRP levels in the evaluation cohort were 0.97 and 0.86, and they were similar in the validation cohort (0.90 and 0.83, respectively). The calculated optimal cutoff values during the course of disease from the evaluation cohort (IL-6 level > 80 pg/mL and CRP level > 97 mg/L) both correctly classified 80% of patients in the validation cohort regarding their risk of respiratory failure.Conclusion: The maximal level of IL-6, followed by CRP level, was highly predictive of the need for mechanical ventilation. This suggests the possibility of using IL-6 or CRP level to guide escalation of treatment in patients with COVID-19-related hyperinflammatory syndrome. AU - Herold, T. AU - Jurinovic, V.* AU - Lipworth, B.J.* AU - Hellmuth, J.C.* AU - von Bergwelt-Baildon, M.* AU - Klein, M.* AU - Weinberger, T.* C1 - 59158 C2 - 48648 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 128-136.e4 TI - Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. JO - J. Allergy Clin. Immunol. VL - 146 IS - 1 PB - Mosby-elsevier PY - 2020 SN - 0091-6749 ER - TY - JOUR AB - Background: Fifteen percent of atopic dermatitis (AD) liability-scale heritability could be attributed to 31 susceptibility loci identified by using genome-wide association studies, with only 3 of them (IL13, IL-6 receptor [IL6R], and filaggrin [FLG]) resolved to protein-coding variants.Objective: We examined whether a significant portion of unexplained AD heritability is further explained by low-frequency and rare variants in the gene-coding sequence.Methods: We evaluated common, low-frequency, and rare protein-coding variants using exome chip and replication genotype data of 15,574 patients and 377,839 control subjects combined with whole-transcriptome data on lesional, nonlesional, and healthy skin samples of 27 patients and 38 control subjects.Results: An additional 12.56% (SE, 0.74%) of AD heritability is explained by rare protein-coding variation. We identified docking protein 2 (DOK2) and CD200 receptor 1 (CD200R1) as novel genome-wide significant susceptibility genes. Rare coding variants associated with AD are further enriched in 5 genes (IL-4 receptor [IL4R], IL13, Janus kinase 1 [JAK1], JAK2, and tyrosine kinase 2 [TYK2]) of the IL13 pathway, all of which are targets for novel systemic AD therapeutics. Multiomics-based network and RNA sequencing analysis revealed DOK2 as a central hub interacting with, among others, CD200R1, IL6R, and signal transducer and activator of transcription 3 (STAT3). Multitissue gene expression profile analysis for 53 tissue types from the Genotype-Tissue Expression project showed that disease-associated protein-coding variants exert their greatest effect in skin tissues.Conclusion: Our discoveries highlight a major role of rare coding variants in AD acting independently of common variants. Further extensive functional studies are required to detect all potential causal variants and to specify the contribution of the novel susceptibility genes DOK2 and CD200R1 to overall disease susceptibility. AU - Mucha, S.* AU - Baurecht, H.* AU - Novak, N.* AU - Rodríguez, E.* AU - Bej, S.* AU - Mayr, G.* AU - Emmert, H.* AU - Stölzl, D.* AU - Gerdes, S.* AU - Jung, E.S.* AU - Degenhardt, F.* AU - Hübenthal, M.* AU - Ellinghaus, E.* AU - Kässens, J.C.* AU - Wienbrandt, L.* AU - Lieb, W.* AU - Müller-Nurasyid, M. AU - Hotze, M.* AU - Dand, N.* AU - Grosche, S.* AU - Marenholz, I.* AU - Arnold, A.* AU - Homuth, G.* AU - Schmidt, C.O.* AU - Wehkamp, U.* AU - Nöthen, M.M.* AU - Hoffmann, P.* AU - Paternoster, L.* AU - Standl, M. AU - Bønnelykke, K.* AU - Ahluwalia, T.S.* AU - Bisgaard, H.* AU - Peters, A. AU - Gieger, C. AU - Waldenberger, M. AU - Schulz, H. AU - Strauch, K. AU - Werfel, T.* AU - Lee, Y.A.* AU - Wolfien, M.* AU - Rosenstiel, P.* AU - Wolkenhauer, O.* AU - Schreiber, S.* AU - Franke, A.* AU - Weidinger, S.* AU - Ellinghaus, D.* C1 - 57706 C2 - 47889 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 1208-1218 TI - Protein-coding variants contribute to the risk of atopic dermatitis and skin-specific gene expression. JO - J. Allergy Clin. Immunol. VL - 145 IS - 4 PB - Mosby-elsevier PY - 2020 SN - 0091-6749 ER - TY - JOUR AB - Asthma is a severe and chronic disabling disease affecting more than 300 million people worldwide. Although in the past few drugs for the treatment of asthma were available, new treatment options are currently emerging, which appear to be highly effective in certain subgroups of patients. Accordingly, there is a need for biomarkers that allow selection of patients for refined and personalized treatment strategies. Recently, serological chip tests based on microarrayed allergen molecules and peptides derived from the most common rhinovirus strains have been developed, which may discriminate 2 of the most common forms of asthma, that is, allergen- and virus-triggered asthma. In this perspective, we argue that classification of patients with asthma according to these common trigger factors may open new possibilities for personalized management of asthma. AU - Niespodziana, K.* AU - Borochova, K.* AU - Pazderova, P.* AU - Schlederer, T.* AU - Astafyeva, N.* AU - Baranovskaya, T.* AU - Barbouche, M.R.* AU - Beltyukov, E.* AU - Berger, A.* AU - Borzova, E.* AU - Bousquet, J.* AU - Bumbacea, R.S.* AU - Bychkovskaya, S.* AU - Caraballo, L.* AU - Chung, K.F.* AU - Custovic, A.* AU - Docena, G.* AU - Eiwegger, T.* AU - Evsegneeva, I.* AU - Emelyanov, A.* AU - Errhalt, P.* AU - Fassakhov, R.* AU - Fayzullina, R.* AU - Fedenko, E.* AU - Fomina, D.* AU - Gao, Z.* AU - Giavina-Bianchi, P.* AU - Gotua, M.* AU - Greber-Platzer, S.* AU - Hedlin, G.* AU - Ilina, N.* AU - Ispayeva, Z.* AU - Idzko, M.* AU - Johnston, S.L.* AU - Kalayci, Ö.* AU - Karaulov, A.* AU - Karsonova, A.* AU - Khaitov, M.* AU - Kovzel, E.* AU - Kowalski, M.L.* AU - Kudlay, D.* AU - Levin, M.* AU - Makarova, S.* AU - Matricardi, P.M.* AU - Nadeau, K.C.* AU - Namazova-Baranova, L.* AU - Naumova, O.* AU - Nazarenko, O.* AU - O'Byrne, P.M.* AU - Osier, F.* AU - Pampura, A.N.* AU - Panaitescu, C.* AU - Papadopoulos, N.G.* AU - Park, H.S.* AU - Pawankar, R.* AU - Pohl, W.* AU - Renz, H.* AU - Riabova, K.* AU - Sampath, V.* AU - Sekerel, B.E.* AU - Sibanda, E.* AU - Siroux, V.* AU - Sizyakina, L.P.* AU - Sun, J.L.* AU - Szepfalusi, Z.* AU - Umanets, T.* AU - Van Bever, H.P.S.* AU - van Hage, M.* AU - Vasileva, M.* AU - von Mutius, E. AU - Wang, J.Y.* AU - Wong, G.W.K.* AU - Zaikov, S.* AU - Zidarn, M.* C1 - 58837 C2 - 48628 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 1529-1534 TI - Toward personalization of asthma treatment according to trigger factors. JO - J. Allergy Clin. Immunol. VL - 145 IS - 6 PB - Mosby-elsevier PY - 2020 SN - 0091-6749 ER - TY - JOUR AB - The mammalian meat allergy known as the "alpha-Gal syndrome'' relates to IgE specific for galactose-alpha-1,3-galactose (alpha-Gal), an oligosaccharide that is present in cells and tissues of nonprimate mammals. The recognition of delayed reactions to food derived from mammals in patients with IgE to alpha-Gal and also the association with tick bites have been increasing worldwide. In 2018, the National Institute of Allergy and Infectious Diseases, Division of Allergy, Immunology and Transplantation, sponsored a workshop on this emerging tick-related disease. International experts from the fields of tick biology, allergy, immunology, infectious disease, and dermatology discussed the current state of our understanding of this emerging medical condition. The participants provided suggestions for specific research priorities and for the development of resources to advance our knowledge of the mechanisms, diagnosis, management, and prevention of this allergic disease. This publication is a summary of the workshop and the panel's recommendations are presented herein. AU - Platts-Mills, T.A.E.* AU - Commins, S.P.* AU - Biedermann, T. AU - van Hage, M.* AU - Levin, M.* AU - Beck, L.A.* AU - Diuk-Wasser, M.* AU - Jappe, U.* AU - Apostolovic, D.* AU - Minnicozzi, M.* AU - Plaut, M.* AU - Wilson, J.M.* C1 - 58536 C2 - 48421 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 1061-1071 TI - On the cause and consequences of IgE to galactose-α-1,3-galactose: A report from the National Institute of Allergy and Infectious Diseases Workshop on Understanding IgE-Mediated Mammalian Meat Allergy. JO - J. Allergy Clin. Immunol. VL - 145 IS - 4 PB - Mosby-elsevier PY - 2020 SN - 0091-6749 ER - TY - JOUR AU - Reiger, M. AU - Traidl-Hoffmann, C. AU - Neumann, A.U. C1 - 57729 C2 - 48114 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 93-96 TI - The skin microbiome as a clinical biomarker in atopic eczema: Promises, navigation, and pitfalls. JO - J. Allergy Clin. Immunol. VL - 145 IS - 1 PB - Mosby-elsevier PY - 2020 SN - 0091-6749 ER - TY - JOUR AB - Allergic Rhinitis and its Impact on Asthma (ARIA) has evolved from a guideline by using the best approach to integrated care pathways using mobile technology in patients with allergic rhinitis (AR) and asthma multimorbidity. The proposed next phase of ARIA is change management, with the aim of providing an active and healthy life to patients with rhinitis and to those with asthma multimorbidity across the lifecycle irrespective of their sex or socioeconomic status to reduce health and social inequities incurred by the disease. ARIA has followed the 8-step model of Kotter to assess and implement the effect of rhinitis on asthma multimorbidity and to propose multimorbid guidelines. A second change management strategy is proposed by ARIA Phase 4 to increase self-medication and shared decision making in rhinitis and asthma multimorbidity. An innovation of ARIA has been the development and validation of information technology evidence-based tools (Mobile Airways Sentinel Network [MASK]) that can inform patient decisions on the basis of a self-care plan proposed by the health care professional. AU - Bousquet, J.* AU - Hellings, P.W.* AU - Agache, I.* AU - Amat, F.* AU - Annesi-Maesano, I.* AU - Ansotegui, I.J.* AU - Antò, J.M.* AU - Bachert, C.* AU - Bateman, E.D.* AU - Bedbrook, A.* AU - Bennoor, K.S.* AU - Bewick, M.* AU - Bindslev-Jensen, C.* AU - Bosnic-Anticevich, S.* AU - Bosse, I.* AU - Brozek, J.L.* AU - Brussino, L.* AU - Canonica, G.W.* AU - Cardona, V.* AU - Casale, T.B.* AU - Cepeda Sarabia, A.M.* AU - Chavannes, N.H.* AU - Cecchi, L.* AU - Correia de Sousa, J.* AU - Costa, E.* AU - Cruz, A.A.* AU - Czarlewski, W.* AU - de Carlo, G.* AU - De Feo, G.* AU - Demoly, P.* AU - Devillier, P.* AU - Dykewicz, M.S.* AU - El-Gamal, Y.* AU - Eller, E.E.* AU - Fonseca, J.A.* AU - Fontaine, J.F.* AU - Fokkens, W.J.* AU - Guzmán, M.A.* AU - Haahtela, T.* AU - Illario, M.* AU - Ivancevich, J.C.* AU - Just, J.* AU - Kaidashev, I.* AU - Khaitov, M.R.* AU - Kalayci, O.* AU - Keil, T.* AU - Klimek, L.* AU - Kowalski, M.L.* AU - Kuna, P.* AU - Kvedariene, V.* AU - Larenas-Linnemann, D.* AU - Laune, D.* AU - Le, L.T.T.* AU - Carlsen, K.L.* AU - Lourenço, O.* AU - Mahboub, B.* AU - Mair, A.* AU - Menditto, E.* AU - Milenkovic, B.* AU - Morais-Almeida, M.* AU - Mösges, R.* AU - Mullol, J.* AU - Murray, R.* AU - Naclerio, R.* AU - Namazova-Baranova, L.* AU - Novellino, E.* AU - O'Hehir, R.E.* AU - Ohta, K.* AU - Okamoto, Y.* AU - Okubo, K.* AU - Onorato, G.L.* AU - Palkonen, S.* AU - Panzner, P.* AU - Papadopoulos, N.G.* AU - Park, H.S.* AU - Paulino, E.* AU - Pawankar, R.* AU - Pfaar, O.* AU - Plavec, D.* AU - Popov, T.A.* AU - Potter, P.* AU - Prokopakis, E.P.* AU - Rottem, M.* AU - Ryan, D.* AU - Salimäki, J.* AU - Samolinski, B.* AU - Sanchez-Borges, M.* AU - Schünemann, H.J.* AU - Sheikh, A.* AU - Sisul, J.C.* AU - Rajabian-Söderlund, R.* AU - Sooronbaev, T.* AU - Stellato, C.* AU - To, T.* AU - Todo-Bom, A.M.* AU - Tomazic, P.V.* AU - Toppila-Salmi, S.* AU - Valero, A.L.* AU - Valiulis, A.* AU - Valovirta, E.* AU - Ventura, M.T.* AU - Wagenmann, M.* AU - Wang, Y.* AU - Wallace, D.C.* AU - Waserman, S.* AU - Wickman, M.* AU - Yorgancioglu, A.* AU - Zhang, L.* AU - Zhong, N.* AU - Zidarn, M.* AU - Zuberbier, T.* AU - MASK Study Group (Darsow, U.) C1 - 57879 C2 - 47968 SP - 864-879 TI - Allergic Rhinitis and its Impact on Asthma (ARIA) Phase 4 (2018): Change management in allergic rhinitis and asthma multimorbidity using mobile technology. JO - J. Allergy Clin. Immunol. VL - 143 IS - 3 PY - 2019 SN - 0091-6749 ER - TY - JOUR AB - Background: IL-22 is potentially a pathogenic cytokine in patients with atopic dermatitis (AD), but the molecular effects of IL-22 antagonism have not been defined in human subjects.Objective: We sought to evaluate the cellular and molecular effects of IL-22 blockade in tissues from patients with moderate-to-severe AD.Methods: We assessed lesional and nonlesional skin from 59 patients with moderate-to-severe AD treated with anti-IL-22 (fezakinumab) versus placebo (2: 1) using transcriptomic and immunohistochemistry analyses.Results: Greater reversal of the AD genomic profile was seen with fezakinumab versus placebo, namely 25.3% versus 10.5% at 4 weeks (P = 1.7 x 10(-5)) and 65.5% versus 13.9% at 12 weeks (P = 9.5 3 10(-19)), respectively. Because IL-22 blockade showed clinical efficacy only in patients with severe AD, we used baseline median IL-22 mRNA expression to stratify for high (n = 30) and low (n = 29) IL-22 expression groups. Much stronger mean transcriptomic improvements were seen with fezakinumab in the IL-22-high drug-treated group (82.8% and 139.4% at 4 and 12 weeks, respectively) than in the respective IL-22-high placebo-treated group (39.6% and 56.3% at 4 and 12 weeks) or the IL-22-low groups. Significant downregulations of multiple immune pathways, including T(H)1/CXCL9, T(H)2/CCL18/CCL22, T(H)17/CCL20/DEFB4A, and T(H)22/IL22/S100A's, were restricted to the IL-22-high drug group (P <.05). Consistently, tissue predictors of clinical response were mostly genes involved in T-cell and dendritic cell activation and differentiation.Conclusions: This is the first report showing a profound effect of IL-22 blockade on multiple inflammatory pathways in AD. These data, supported by robust effects in patients with high IL-22 baseline expression, suggest a central role for IL-22 in AD, indicating the need for a precision medicine approach for improving therapeutic outcomes in patients with AD. AU - Brunner, P.M.* AU - Pavel, A.B.* AU - Khattri, S.* AU - Leonard, A.* AU - Malik, K.A.* AU - Rose, S.* AU - On, S.J.* AU - Vekaria, A.S.* AU - Traidl-Hoffmann, C. AU - Singer, G.K.* AU - Baum, D.* AU - Gilleaudeau, P.* AU - Sullivan-Whalen, M.* AU - Fuentes-Duculan, J.* AU - Li, X.* AU - Zheng, X.* AU - Estrada, Y.* AU - Garcet, S.* AU - Wen, H.C.* AU - Gonzalez, J.R.* AU - Coats, I.* AU - Cueto, I.* AU - Neumann, A.U. AU - Lebwohl, M.G.* AU - Krueger, J.G.* AU - Guttman-Yassky, E.* C1 - 54156 C2 - 45376 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 142-154 TI - Baseline IL-22 expression in patients with atopic dermatitis stratifies tissue responses to fezakinumab. JO - J. Allergy Clin. Immunol. VL - 143 IS - 1 PB - Mosby-elsevier PY - 2019 SN - 0091-6749 ER - TY - JOUR AB - Mast cells (MCs), which are well known for their effector functions in T(H)2-skewed allergic and also autoimmune inflammation, have become increasingly acknowledged for their role in protection of health. It is now clear that they are also key modulators of immune responses at interface organs, such as the skin or gut. MCs can prime tissues for adequate inflammatory responses and cooperate with dendritic cells in T-cell activation. They also regulate harmful immune responses in trauma and help to successfully orchestrate pregnancy. This review focuses on the beneficial effects of MCs on tissue homeostasis and elimination of toxins or venoms. MCs can enhance pathogen clearance in many bacterial, viral, and parasitic infections, such as through Toll-like receptor 2-triggered degranulation, secretion of antimicrobial cathelicidins, neutrophil recruitment, or provision of extracellular DNA traps. The role of MCs in tumors is more ambiguous; however, encouraging new findings show they can change the tumor microenvironment toward antitumor immunity when adequately triggered. Uterine tissue remodeling by alpha-chymase (mast cell protease [MCP] 5) is crucial for successful embryo implantation. MCP-4 and the tryptase MCP-6 emerge to be protective in central nervous system trauma by reducing inflammatory damage and excessive scar formation, thereby protecting axon growth. Last but not least, proteases, such as carboxypeptidase A, released by Fc epsilon RI-activated MCs detoxify an increasing number of venoms and endogenous toxins. A better understanding of the plasticity of MCs will help improve these advantageous effects and hint at ways to cut down detrimental MC actions. AU - Dudeck, A.* AU - Köberle, M.* AU - Goldmann, O.* AU - Meyer, N.* AU - Dudeck, J.* AU - Lemmens, S.* AU - Rohde, M.* AU - Roldán, N.G.* AU - Dietze-Schwonberg, K.* AU - Orinska, Z.* AU - Medina, E.* AU - Hendrix, S.* AU - Metz, M.* AU - Zenclussen, A.C.* AU - von Stebut, E.* AU - Biedermann, T. C1 - 54782 C2 - 45884 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - S4-S18 TI - Mast cells as protectors of health. JO - J. Allergy Clin. Immunol. VL - 144 IS - 4 PB - Mosby-elsevier PY - 2019 SN - 0091-6749 ER - TY - JOUR AB - Background: Mast cells (MCs) are best known as key effector cells of allergic reactions, but they also play an important role in host defense against pathogens. Despite increasing evidence for a critical effect of MCs on adaptive immunity, the underlying mechanisms are poorly understood.Objective: Here we monitored MC intercellular communication with dendritic cells (DCs), MC activation, and degranulation and tracked the fate of exocytosed mast cell granules (MCGs) during skin inflammation.Methods: Using a strategy to stain intracellular MCGs in vivo, we tracked the MCG fate after skin inflammation-induced MC degranulation. Furthermore, exogenous MCGs were applied to MC-deficient mice by means of intradermal injection. MCG effects on DC functionality and adaptive immune responses in vivo were assessed by combining intravital multiphoton microscopy with flow cytometry and functional assays.Results: We demonstrate that dermal DCs engulf the intact granules exocytosed by MCs on skin inflammation. Subsequently, the engulfed MCGs are actively shuttled to skin-draining lymph nodes and finally degraded inside DCs within the lymphoid tissue. Most importantly, MCG uptake promotes DC maturation and migration to skin-draining lymph nodes, partially through MCderived TNF, and boosts their T-cell priming efficiency. Surprisingly, exogenous MCGs alone are sufficient to induce a prominent DC activation and T-cell response.Conclusion: Our study highlights a unique feature of peripheral MCs to affect lymphoid tissue-borne adaptive immunity over distance by modifying DC functionality through delivery of granule-stored mediators. AU - Dudeck, J.* AU - Froebel, J.* AU - Kotrba, J.* AU - Lehmann, C.H.K.* AU - Dudziak, D.* AU - Speier, S. AU - Nedospasov, S.A.* AU - Schraven, B.* AU - Dudeck, A.* C1 - 54550 C2 - 45660 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 1849-1864.e4 TI - Engulfment of mast cell secretory granules on skin inflammation boosts dendritic cell migration and priming efficiency. JO - J. Allergy Clin. Immunol. VL - 143 IS - 5 PB - Mosby-elsevier PY - 2019 SN - 0091-6749 ER - TY - JOUR AB - Atopic dermatitis (AD) is a prevalent disease worldwide and is associated with systemic comorbidities representing a significant burden on patients, their families, and society. Therapeutic options for AD remain limited, in part because of a lack of well-characterized animal models. There has been increasing interest in developing experimental approaches to study the pathogenesis of human AD in vivo, in vitro, and in silico to better define pathophysiologic mechanisms and identify novel therapeutic targets and biomarkers that predict therapeutic response. This review critically appraises a range of models, including genetic mutations relevant to AD, experimental challenge of human skin in vivo, tissue culture models, integration of "omics" data sets, and development of predictive computational models. Although no one individual model recapitulates the complex AD pathophysiology, our review highlights insights gained into key elements of cutaneous biology, molecular pathways, and therapeutic target identification through each approach. Recent developments in computational analysis, including application of machine learning and a systems approach to data integration and predictive modeling, highlight the applicability of these methods to AD subclassification (endotyping), therapy development, and precision medicine. Such predictive modeling will highlight knowledge gaps, further inform refinement of biological models, and support new experimental and systems approaches to AD. AU - Eyerich, K. AU - Brown, S.J.* AU - White, B.E.P.* AU - Tanaka, R.J.* AU - Bissonette, R.* AU - Dhar, S.* AU - Bieber, T.* AU - Hijnen, D.J.* AU - Guttman-Yassky, E.* AU - Irvine, A.* AU - Thyssen, J.P.* AU - Vestergaard, C.* AU - Werfel, T.* AU - Wollenberg, A.* AU - Paller, A.S.* AU - Reynolds, N.J.* C1 - 55206 C2 - 46092 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 36-45 TI - Human and computational models of atopic dermatitis: A review and perspectives by an expert panel of the International Eczema Council. JO - J. Allergy Clin. Immunol. VL - 143 IS - 1 PB - Mosby-elsevier PY - 2019 SN - 0091-6749 ER - TY - JOUR AB - Background: Early-life indoor bacterial exposure is associated with the risk of asthma, but the roles of specific bacterial genera are poorly understood.Objective: We sought to determine whether individual bacterial genera in indoor microbiota predict the development of asthma.Methods: Dust samples from living rooms were collected at 2 months of age. The dust microbiota was characterized by using Illumina MiSeq sequencing amplicons of the bacterial 16S ribosomal RNA gene. Children (n = 373) were followed up for ever asthma until the age of 10.5 years.Results: Richness was inversely associated with asthma after adjustments (P = .03). The phylogenetic microbiota composition in asthmatics patients' homes was characteristically different from that in nonasthmatic subjects' homes (P = .02, weighted UniFrac, adjusted association, permutational multivariate analysis of variance, PERMANOVA-S). The first 2 axis scores of principal coordinate analysis of the weighted UniFrac distance matrix were inversely associated with asthma. Of 658 genera detected in the dust samples, the relative abundances of 41 genera correlated (r > vertical bar 0.4 vertical bar) with one of these axes. Lactococcus genus was a risk factor for asthma (adjusted odds ratio, 1.36 [95% CI, 1.13-1.63] per interquartile range change). The abundance of 12 bacterial genera (mostly from the Actinomycetales order) was associated with lower asthma risk (P < .10), although not independently of each other. The sum relative abundance of these 12 intercorrelated genera was significantly protective and explained the majority of the association of richness with less asthma.Conclusion: Our data confirm that phylogenetic differences in the microbiota of infants' homes are associated with subsequent asthma risk and suggest that communities of selected bacteria are more strongly linked to asthma protection than individual bacterial taxa or mere richness. AU - Karvonen, A.M.* AU - Kirjavainen, P.V.* AU - Täubel, M.* AU - Jayaprakash, B.* AU - Adams, R.I.* AU - Sordillo, J.E.* AU - Gold, D.R.* AU - Hyvärinen, A.* AU - Remes, S.* AU - von Mutius, E. AU - Pekkanen, J.* C1 - 56907 C2 - 47426 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 1402-1410 TI - Indoor bacterial microbiota and development of asthma by 10.5 years of age. JO - J. Allergy Clin. Immunol. VL - 144 IS - 5 PB - Mosby-elsevier PY - 2019 SN - 0091-6749 ER - TY - JOUR AB - Background: Galactose-alpha-1,3-galactose (alpha-gal) syndrome is characterized by the presence of serum specific IgE antibodies to alpha-gal and delayed type I allergic reactions to the carbohydrate alpha-gal after consumption of mammalian (red) meat products and drugs of mammalian origin. Diagnostics currently rely on patient history, skin tests, determination of serum specific IgE antibodies, and oral food or drug challenges.Objective: We sought to assess the utility of different basophil parameters (basophil reactivity and sensitivity, the ratio of the percentage of CD63(+) basophils induced by the alpha-gal-containing allergen to the percentage of CD63(+) basophils after stimulation with anti-Fc epsilon RI antibody [%CD63(+)/anti-Fc epsilon RI], and area under the dose-response curve [AUC]) as biomarkers for the clinical outcome of patients with alpha-gal syndrome compared with subjects with asymptomatic alpha-gal sensitization.Methods: In addition to routine diagnostics, a basophil activation test (Flow CAST) with different concentrations of alpha-gal-containing allergens (eg, commercially available alpha-gal-carrying proteins and pork kidney extracts) was performed in 21 patients with alpha-gal syndrome, 12 alphagal-sensitized subjects, and 18 control subjects.Results: Alpha-gal-containing allergens induced strong basophil activation in a dose-dependent manner in patients. Basophil reactivity at distinct allergen concentrations, the % CD63(+)/anti-FceRI ratio across most allergen concentrations, the AUC of dose-response curves, and basophil allergen threshold sensitivity (CD-sens) with pork kidney extract were significantly higher in patients with alpha-gal syndrome compared with those in sensitized subjects. All parameters were negative in control subjects.Conclusion: The basophil activation test should be considered as an additional diagnostic test before performing time-consuming and potentially risky oral provocation tests. The % CD63(+)/anti-Fc epsilon RI ratio for all allergens and AUCs for pork kidney were the best parameters for distinguishing patients with alpha-gal syndrome from subjects with asymptomatic alpha-gal sensitization. AU - Mehlich, J.* AU - Fischer, J.* AU - Hilger, C.* AU - Swiontek, K.* AU - Morisset, M.* AU - Codreanu-Morel, F.* AU - Schiener, M. AU - Blank, S. AU - Ollert, M.* AU - Darsow, U.* AU - Biedermann, T.* AU - Eberlein, B.* C1 - 54159 C2 - 45375 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 182-189 TI - The basophil activation test differentiates between patients with alpha-gal syndrome and asymptomatic alpha-gal sensitization. JO - J. Allergy Clin. Immunol. VL - 143 IS - 1 PB - Mosby-elsevier PY - 2019 SN - 0091-6749 ER - TY - JOUR AB - Background: Endotoxin (LPS) released from gram-negative bacteria causes strong immunologic and inflammatory effects and, when airborne, can contribute to respiratory conditions, such as allergic asthma.Objectives: We sought to identify the source of airborne endotoxin and the effect of this endotoxin on allergic sensitization.Methods: We determinedLPS levels in outdoor air on a daily basis for 4 consecutive years in Munich (Germany) and Davos (Switzerland). Airwas sampled as particulate matter (PM) greater than 10 mm(PM > 10) and PMbetween 2.5 and 10 mm. LPS levels were determined by using the recombinant Factor C assay.Results: More than 60% of the annual endotoxin exposure was detected in the PM > 10 fraction, showing that bacteria do not aerosolize as independent units or aggregates but adhered to large particles. In Munich 70% of annual exposure was detected between June 12th and August 28th. Multivariate modeling showed that endotoxin levels could be explained by phenological parameters (ie, plant growth). Indeed, days with high airborne endotoxin levels correlated well with the amount of Artemisia pollen in the air. Pollen collected from plants across Europe (100 locations) showed that the highest levels of endotoxin were detected on Artemisia vulgaris (mugwort) pollen, with little on other pollen. Microbiome analysis showed that LPS concentrations on mugwort pollen were related to the presence of Pseudomonas species and Pantoea species communities. In a mouse model of allergic disease, the presence of LPS on mugwort pollen was needed for allergic sensitization.Conclusions: The majority of airborne endotoxin stems from bacteria dispersed with pollen of only one plant: mugwort. This LPS was essential for inducing inflammation of the lung and allergic sensitization. AU - Oteros, J. AU - Bartusel, E. AU - Alessandrini, F. AU - Núñez, A.* AU - Moreno, D.A.* AU - Behrendt, H. AU - Schmidt-Weber, C.B. AU - Traidl-Hoffmann, C.* AU - Buters, J.T.M. C1 - 53959 C2 - 45140 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 369-377.e5 TI - Artemisia pollen is the main vector for airborne endotoxin. JO - J. Allergy Clin. Immunol. VL - 143 IS - 1 PB - Mosby-elsevier PY - 2019 SN - 0091-6749 ER - TY - JOUR AB - Background: Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis.Objective: We sought to identify differential DNA methylation in newborns and children related to childhood asthma.Methods: Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions.Results: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2.Conclusion: Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium. AU - Reese, S.E.* AU - Xu, C.J.* AU - den Dekker, H.T.* AU - Lee, M.K.* AU - Sikdar, S.* AU - Ruiz-Arenas, C.* AU - Merid, S.K.* AU - Rezwan, F.I.* AU - Page, C.M.* AU - Ullemar, V.* AU - Melton, P.E.* AU - Oh, S.S.* AU - Yang, I.V.* AU - Burrows, K.* AU - Söderhäll, C.* AU - Jima, D.D.* AU - Gao, L.* AU - Arathimos, R.* AU - Küpers, L.K.* AU - Wielscher, M.* AU - Rzehak, P.* AU - Lahti, J.* AU - Laprise, C.* AU - Madore, A.M.* AU - Ward, J.* AU - Bennett, B.D.* AU - Wang, T.* AU - Bell, D.A.* AU - Vonk, J.M.* AU - Håberg, S.E.* AU - Zhao, S.* AU - Karlsson, R.* AU - Hollams, E.* AU - Hu, D.* AU - Richards, A.J.* AU - Bergström, A.* AU - Sharp, G.C.* AU - Felix, J.F.* AU - Bustamante, M.* AU - Gruzieva, O.* AU - Maguire, R.L.* AU - Gilliland, F.* AU - Baïz, N.* AU - Nohr, E.A.* AU - Corpeleijn, E.* AU - Sebert, S.* AU - Karmaus, W.* AU - Grote, V.* AU - Kajantie, E.* AU - Magnus, M.C.* AU - Örtqvist, A.K.* AU - Eng, C.* AU - Liu, A.H.* AU - Kull, I.* AU - Jaddoe, V.W.V.* AU - Sunyer, J.* AU - Kere, J.* AU - Hoyo, C.* AU - Annesi-Maesano, I.* AU - Arshad, S.H.* AU - Koletzko, B.* AU - Brunekreef, B.* AU - Binder, E.B.* AU - Räikkönen, K.* AU - Reischl, E. AU - Holloway, J.W.* AU - Jarvelin, M.R.* AU - Snieder, H.* AU - Kazmi, N.* AU - Breton, C.V.* AU - Murphy, S.K.* AU - Pershagen, G.* AU - Antò, J.M.* AU - Relton, C.L.* AU - Schwartz, D.A.* AU - Burchard, E.G.* AU - Huang, R.C.* AU - Nystad, W.* AU - Almqvist, C.* AU - Henderson, A.J.* AU - Melén, E.* AU - Duijts, L.* AU - Koppelman, G.H.* AU - London, S.J.* C1 - 55046 C2 - 46073 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 2062-2074 TI - Epigenome-wide meta-analysis of DNA methylation and childhood asthma. JO - J. Allergy Clin. Immunol. VL - 143 IS - 6 PB - Mosby-elsevier PY - 2019 SN - 0091-6749 ER - TY - JOUR AB - Background: The prevalence of atopy is associated with a Western lifestyle, as shown by studies comparing neighboring regions with different socioeconomic backgrounds. Atopy might reflect various conditions differing in their susceptibility to environmental factors.Objective: We sought to define phenotypes of atopic sensitization in early childhood and examine their association with allergic diseases and hereditary background in Finland and Estonia.Methods: The analysis included 1603 Finnish and 1657 Estonian children from the DIABIMMUNE multicenter young children cohort. Specific IgE levels were measured at age 3, 4, and 5 years, respectively, and categorized into 3 CAP classes. Latent class analysis was performed with the statistical software package poLCA in R software.Results: Both populations differed in terms of socioeconomic status and environmental determinants, such as pet ownership, farm-related exposure, time spent playing outdoors, and prevalence of allergic diseases (all P <.001). Nevertheless, we found similar latent classes in both populations: an unsensitized class, a food class, 2 inhalant classes differentiating between seasonal and perennial aeroallergens, and a severe atopy class. The latter was characterized by high total and specific IgE levels and strongly associated with wheeze (odds ratio [OR], 5.64 [95% CI, 3.07-10.52] and 4.56 [95% CI, 2.35-8.52]), allergic rhinitis (OR, 22.4 [95% CI, 11.67-44.54] and 13.97 [95% CI, 7.33-26.4]), and atopic eczema (OR, 9.39 [95% CI, 4.9-19.3] and 9.5 [95% CI, 5.2-17.5] for Finland and Estonia, respectively). Environmental differences were reflected in the larger seasonal inhalant atopy class in Finland, although composition of classes was comparable between countries.Conclusion: Despite profound differences in environmental exposures, there might exist genuine patterns of atopic sensitization. The distribution of these patterns might determine the contribution of atopic sensitization to disease onset. AU - Schmidt, F.* AU - Hose, A.J. AU - Mueller-Rompa, S.* AU - Brick, T.* AU - Hämäläinen, A.M.* AU - Peet, A.* AU - Tillmann, V.* AU - Niemelä, O.* AU - Siljander, H.* AU - Knip, M.* AU - Weber, J.* AU - Von Mutius, E.* AU - Ege, M.J.* C1 - 55326 C2 - 46248 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 1904-1913.e9 TI - Development of atopic sensitization in Finnish and Estonian children: A latent class analysis in a multicenter cohort. JO - J. Allergy Clin. Immunol. VL - 143 IS - 5 PB - Mosby-elsevier PY - 2019 SN - 0091-6749 ER - TY - JOUR AB - In contrast to the pollen context, the major allergen Bet v 1 alone is not responsible for Th2 polarization in allergic sensitization. These findings are highly relevant for birch pollen allergy prophylaxis. AU - Aglas, L.* AU - Gilles, S. AU - Bauer, R.* AU - Huber, S.* AU - Araujo, G.R.* AU - Mueller, G.* AU - Scheiblhofer, S.* AU - Amisi, M. AU - Dang, H.H.* AU - Briza, P.* AU - Bohle, B.* AU - Horejs-Hoeck, J.* AU - Traidl-Hoffmann, C. AU - Ferreira, F.* C1 - 53556 C2 - 44903 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 984-987.e6 TI - Context matters: T(H)2 polarization resulting from pollen composition and not from protein-intrinsic allergenicity. JO - J. Allergy Clin. Immunol. VL - 142 IS - 3 PB - Mosby-elsevier PY - 2018 SN - 0091-6749 ER - TY - JOUR AU - Altunbulakli, C.* AU - Reiger, M. AU - Neumann, A.U. AU - Garzorz-Stark, N.* AU - Fleming, M. AU - Huelpuesch, C. AU - Castro-Giner, F.* AU - Eyerich, K.* AU - Akdis, C.A.* AU - Traidl-Hoffmann, C. C1 - 54015 C2 - 45202 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 1643-1647.e12 TI - Relations between epidermal barrier dysregulation and species-dominated microbiome dysbiosis in patients with atopic dermatitis. JO - J. Allergy Clin. Immunol. VL - 142 IS - 5 PB - Mosby-elsevier PY - 2018 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: A standardized human model to study early pathogenic events in patients with psoriasis is missing. Activation of Toll-like receptor 7/8 by means of topical application of imiquimod is the most commonly used mouse model of psoriasis. OBJECTIVE: We sought to investigate the potential of a human imiquimod patch test model to resemble human psoriasis. METHODS: Imiquimod (Aldara 5% cream; 3M Pharmaceuticals, St Paul, Minn) was applied twice a week to the backs of volunteers (n = 18), and development of skin lesions was monitored over a period of 4 weeks. Consecutive biopsy specimens were taken for whole-genome expression analysis, histology, and T-cell isolation. Plasmacytoid dendritic cells (pDCs) were isolated from whole blood, stimulated with Toll-like receptor 7 agonist, and analyzed by means of extracellular flux analysis and real-time PCR. RESULTS: We demonstrate that imiquimod induces a monomorphic and self-limited inflammatory response in healthy subjects, as well as patients with psoriasis or eczema. The clinical and histologic phenotype, as well as the transcriptome, of imiquimod-induced inflammation in human skin resembles acute contact dermatitis rather than psoriasis. Nevertheless, the imiquimod model mimics the hallmarks of psoriasis. In contrast to classical contact dermatitis, in which myeloid dendritic cells sense haptens, pDCs are primary sensors of imiquimod. They respond with production of proinflammatory and T17-skewing cytokines, resulting in a T17 immune response with IL-23 as a key driver. In a proof-of-concept setting systemic treatment with ustekinumab diminished imiquimod-induced inflammation. CONCLUSION: In human subjects imiquimod induces contact dermatitis with the distinctive feature that pDCs are the primary sensors, leading to an IL-23/T17 deviation. Despite these shortcomings, the human imiquimod model might be useful to investigate early pathogenic events and prove molecular concepts in patients with psoriasis. AU - Garzorz-Stark, N.* AU - Lauffer, F.* AU - Krause, L. AU - Thomas, J. AU - Atenhan, A. AU - Franz, R.* AU - Roenneberg, S.* AU - Boehner, A.* AU - Jargosch, M. AU - Batra, R. AU - Müller, N.S. AU - Haak, S. AU - Groß, C.* AU - Groß, O.* AU - Traidl-Hoffmann, C. AU - Theis, F.J. AU - Schmidt-Weber, C.B. AU - Biedermann, T.* AU - Eyerich, S. AU - Eyerich, K.* C1 - 51960 C2 - 43620 SP - 1320-1333.e11 TI - Toll-like receptor 7/8 agonists stimulate plasmacytoid dendritic cells to initiate T(H)17-deviated acute contact dermatitis in human subjects. JO - J. Allergy Clin. Immunol. VL - 141 IS - 4 PY - 2018 SN - 0091-6749 ER - TY - JOUR AU - von Mutius, E. C1 - 52987 C2 - 44682 SP - 1215-1216 TI - Biodiversity: The new kid on the block? JO - J. Allergy Clin. Immunol. VL - 141 IS - 4 PY - 2018 SN - 0091-6749 ER - TY - JOUR AB - Comprehensive analysis of biomarkers in upper and lower airways revealed greatest relation to lower airway biomarker specifically IL-24. All other biomarker candidates showed weak to moderate correlation between upper and lower airways (r < 0.5). AU - Zissler, U.M. AU - Ulrich, M. AU - Jakwerth, C.A. AU - Rothkirch, S. AU - Guerth, F. AU - Weckmann, M.* AU - Schiemann, M.* AU - Haller, B.* AU - Schmidt-Weber, C.B. AU - Chaker, A. C1 - 54157 C2 - 45373 CY - 360 Park Avenue South, New York, Ny 10010-1710 Usa SP - 1980-1983 TI - Biomatrix for upper and lower airway biomarkers in patients with allergic asthma. JO - J. Allergy Clin. Immunol. VL - 142 IS - 6 PB - Mosby-elsevier PY - 2018 SN - 0091-6749 ER - TY - JOUR AB - Asthma, rhinitis, and eczema are complex diseases with multiple genetic and environmental factors interlinked through IgE-associated and non–IgE-associated mechanisms. Mechanisms of the Development of ALLergy (MeDALL; EU FP7-CP-IP; project no: 261357; 2010-2015) studied the complex links of allergic diseases at the clinical and mechanistic levels by linking epidemiologic, clinical, and mechanistic research, including in vivo and in vitro models. MeDALL integrated 14 European birth cohorts, including 44,010 participants and 160 cohort follow-ups between pregnancy and age 20 years. Thirteen thousand children were prospectively followed after puberty by using a newly standardized MeDALL Core Questionnaire. A microarray developed for allergen molecules with increased IgE sensitivity was obtained for 3,292 children. Estimates of air pollution exposure from previous studies were available for 10,000 children. Omics data included those from historical genome-wide association studies (23,000 children) and DNA methylation (2,173), targeted multiplex biomarker (1,427), and transcriptomic (723) studies. Using classical epidemiology and machine-learning methods in 16,147 children aged 4 years and 11,080 children aged 8 years, MeDALL showed the multimorbidity of eczema, rhinitis, and asthma and estimated that only 38% of multimorbidity was attributable to IgE sensitization. MeDALL has proposed a new vision of multimorbidity independent of IgE sensitization, and has shown that monosensitization and polysensitization represent 2 distinct phenotypes. The translational component of MeDALL is shown by the identification of a novel allergic phenotype characterized by polysensitization and multimorbidity, which is associated with the frequency, persistence, and severity of allergic symptoms. The results of MeDALL will help integrate personalized, predictive, preventative, and participatory approaches in allergic diseases. AU - Antò, J.M.* AU - Bousquet, J.* AU - Akdis, M.* AU - Auffray, C.* AU - Keil, T.* AU - Momas, I.* AU - Postma, D.S.* AU - Valenta, R.* AU - Wickman, M.* AU - Cambon-Thomsen, A.* AU - Haahtela, T.* AU - Lambrecht, B.N.* AU - Lodrup Carlsen, K.C.* AU - Koppelman, G.H.* AU - Sunyer, J.* AU - Zuberbier, T.* AU - Annesi-Maesano, I.* AU - Arno, A.* AU - Bindslev-Jensen, C.* AU - de Carlo, G.* AU - Forastiere, F.* AU - Heinrich, J. AU - Kowalski, M.L.* AU - Maier, D.* AU - Melén, E.* AU - Smit, H.A.* AU - Standl, M. AU - Wright, J.* AU - Asarnoj, A.* AU - Benet, M.* AU - Ballardini, N.* AU - Garcia-Aymerich, J.* AU - Gehring, U.* AU - Guerra, S.* AU - Hohmann, C.* AU - Kull, I.* AU - Lupinek, C.* AU - Pinart, M.* AU - Skrindo, I.* AU - Westman, M.* AU - Smagghe, D.* AU - Akdis, C.* AU - Andersson, N.* AU - Bachert, C.* AU - Ballereau, S.* AU - Ballester, F.* AU - Basagana, X.* AU - Bedbrook, A.* AU - Bergström, A.* AU - von Berg, A.* AU - Brunekreef, B.* AU - Burte, E.* AU - Carlsen, K.H.* AU - Chatzi, L.* AU - Coquet, J.M.* AU - Curin, M.* AU - Demoly, P.* AU - Eller, E.* AU - Fantini, M.P.* AU - von Hertzen, L.* AU - Hovland, V.* AU - Jacquemin, B.* AU - Just, J.* AU - Keller, T.* AU - Kiss, R.* AU - Kogevinas, M.* AU - Koletzko, S.* AU - Lau, S.* AU - Lehmann, I.* AU - Lemonnier, N.* AU - Makela, M.J.* AU - Mestres, J.* AU - Mowinckel, P.* AU - Nadif, R.* AU - Nawijn, M.C.* AU - Pellet, J.* AU - Pin, I.* AU - Porta, D.* AU - Ranciere, F.* AU - Rial-Sebbag, E.* AU - Saeys, Y.* AU - Schuijs, M.J.* AU - Siroux, V.* C1 - 50533 C2 - 42410 CY - New York SP - 388-399 TI - Mechanisms of the Development of Allergy (MeDALL): Introducing novel concepts in allergy phenotypes. JO - J. Allergy Clin. Immunol. VL - 139 IS - 2 PB - Mosby-elsevier PY - 2017 SN - 0091-6749 ER - TY - JOUR AB - Myb-like, SWIRM, and MPN domains 1 (MYSM1) is a transcriptional regulator mediating histone deubiquitination. Its role in human immunity and hematopoiesis is poorly understood. OBJECTIVES: We sought to investigate the clinical, cellular, and molecular features in 2 siblings presenting with progressive bone marrow failure (BMF), immunodeficiency, and developmental aberrations. METHODS: We performed genome-wide homozygosity mapping, whole-exome and Sanger sequencing, immunophenotyping studies, and analysis of genotoxic stress responses. p38 activation, reactive oxygen species levels, rate of apoptosis and clonogenic survival, and growth in immune and nonimmune cells were assessed. The outcome of allogeneic hematopoietic stem cell transplantation (HSCT) was monitored. RESULTS: We report 2 patients with progressive BMF associated with myelodysplastic features, immunodeficiency affecting B cells and neutrophil granulocytes, and complex developmental aberrations, including mild skeletal anomalies, neurocognitive developmental delay, and cataracts. Whole-exome sequencing revealed a homozygous premature stop codon mutation in the gene encoding MYSM1. MYSM1-deficient cells are characterized by increased sensitivity to genotoxic stress associated with sustained induction of phosphorylated p38 protein, increased reactive oxygen species production, and decreased survival following UV light-induced DNA damage. Both patients were successfully treated with allogeneic HSCT with sustained reconstitution of hematopoietic defects. CONCLUSIONS: Here we show that MYSM1 deficiency is associated with developmental aberrations, progressive BMF with myelodysplastic features, and increased susceptibility to genotoxic stress. HSCT represents a curative therapy for patients with MYSM1 deficiency. AU - Bahrami, E.* AU - Witzel, M.* AU - Racek, T.* AU - Puchaka, J.* AU - Hollizeck, S.* AU - Greif-Kohistani, N.* AU - Kotlarz, D.* AU - Horny, H.-P.* AU - Feederle, R. AU - Schmidt, H.* AU - Sherkat, R.* AU - Steinemann, D.* AU - Göhring, G.* AU - Schlegelbeger, B.* AU - Albert, M.H.* AU - Al-Herz, W.* AU - Klein, C.* C1 - 50570 C2 - 42362 CY - New York SP - 1112-1119 TI - Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations. JO - J. Allergy Clin. Immunol. VL - 140 IS - 4 PB - Mosby-elsevier PY - 2017 SN - 0091-6749 ER - TY - JOUR AB - Atopic dermatitis (AD) is a paradigmatic chronic inflammatory skin disease characterized by a complex pathophysiology and a wide spectrum of the clinical phenotype. Despite this high degree of heterogeneity, ADis still considered a single disease and usually treated according to the "one-size-fits-all'' approach. Thus more tailored prevention and therapeutic strategies are still lacking. As for other disciplines, such as oncology or rheumatology, we have to approach AD in a more differentiated way (ie, to dissect and stratify the complex clinical phenotype into more homogeneous subgroups based on the endophenotype [panel of biomarkers]) with the aim to refine the management of this condition. Because we are now entering the era of personalized medicine, a systems biology approach merging the numerous clinical phenotypes with robust (ie, relevant and validated) biomarkers will be needed to best exploit their potential significance for the future molecular taxonomy of AD. This approach will not only allow an optimized prevention and treatment with the available drugs but also hopefully help assign newly developed medicinal products to those patients who will have the best benefit/risk ratio. AU - Bieber, T.* AU - D'Erme, A.M.* AU - Akdis, C.A.* AU - Traidl-Hoffmann, C. AU - Lauener, R.* AU - Schappi, G.* AU - Schmid-Grendelmeier, P.* C1 - 50991 C2 - 42749 CY - New York SP - S58-S64 TI - Clinical phenotypes and endophenotypes of atopic dermatitis: Where are we, and where should we go? JO - J. Allergy Clin. Immunol. VL - 139 IS - 4 PB - Mosby-elsevier PY - 2017 SN - 0091-6749 ER - TY - JOUR AB - This is the first study determining the three-dimensional structure of Phl p 5a which reveals a novel mechanism for high allergenic activity based on flexibly connected IgE-reactive domains which cross-link effector cell-bound IgE more efficiently than isolated rigid globular proteins. These findings may also form a basis for specific immunotherapy strategies. AU - Göbl, C. AU - Focke-Tejkl, M.* AU - Najafi, N.* AU - Schrank, E.* AU - Madl, T. AU - Kosol, S.* AU - Madritsch, C.* AU - Dorofeeva, Y.* AU - Flicker, S.* AU - Thalhamer, J.* AU - Valenta, R.* AU - Zangger, K.* AU - Tjandra, N.* C1 - 51182 C2 - 43075 CY - New York SP - 1187-1191 TI - Flexible IgE epitope containing domains of Phl p 5 cause high allergenic activity. JO - J. Allergy Clin. Immunol. VL - 140 IS - 4 PB - Mosby-elsevier PY - 2017 SN - 0091-6749 ER - TY - JOUR AB - Background: Phenotypes of childhood-onset asthma are characterized by distinct trajectories and functional features. For atopy, definition of phenotypes during childhood is less clear. Objective: We sought to define phenotypes of atopic sensitization over the first 6 years of life using a latent class analysis (LCA) integrating 3 dimensions of atopy: allergen specificity, time course, and levels of specific IgE (sIgE). Methods: Phenotypes were defined by means of LCA in 680 children of the Multizentrische Allergiestudie (MAS) and 766 children of the Protection against allergy: Study in Rural Environments (PASTURE) birth cohorts and compared with classical nondisjunctive definitions of seasonal, perennial, and food sensitization with respect to atopic diseases and lung function. Cytokine levels were measured in the PASTURE cohort. Results: The LCA classified predominantly by type and multiplicity of sensitization (food vs inhalant), allergen combinations, and sIgE levels. Latent classes were related to atopic disease manifestations with higher sensitivity and specificity than the classical definitions. LCA detected consistently in both cohorts a distinct group of children with severe atopy characterized by high seasonal sIgE levels and a strong propensity for asthma; hay fever; eczema; and impaired lung function, also in children without an established asthma diagnosis. Severe atopy was associated with an increased IL-5/IFN-gamma ratio. A path analysis among sensitized children revealed that among all features of severe atopy, only excessive sIgE production early in life affected asthma risk. Conclusions: LCA revealed a set of benign, symptomatic, and severe atopy phenotypes. The severe phenotype emerged as a latent condition with signs of a dysbalanced immune response. It determined high asthma risk through excessive sIgE production and directly affected impaired lung function. AU - Hose, A.J.* AU - Depner, M.* AU - Illi, S.* AU - Lau, S.* AU - Keil, T.* AU - Wahn, U.* AU - Fuchs, O. AU - Pfefferle, P.I.* AU - Schmaußer-Hechfellner, E.* AU - Genuneit, J.* AU - Lauener, R.* AU - Karvonen, A.M.* AU - Roduit, C.* AU - Dalphin, J.-C.* AU - Riedler, J.* AU - Pekkanen, J.* AU - von Mutius, E. AU - Ege, M.J.* AU - Bauer, C.P.* AU - Forster, J.* AU - Zepp, F.* AU - Wahn, V.* AU - Schuster, A.* AU - Bergmann, R.L.* AU - Bergmann, K.E.* AU - Reich, A.* AU - Grabenhenrich, L.* AU - Schaub, B.* AU - Loss, G.J.* AU - Renz, H.* AU - Kabesch, M.* AU - Roponen, M.* AU - Hyvärinen, A.* AU - Tiittanen, P.* AU - Remes, S.* AU - Braun-Fahrländer, C.* AU - Frei, R.* AU - Kaulek, V.* AU - Dalphin, M.* AU - Doekes, G.* AU - Blümer, N.* AU - Frey, U.H.* C1 - 51304 C2 - 43126 CY - New York SP - 1935-1945.e12 TI - Latent class analysis reveals clinically relevant atopy phenotypes in 2 birth cohorts. JO - J. Allergy Clin. Immunol. VL - 139 IS - 6 PB - Mosby-elsevier PY - 2017 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Chronic immune diseases (CIDs), such as asthma, are highly prevalent. Currently available pharmaceuticals improve symptoms, but cannot cure the disease. This prompted demands for alternatives to pharmaceuticals such as probiotics for prevention of allergic disease. However, clinical trials have given inconsistent results. This is at least partly explained by the highly complex crosstalk among probiotic bacteria, the host´s microbiota, and immune cells. The identification of a bioactive substance from probiotic bacteria could circumvent this difficulty. OBJECTIVE: To identify and characterize a bioactive, probiotic metabolite for potential prevention of allergic airway disease. METHODS: Probiotic supernatants were screened for their ability to concordantly lower the constitutive CCL17 secretion of a human Hodgkin lymphoma cell line and prevent upregulation of costimulatory molecules of LPS-stimulated human dendritic cells. RESULTS: Supernatants from 13 of 37 tested probiotic strains showed immunoactivity. Bioassay-guided chromatographic fractionation of two supernatants according to polarity, followed by total ion chromatograms and mass spectrometry, yielded C11H12N2O2 as molecular formula of a bioactive substance. Proton nuclear magnetic resonance and enantiomeric separation identified D-Tryptophan. In contrast, L-Tryptophan and eleven other D-amino acids were inactive. Feeding D-Tryptophan to mice prior to experimental asthma induction, increased numbers of lung and gut regulatory T cells, lowered lung Th2 responses, and ameliorated allergic airway inflammation and hyperresponsiveness. Allergic airway inflammation reduced the gut microbial diversity, which was increased by D-Tryptophan. CONCLUSIONS: D-Tryptophan is a newly identified product from probiotic bacteria. Our findings support the concept that defined bacterial products might be exploited in novel preventative strategies for CIDs. AU - Kepert, I. AU - Fonseca, J. AU - Müller, C. AU - Milger, K. AU - Hochwind, K. AU - Kostric, M. AU - Fedoseeva, M. AU - Ohnmacht, C. AU - Dehmel, S. AU - Nathan, P. AU - Bartel, S. AU - Eickelberg, O. AU - Schloter, M. AU - Hartmann, A. AU - Schmitt-Kopplin, P. AU - Krauss-Etschmann, S. C1 - 49570 C2 - 40810 SP - 1525-1535 TI - D-Tryptophan from probiotic bacteria influences the gut microbiome and allergic airway disease. JO - J. Allergy Clin. Immunol. VL - 139 IS - 5 PY - 2017 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: The relationship between allergy and autoimmune disorders is complex and poorly understood. OBJECTIVE: To investigate commonalities in genetic loci and pathways between allergy and autoimmune diseases to elucidate shared disease mechanisms. METHODS: We meta-analyzed two GWAS on self-reported allergy and sensitization comprising a total of 62,330 individuals. These results were used to calculate enrichment for SNPs previously associated with autoimmune diseases. Furthermore, we probed for enrichment within genetic pathways and of transcription factor binding sites, and characterized commonalities in the variant burden on tissue-specific regulatory sites by calculating the enrichment of allergy SNPs falling in gene regulatory regions in various cells using Encode Roadmap DHS data, and compared the allergy data with all known diseases. RESULTS: Among 290 loci previously associated with 16 autoimmune diseases, we found a significant enrichment of loci also associated with allergy (p=1.4e-17) encompassing 29 loci at a false discovery rate<0.05. Such enrichment seemed to be a general characteristic for all autoimmune diseases. Among the common loci, 48% had the same direction of effect for allergy and autoimmune diseases. Additionally, we observed an enrichment of allergy SNPs falling within immune pathways and regions of chromatin accessible in immune cells that was also represented in autoimmune diseases, but not in other diseases. CONCLUSION: We identified shared susceptibility loci and commonalities in pathways between allergy and autoimmune diseases, suggesting shared diseases mechanisms. Further studies of these shared genetic mechanisms might help understanding the complex relationship between these diseases, including the parallel increase in disease prevalence. AU - Kreiner, E.* AU - Waage, J.* AU - Standl, M. AU - Brix, S.* AU - Pers, T.H.* AU - Couto Alves, A.* AU - Warrington, N.M.* AU - Tiesler, C.M. AU - Fuertes, E. AU - Franke, L.* AU - Hirschhorn, J.N.* AU - James, A.* AU - Simpson, A.* AU - Tung, J.Y.* AU - Koppelman, G.H.* AU - Postma, D.S.* AU - Pennell, C.E.* AU - Jarvelin, M.R.* AU - Custovic, A.* AU - Timpson, N.* AU - Ferreira, M.A.* AU - Strachan, D.P.* AU - Henderson, J.* AU - Hinds, D.A.* AU - Bisgaard, H.* AU - Bønnelykke, K.* C1 - 50650 C2 - 42766 CY - New York SP - 771-781 TI - Shared genetic variants suggest common pathways in allergy and autoimmune diseases. JO - J. Allergy Clin. Immunol. VL - 140 IS - 3 PB - Mosby-elsevier PY - 2017 SN - 0091-6749 ER - TY - JOUR AU - Li, S.* AU - Morita, H.* AU - Rückert, B.* AU - Boonpiyathad, T.* AU - Neumann, A.U. AU - Akdis, C.A.* C1 - 55470 C2 - 46176 SP - 1156-1159.e7 TI - Type 3 innate lymphoid cells induce proliferation of CD94+ natural killer cells. JO - J. Allergy Clin. Immunol. VL - 140 IS - 4 PY - 2017 SN - 0091-6749 ER - TY - JOUR AB - Higher food diversity during the first year of life appears to decrease the risk of allergic sensitization to aeroallergens up to 15 years only among children with early skin symptoms in German birth cohort. AU - Markevych, I. AU - Standl, M. AU - Lehmann, I.* AU - von Berg, A.* AU - Heinrich, J. C1 - 51814 C2 - 43472 CY - New York SP - 1751-1754.e4 TI - Food diversity during the first year of life and allergic diseases until 15 years. JO - J. Allergy Clin. Immunol. VL - 140 IS - 6 PB - Mosby-elsevier PY - 2017 SN - 0091-6749 ER - TY - JOUR AU - Piasecka, J.* AU - Hennig, H. AU - Theis, F.J. AU - Rees, P.* AU - Summers, H.D.* AU - Thornton, C.A.* C1 - 51272 C2 - 42845 CY - New York SP - AB163-AB163 TI - Label free identification of peripheral blood eosinophils using high-throughput imaging flow cytometry. JO - J. Allergy Clin. Immunol. VL - 139 IS - 2 PB - Mosby-elsevier PY - 2017 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Cross-sectional studies have reported a lower prevalence of sensitization in older adults, but few longitudinal studies have examined whether this is an aging or a year-of-birth cohort effect. OBJECTIVE: We sought to assess changes in sensitization and total IgE levels in a cohort of European adults as they aged over a 20-year period. METHODS: Levels of serum specific IgE to common aeroallergens (house dust mite, cat, and grass) and total IgE levels were measured in 3206 adults from 25 centers in the European Community Respiratory Health Survey on 3 occasions over 20 years. Changes in sensitization and total IgE levels were analyzed by using regression analysis corrected for potential differences in laboratory equipment and by using inverse sampling probability weights to account for nonresponse. RESULTS: Over the 20-year follow-up, the prevalence of sensitization to at least 1 of the 3 allergens decreased from 29.4% to 24.8% (-4.6%; 95% CI, -7.0% to -2.1%). The prevalence of sensitization to house dust mite (-4.3%; 95% CI, -6.0% to -2.6%) and cat (-2.1%; 95% CI, -3.6% to -0.7%) decreased more than sensitization to grass (-0.6%; 95% CI, -2.5% to 1.3%). Age-specific prevalence of sensitization to house dust mite and cat did not differ between year-of-birth cohorts, but sensitization to grass was most prevalent in the most recent ones. Overall, total IgE levels decreased significantly (geometric mean ratio, 0.63; 95% CI, 0.58-0.68) at all ages in all year-of-birth cohorts. CONCLUSION: Aging was associated with lower levels of sensitization, especially to house dust mite and cat, after the age of 20 years. AU - Amaral, A.F.* AU - Newson, R.B.* AU - Abramson, M.J.* AU - Antò, J.M.* AU - Bono, R.* AU - Corsico, A.G.* AU - de Marco, R.* AU - Demoly, P.* AU - Forsberg, B.* AU - Gislason, T.* AU - Heinrich, J. AU - Huerta, I.* AU - Janson, C.* AU - Jõgi, R.* AU - Kim, J.L.* AU - Maldonado, J.A.* AU - Martinez-Moratalla Rovira, J.* AU - Neukirch, C.* AU - Nowak, D.* AU - Pin, I.* AU - Probst-Hensch, N.* AU - Raherison-Semjen, C.* AU - Svanes, C.* AU - Urrutia Landa, I.* AU - van Ree, R.* AU - Versteeg, S.A.* AU - Weyler, J.* AU - Zock, J.P.* AU - Burney, P.G.* AU - Jarvis, D.L.* C1 - 47350 C2 - 40579 CY - New York SP - 1788-1795 TI - Changes in IgE sensitization and total IgE levels over 20 years of follow-up. JO - J. Allergy Clin. Immunol. VL - 137 IS - 6 PB - Mosby-elsevier PY - 2016 SN - 0091-6749 ER - TY - JOUR AB - The selection of pharmacotherapy for patients with allergic rhinitis (AR) depends on several factors, including age, prominent symptoms, symptom severity, control of AR, patient preferences, and cost. Allergen exposure and the resulting symptoms vary, and treatment adjustment is required. Clinical decision support systems (CDSSs) might be beneficial for the assessment of disease control. CDSSs should be based on the best evidence and algorithms to aid patients and health care professionals to jointly determine treatment and its step-up or step-down strategy depending on AR control. Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon (MACVIA-LR [fighting chronic diseases for active and healthy ageing]), one of the reference sites of the European Innovation Partnership on Active and Healthy Ageing, has initiated an allergy sentinel network (the MACVIA-ARIA Sentinel Network). A CDSS is currently being developed to optimize AR control. An algorithm developed by consensus is presented in this article. This algorithm should be confirmed by appropriate trials. AU - Bousquet, J.* AU - Schünemann, H.J.* AU - Hellings, P.W.* AU - Arnavielhe, S.* AU - Bachert, C.* AU - Bedbrook, A.* AU - Bergmann, K.C.* AU - Bosnic-Anticevich, S.* AU - Brozek, J.L.* AU - Calderon, M.* AU - Canonica, G.W.* AU - Casale, T.B.* AU - Chavannes, N.H.* AU - Cox, L.* AU - Chrystyn, H.* AU - Cruz, A.A.* AU - Dahl, R.* AU - de Carlo, G.* AU - Demoly, P.* AU - Devillier, P.* AU - Dray, G.* AU - Fletcher, M.* AU - Fokkens, W.J.* AU - Fonseca, J.* AU - Gonzalez-Diaz, S.N.* AU - Grouse, L.* AU - Keil, T.* AU - Kuna, P.* AU - Larenas-Linnemann, D.* AU - Lodrup Carlsen, K.C.* AU - Meltzer, E.O.* AU - Mullol, J.* AU - Muraro, A.* AU - Naclerio, R.N.* AU - Palkonen, S.* AU - Papadopoulos, N.G.* AU - Passalacqua, G.* AU - Price, D.* AU - Ryan, D.* AU - Samolinski, B.* AU - Scadding, G.K.* AU - Sheikh, A.* AU - Spertini, F.* AU - Valiulis, A.* AU - Valovirta, E.* AU - Walker, S.* AU - Wickman, M.* AU - Yorgancioglu, A.* AU - Haahtela, T.* AU - Zuberbier, T.* AU - MASK Study Group (Heinrich, J.) C1 - 49377 C2 - 41797 SP - 367-374 TI - MACVIA clinical decision algorithm in adolescents and adults with allergic rhinitis. JO - J. Allergy Clin. Immunol. VL - 138 IS - 2 PY - 2016 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Allergen immunotherapy is currently the only disease-modifying treatment available for allergic rhinitis and allergic asthma. OBJECTIVES: We sought to evaluate the induction of sustained tolerance to allergen when anti-IL-4 was combined with a suboptimal course of grass pollen subcutaneous immunotherapy (SCIT) using the allergen-induced skin late-phase response (LPR) and exploratory immune monitoring as surrogate markers of therapeutic response. METHODS: In this randomized, double-blind, 3-group parallel design trial, 37 participants with seasonal allergic rhinitis received suboptimal SCIT (30,000 standardized quality units) in combination with anti-IL-4 (VAK694) and suboptimal SCIT (30,000 standardized quality units) plus placebo antibody or double placebo (placebo SCIT and placebo antibody) restricted to 13 weeks before the grass pollen season. The primary end point was the size of the LPR at 12 months. Exploratory end points included measures of the immunomodulatory activity of treatment by using IL-4 and IL-10 FluoroSpot assays, flow cytometry of T cells, and measurement of IgE, IgG4, and facilitated antigen binding. RESULTS: Both active treatment arms led to a substantial and sustained reduction of the LPR with no additional suppression with addition of anti-IL-4. Treatment with anti-IL-4 and SCIT compared with SCIT alone led to a sustained reduction in allergen-specific IL-4-producing cell counts (P < .01). Both active treatment arms led to induction of dual IL-4/IL-10-producing cells during the pollen season. CONCLUSION: The combination of anti-IL-4 with SCIT provided no additional benefit over SCIT alone in suppressing the allergen-induced skin LPR. A larger trial is needed to assess whether the observed ex vivo downregulation of TH2 responses might translate into clinical benefit. AU - Chaker, A. AU - Shamji, M.H.* AU - Dumitru, F.A.* AU - Calderon, M.A.* AU - Scadding, G.W.* AU - Makatsori, M.* AU - Jones, I.L.* AU - He, Q.A.* AU - Subramanian, K.K.* AU - Arm, J.P.* AU - Durham, S.R.* AU - Schmidt-Weber, C.B. C1 - 47206 C2 - 39155 CY - New York SP - 452-461 TI - Short-term subcutaneous grass pollen immunotherapy under the umbrella of anti-IL-4: A randomized controlled trial. JO - J. Allergy Clin. Immunol. VL - 137 IS - 2 PB - Mosby-elsevier PY - 2016 SN - 0091-6749 ER - TY - JOUR AU - de Schryver, E.* AU - Calus, L.* AU - Bonte, H.* AU - Natalie, R.* AU - Gould, H.* AU - Donovan, E.* AU - Elewaut, D.* AU - Valenta, R.* AU - Mittermann, I.* AU - Gutermuth, J. AU - Seher, T. AU - Schleimer, R.P.* AU - Tan, B.K.* AU - Derycke, L.* AU - van Zele, T.* AU - Bachert, C.* AU - Gevaert, P.* C1 - 48791 C2 - 41336 CY - New York SP - 893-895.e5 TI - The quest for autoreactive antibodies in nasal polyps. JO - J. Allergy Clin. Immunol. VL - 138 IS - 3 PB - Mosby-elsevier PY - 2016 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Children born preterm or with a small size for gestational age are at increased risk for childhood asthma. OBJECTIVE: We sought to assess the hypothesis that these associations are explained by reduced airway patency. METHODS: We used individual participant data of 24,938 children from 24 birth cohorts to examine and meta-analyze the associations of gestational age, size for gestational age, and infant weight gain with childhood lung function and asthma (age range, 3.9-19.1 years). Second, we explored whether these lung function outcomes mediated the associations of early growth characteristics with childhood asthma. RESULTS: Children born with a younger gestational age had a lower FEV1, FEV1/forced vital capacity (FVC) ratio, and forced expiratory volume after exhaling 75% of vital capacity (FEF75), whereas those born with a smaller size for gestational age at birth had a lower FEV1 but higher FEV1/FVC ratio (P < .05). Greater infant weight gain was associated with higher FEV1 but lower FEV1/FVC ratio and FEF75 in childhood (P < .05). All associations were present across the full range and independent of other early-life growth characteristics. Preterm birth, low birth weight, and greater infant weight gain were associated with an increased risk of childhood asthma (pooled odds ratio, 1.34 [95% CI, 1.15-1.57], 1.32 [95% CI, 1.07-1.62], and 1.27 [95% CI, 1.21-1.34], respectively). Mediation analyses suggested that FEV1, FEV1/FVC ratio, and FEF75 might explain 7% (95% CI, 2% to 10%) to 45% (95% CI, 15% to 81%) of the associations between early growth characteristics and asthma. CONCLUSIONS: Younger gestational age, smaller size for gestational age, and greater infant weight gain were across the full ranges associated with childhood lung function. These associations explain the risk of childhood asthma to a substantial extent. AU - den Dekker, H.T.* AU - Sonnenschein-van der Voort, A.M.* AU - de Jongste, J.C.* AU - Anessi-Maesano, I.* AU - Arshad, S.H.* AU - Barros, H.* AU - Beardsmore, C.S.* AU - Bisgaard, H.* AU - Phar, S.C.* AU - Craig, L.* AU - Devereux, G.* AU - van der Ent, C.K.* AU - Esplugues, A.* AU - Fantini, M.P.* AU - Flexeder, C. AU - Frey, U.H.* AU - Forastiere, F.* AU - Gehring, U.* AU - Gori, D.* AU - van der Gugten, A.C.* AU - Henderson, A.J.* AU - Heude, B.* AU - Ibarluzea, J.* AU - Inskip, H.M.* AU - Keil, T.* AU - Kogevinas, M.* AU - Kreiner-Møller, E.* AU - Kuehni, C.E.* AU - Lau, S.* AU - Melén, E.* AU - Mommers, M.* AU - Morales, E.* AU - Penders, J.* AU - Pike, K.C.* AU - Porta, D.* AU - Reiss, I.K.* AU - Roberts, G.* AU - Schmidt, A.* AU - Schultz, E.S.* AU - Schulz, H. AU - Sunyer, J.* AU - Torrent, M.* AU - Vassilaki, M.* AU - Wijga, A.H.* AU - Zabaleta, C.* AU - Jaddoe, V.W.* AU - Duijts, L.* C1 - 47227 C2 - 39355 CY - New York SP - 1026-1035 TI - Early growth characteristics and the risk of reduced lung function and asthma: A meta-analysis of 25,000 children. JO - J. Allergy Clin. Immunol. VL - 137 IS - 4 PB - Mosby-elsevier PY - 2016 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Airway remodeling is a detrimental and refractory process showing age-dependent clinical manifestations, which are mechanistically undefined. The leukotriene (LT) and wingless/ integrase (Wnt) pathways have been implicated in remodeling, but age-specific expression profiles and common regulators remained elusive. OBJECTIVE: We sought to study the activation of the LT and Wnt pathways during early- or late-onset allergic airway inflammation and to address regulatory mechanisms and clinical relevance in normal human bronchial epithelial cells (NHBEs) and nasal polyp tissues. METHODS: Mice were sensitized with house dust mite allergens (HDM) from day 3, 15 or 60 after birth. Remodeling factors in murine bronchoalveolar lavage fluid (BALF), lung or human nasal polyp tissues were analyzed by westernblot, immunoassays or histology. Regulatory mechanisms were studied in cytokine/HDM- stimulated NHBEs and macrophages. RESULTS: BALF LT levels were increased in neonatal and adult, but reduced in juvenile HDM-sensitized mice. Lungs of neonatally-sensitized mice showed increased 5-lipoxygenase levels, whilst adult mice expressed more secretory phospholipase A2 (sPLA2-X), Wnt5a and transglutaminase 2 (TGM2). Older mice showed co-localization of Wnt5a and LT enzymes in the epithelium, a pattern also observed in human nasal polyps. IL-4 promoted epithelial Wnt5a secretion, which upregulated macrophage TGM2 expression and TGM2 inhibition in turn reduced LT release. TGM2, sPLA2-X and LT enzymes in NHBEs and nasal polyps were refractory to corticosteroids. CONCLUSION: Our findings reveal age differences in LT and Wnt pathways during airway inflammation and identify a steroid-resistant cascade of Wnt5a, TGM2 and LTs, which may represent a therapeutic target for airway inflammation and remodeling. AU - Dietz, K. AU - de los Reyes Jimenez, M. AU - Gollwitzer, E.S.* AU - Chaker, A. AU - Zissler, U.M. AU - Rådmark, O.P.* AU - Baarsma, H.A. AU - Königshoff, M. AU - Schmidt-Weber, C.B. AU - Marsland, B.J.* AU - Esser-von Bieren, J. C1 - 49321 C2 - 41735 CY - New York SP - 1343-1354.e6 TI - Age dictates a steroid resistant cascade of Wnt5a, transglutaminase-2 and leukotrienes in inflamed airways. JO - J. Allergy Clin. Immunol. VL - 139 IS - 4 PB - Mosby-elsevier PY - 2016 SN - 0091-6749 ER - TY - JOUR AU - Krause, L. AU - Mourantchanian, V.* AU - Brockow, K.* AU - Theis, F.J. AU - Schmidt-Weber, C.B. AU - Knapp, B. AU - Müller, N.S. AU - Eyerich, S. C1 - 48606 C2 - 41196 CY - New York SP - 1207-1210.e2 TI - A computational model to predict severity of atopic eczema from 30 serum proteins. JO - J. Allergy Clin. Immunol. VL - 138 IS - 4 PB - Mosby-elsevier PY - 2016 SN - 0091-6749 ER - TY - JOUR AU - Krause, L. AU - Müller, N.S. AU - Eyerich, S. C1 - 49924 C2 - 41902 CY - New York SP - 1065-1066 TI - Reply. JO - J. Allergy Clin. Immunol. VL - 139 IS - 3 PB - Mosby-elsevier PY - 2016 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Asthma is a disease affecting more boys than girls in childhood and more women than men in adulthood. The mechanisms behind these sex-specific differences are not yet understood. OBJECTIVE: We analyzed whether and how genetic factors contribute to sex-specific predisposition to childhood-onset asthma. METHODS: Interactions between sex and polymorphisms on childhood asthma risk were evaluated in the Multicentre Asthma Genetics in Childhood Study (MAGICS)/Phase II International Study of Asthma and Allergies in Childhood (ISAAC II) population on a genome-wide level, and findings were validated in independent populations. Genetic fine mapping of sex-specific asthma association signals was performed, and putatively causal polymorphisms were characterized in vitro by using electrophoretic mobility shift and luciferase activity assays. Gene and protein expression of the identified gene doublesex and mab-3 related transcription factor 1 (DMRT1) were measured in different human tissues by using quantitative real-time PCR and immunohistochemistry. RESULTS: Polymorphisms in the testis-associated gene DMRT1 displayed interactions with sex on asthma status in a population of primarily clinically defined asthmatic children and nonasthmatic control subjects (lowest P = 5.21 × 10(-6)). Replication of this interaction was successful in 2 childhood populations clinically assessed for asthma but showed heterogeneous results in other population-based samples. Polymorphism rs3812523 located in the putative DMRT1 promoter was associated with allele-specific changes in transcription factor binding and promoter activity in vitro. DMRT1 expression was observed not only in the testis but also in lung macrophages. CONCLUSION: DMRT1 might influence sex-specific patterns of childhood asthma, and its expression in testis tissue and lung macrophages suggests a potential involvement in hormone or immune cell regulation. AU - Schieck, M.* AU - Schouten, J.P.* AU - Michel, S.* AU - Suttner, K. AU - Toncheva, A.A.* AU - Gaertner, V.D.* AU - Illig, T. AU - Lipinski, S.* AU - Franke, A.* AU - Klintschar, M.* AU - Kalayci, O.* AU - Sahiner, U.M.* AU - Birben, E.* AU - Melén, E.* AU - Pershagen, G.* AU - Freidin, M.B.* AU - Ogorodova, L.M.* AU - Granell, R.* AU - Henderson, J.* AU - Brunekreef, B.* AU - Smit, H.A.* AU - Vogelberg, C.* AU - von Berg, A.* AU - Bufe, A.* AU - Heinzmann, A.* AU - Laub, O.* AU - Rietschel, E.* AU - Simma, B.* AU - Genuneit, J.* AU - Jonigk, D.* AU - Postma, D.S.* AU - Koppelman, G.H.* AU - Vonk, J.M.* AU - Timens, W.* AU - Boezen, H.M.* AU - Kabesch, M.* C1 - 47975 C2 - 39806 CY - New York SP - 421-431 TI - Doublesex and Mab-3 Related Transcription factor 1 (DMRT1) is a sex-specific genetic determinant of childhood-onset asthma and is expressed in testis and macrophages. JO - J. Allergy Clin. Immunol. VL - 138 IS - 2 PB - Mosby-elsevier PY - 2016 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Atopic dermatitis (AD) is characterized by epidermal barrier failure and immune-mediated inflammation. Evidence on AD as a potential risk factor for inflammatory comorbidities is scarce. OBJECTIVES: We sought to test the hypothesis that prevalent AD is a risk factor for incident rheumatoid arthritis (RA) and inflammatory bowel disease (IBD; Crohn disease [CD], ulcerative colitis [UC]) and is inversely related to type 1 diabetes (T1D) and to investigate established RA, IBD, and T1D susceptibility loci in AD. METHODS: This cohort study used data from German National Health Insurance beneficiaries aged 40 years or younger (n = 655,815) from 2005 through 2011. Prevalent AD in the period 2005 to 2006 was defined as primary exposure, and incident RA, IBD, and T1D in the period 2007 to 2011 were defined as primary outcomes. Risk ratios were calculated with generalized linear models. Established RA, IBD, and T1D loci were explored in high-density genotyping data from 2,425 cases with AD and 5,449 controls. RESULTS: Patients with AD (n = 49,847) were at increased risk for incident RA (risk ratio [RR], 1.72; 95% CI, 1.25-2.37) and/or IBD (CD: RR, 1.34; 95% CI, 1.11-1.61; UC: RR, 1.25; 95% CI, 1.03-1.53). After adjusting for health care utilization, there was a nominally significant inverse effect on T1D risk (RR, 0.72; 95% CI, 0.53-0.998). There was no disproportionate occurrence of known RA, CD, UC, or T1D risk alleles in AD. CONCLUSIONS: AD is a risk factor for the development of RA and IBD. This excess comorbidity cannot be attributed to major known IBD and RA genetic risk factors. AU - Schmitt, J.* AU - Schwarz, K.* AU - Baurecht, H.* AU - Hotze, M.* AU - Fölster-Holst, R.* AU - Rodriguez, E.* AU - Lee, Y.A.* AU - Franke, A.* AU - Degenhardt, F.* AU - Lieb, W.* AU - Gieger, C. AU - Kabesch, M.* AU - Nöthen, M.M.* AU - Irvine, A.D.* AU - McLean, W.H.* AU - Deckert, S.* AU - Stephan, V.* AU - Schwarz, P.* AU - Aringer, M.* AU - Novak, N.* AU - Weidinger, S.* C1 - 46550 C2 - 37712 SP - 130–136 TI - Atopic dermatitis is associated with an increased risk for rheumatoid arthritis and inflammatory bowel disease, and a decreased risk for type 1 diabetes. JO - J. Allergy Clin. Immunol. VL - 137 IS - 1 PY - 2016 SN - 0091-6749 ER - TY - JOUR AB - Atopic dermatitis (AD) is a complex skin disease frequently associated with other diseases of the atopic diathesis. Recent evidence supports the concept that AD can also recognize other comorbidities, such as chronic inflammatory bowel or cardiovascular diseases. These comorbidities might result from chronic cutaneous inflammation or from a common, yet-to-be-defined immunologic background leading to immune deviations. The activation of immune cells and their migration to the skin play an essential role in the pathogenesis of AD. In patients with AD, an underlying immune deviation might result in higher susceptibility of the skin to environmental factors. There is a high unmet medical need to define immunologic endotypes of AD because it has significant implications on upcoming stratification of the phenotype of AD and the resulting targeted therapies in the development of precision medicine. This review article emphasizes studies on environmental factors affecting AD development and novel biological agents used in the treatment of AD. Best evidence of the clinical efficacy of novel immunologic approaches using biological agents in patients with AD is available for the anti-IL-4 receptor α-chain antibody dupilumab, but a number of studies are currently ongoing with other specific antagonists to immune system players. These targeted molecules can be expressed on or drive the cellular players infiltrating the skin (eg, T lymphocytes, dendritic cells, or eosinophils). Such approaches can have immunomodulatory and thereby beneficial clinical effects on the overall skin condition, as well as on the underlying immune deviation that might play a role in comorbidities. An effect of these immunologic treatments on pruritus and the disturbed microbiome in patients with AD has other potential consequences for treatment. AU - Werfel, T.* AU - Allam, J.P.* AU - Biedermann, T.* AU - Eyerich, K.* AU - Gilles, S. AU - Guttman-Yassky, E.* AU - Hoetzenecker, W.* AU - Knol, E.* AU - Simon, H.U.* AU - Wollenberg, A.* AU - Bieber, T.* AU - Lauener, R.* AU - Schmid-Grendelmeier, P.* AU - Traidl-Hoffmann, C. AU - Akdis, C.A.* C1 - 49239 C2 - 33670 CY - New York SP - 336-349 TI - Cellular and molecular immunologic mechanisms in patients with atopic dermatitis. JO - J. Allergy Clin. Immunol. VL - 138 IS - 2 PB - Mosby-elsevier PY - 2016 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Allergies to grass pollen are the number one cause of outdoor hay fever. The human immune system reacts with symptoms to allergen from pollen. OBJECTIVE: We investigated the natural variability in release of the major group 5 allergen from grass pollen across Europe. METHODS: Airborne pollen and allergens were simultaneously collected daily with a volumetric spore trap and a high-volume cascade impactor at 10 sites across Europe for 3 consecutive years. Group 5 allergen levels were determined with a Phl p 5-specific ELISA in 2 fractions of ambient air: particulate matter of greater than 10 μm in diameter and particulate matter greater than 2.5 μm and less than 10 μm in diameter. Mediator release by ambient air was determined in FcεRI-humanized basophils. The origin of pollen was modeled and condensed to pollen potency maps. RESULTS: On average, grass pollen released 2.3 pg of Phl p 5 per pollen. Allergen release per pollen (potency) varied substantially, ranging from less than 1 to 9 pg of Phl p 5 per pollen (5% to 95% percentile). The main variation was locally day to day. Average potency maps across Europe varied between years. Mediator release from basophilic granulocytes correlated better with allergen levels per cubic meter (r(2) = 0.80, P < .001) than with pollen grains per cubic meter (r(2) = 0.61, P < .001). In addition, pollen released different amounts of allergen in the non-pollen-bearing fraction of ambient air, depending on humidity. CONCLUSION: Across Europe, the same amount of pollen released substantially different amounts of group 5 grass pollen allergen. This variation in allergen release is in addition to variations in pollen counts. Molecular aerobiology (ie, determining allergen in ambient air) might be a valuable addition to pollen counting. AU - Buters, J.T.M. AU - Prank, M.* AU - Sofiev, M.* AU - Pusch, G. AU - Albertini, R.* AU - Annesi-Maesano, I.* AU - Antunes, C.* AU - Behrendt, H. AU - Berger, U.* AU - Brandao, R.* AU - Celenk, S.* AU - Galan, C.* AU - Grewling, L.* AU - Jackowiak, B.* AU - Kennedy, R.* AU - Rantio-Lehtimaki, A.* AU - Reese, G.* AU - Sauliene, I.* AU - Smith, M.* AU - Thibaudon, M.* AU - Weber, B.* AU - Cecchi, L.* C1 - 44814 C2 - 37060 CY - New York SP - 87-95 TI - Variation of the group 5 grass pollen allergen content of airborne pollen in relation to geographic location and time in season. JO - J. Allergy Clin. Immunol. VL - 136 IS - 1 PB - Mosby-elsevier PY - 2015 SN - 0091-6749 ER - TY - JOUR AU - Fuertes, E. AU - Söderhäll, C.* AU - Acevedo, N.* AU - Becker, A.* AU - Brauer, M.* AU - Chan-Yeung, M.* AU - Dijk, N.F.* AU - Heinrich, J. AU - de Jongste, J.* AU - Koppelman, G.H.* AU - Postma, D.S.* AU - Kere, J.* AU - Kozyrskyj, A.L.* AU - Pershagen, G.* AU - Sandford, A.J.* AU - Standl, M. AU - Tiesler, C.M. AU - Waldenberger, M. AU - Westman, M.* AU - Carlsten, C.* AU - Melén, E.* C1 - 32406 C2 - 35028 CY - New York SP - 573-576 TI - Associations between the 17q21 region and allergic rhinitis in 5 birth cohorts. JO - J. Allergy Clin. Immunol. VL - 135 IS - 2 PB - Mosby-elsevier PY - 2015 SN - 0091-6749 ER - TY - JOUR AB - Background: Breast-feeding is protective against respiratory infections in early life. Given the co-evolutionary adaptations of humans and cattle, bovine milk might exert similar anti-infective effects in human infants. Objective: To study effects of consumption of raw and processed cow's milk on common infections in infants. Methods: The PASTURE birth cohort followed 983 infants from rural areas in Austria, Finland, France, Germany, and Switzerland, for the first year of life, covering 37,306 person-weeks. Consumption of different types of cow's milk and occurrence of rhinitis, respiratory tract infections, otitis, and fever were assessed by weekly health diaries. C-reactive protein levels were assessed using blood samples taken at 12 months. Results: When contrasted with ultra-heat treated milk, raw milk consumption was inversely associated with occurrence of rhinitis (adjusted odds ratio from longitudinal models [95% CI]: 0.71 [0.54-0.94]), respiratory tract infections (0.77 [0.59-0.99]), otitis (0.14 [0.05-0.42]), and fever (0.69 [0.47-1.01]). Boiled farm milk showed similar but weaker associations. Industrially processed pasteurized milk was inversely associated with fever. Raw farm milk consumption was inversely associated with C-reactive protein levels at 12 months (geometric means ratio [95% CI]: 0.66 [0.45-0.98]). Conclusions: Early life consumption of raw cow's milk reduced the risk of manifest respiratory infections and fever by about 30%. If the health hazards of raw milk could be overcome, the public health impact of minimally processed but pathogen-free milk might be enormous, given the high prevalence of respiratory infections in the first year of life and the associated direct and indirect costs. AU - Loss, G.* AU - Depner, M.* AU - Ulfman, L.H.* AU - van Neerven, R.J.* AU - Hose, A.J.* AU - Genuneit, J.* AU - Karvonen, A.M.* AU - Hyvärinen, A.* AU - Kaulek, V.* AU - Roduit, C.* AU - Weber, J.* AU - Lauener, R.* AU - Pfefferle, P.I.* AU - Pekkanen, J.* AU - Vaarala, O.* AU - Dalphin, J.-C.* AU - Riedler, J.* AU - Braun-Fahrländer, C.* AU - von Mutius, E. AU - Ege, M.J. C1 - 43240 C2 - 36289 CY - New York SP - 56-62 TI - Consumption of unprocessed cow's milk protects infants from common respiratory infections. JO - J. Allergy Clin. Immunol. VL - 135 IS - 1 PB - Mosby-elsevier PY - 2015 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Childhood asthma is classified into allergic asthma (AA) and nonallergic asthma (NA), yet both are treated identically, with only partial success. OBJECTIVE: We sought to identify novel immune phenotypes for childhood AA and NA. METHODS: The Clinical Asthma Research Association cohort study includes 275 steroid-naive 4- to 15-year-old German children (healthy control subjects [HCs], patients with AA, and patients with NA). In PBMCs both quantitative and functional analysis of regulatory T (Treg) and TH17 cells (flow cytometry/Treg cell suppression) before/after anti-CD3/CD28, lipid A, and peptidoglycan stimulation were performed. Cytokines and gene expression, as assessed by using Luminex or transcriptomics/quantitative real-time RT-PCR, were analyzed by means of regression analysis. Linear discriminant analysis was applied to discriminate between phenotypes. RESULTS: The 3 phenotypes were immunologically well discriminated by means of microarray and protein analysis with linear discriminant analysis. Patients with AA were characterized by increased Treg cells compared with those in HCs but not those in patients with NA. Treg cells from patients with AA, but not patients with NA, significantly suppressed IL-5, IL-13, and IFN-γ secretion. Patients with AA had decreased expression of chloride intracellular channel 4 (CLIC4) and tuberous sclerosis 1 (TSC1), important innate immunity regulators. Patients with NA were characterized by increased proinflammatory IL-1β levels, neutrophil counts, and IL-17-shifted immunity. In parallel, expressions of anti-inflammatory IL37, proline-serine-threonine phosphatase-interacting protein 2 (PSTPIP2), and the neutrophil-associated genes CD93, triggering receptor expressed on myeloid cells 1 (TREM1), and regulator of G-protein signaling 13 (RGS13) were increased in patients with NA. A shared TH2 immunity was present in both asthma phenotypes. CONCLUSION: Novel immune-regulatory mechanisms in childhood asthma identified increased Treg cells in patients with AA compared with those in HCs but not those in NA and decreased innate immunity genes for patients with AA, the first potentially indicating a counterregulatory mechanism to suppress cytokines yet not sufficient to control allergic inflammation. Very distinctly, patients with NA showed an IL-17-shifted proinflammatory immunity, promoting neutrophil inflammation and less functional Treg cells. Identification of these unique pathways provides a profound basis for future strategies for individualized prediction of asthma development, disease course, and prevention. AU - Rädler, D.* AU - Ballenberger, N.* AU - Klucker, E.* AU - Böck, A.* AU - Otto, R.* AU - Prazeres da Costa, O.* AU - Holst, O.* AU - Illig, T. AU - Buch, T.* AU - von Mutius, E.* AU - Schaub, B.* C1 - 32230 C2 - 34981 CY - New York SP - 81-91 TI - Identification of novel immune phenotypes for allergic and nonallergic childhood asthma. JO - J. Allergy Clin. Immunol. VL - 135 IS - 1 PB - Mosby-elsevier PY - 2015 SN - 0091-6749 ER - TY - JOUR AU - Schaarschmidt, H.* AU - Ellinghaus, D.* AU - Rodriguez, E.* AU - Kretschmer, A. AU - Baurecht, H.* AU - Lipinski, S.* AU - Meyer-Hoffert, U.* AU - Harder, J.* AU - Lieb, W.* AU - Novak, N.* AU - Fölster-Holst, R.* AU - Esparza-Gordillo, J.* AU - Marenholz, I.* AU - Ruschendorf, F.* AU - Hubner, N.* AU - Reischl, E. AU - Waldenberger, M. AU - Gieger, C. AU - Illig, T.* AU - Kabesch, M.* AU - Zhang, X.J.* AU - Xiao, F.L.* AU - Lee, Y.A.* AU - Franke, A.* AU - Weidinger, S.* C1 - 44373 C2 - 36824 SP - 802-806 TI - A genome-wide association study reveals 2 new susceptibility loci for atopic dermatitis.ϖ JO - J. Allergy Clin. Immunol. VL - 136 IS - 3 PY - 2015 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Chromosome 17q21, harboring the orosomucoid 1-like 3 (ORMDL3) gene, has been consistently associated with childhood asthma in genome-wide association studies. OBJECTIVE: We investigated genetic variants in and around ORMDL3 that can change the function of ORMDL3 and thus contribute to asthma susceptibility. METHODS: We performed haplotype analyses and fine mapping of the ORMDL3 locus in a cross-sectional (International Study of Asthma and Allergies in Childhood Phase II, n = 3557 total subjects, n = 281 asthmatic patients) and case-control (Multicenter Asthma Genetics in Childhood Study/International Study of Asthma and Allergies in Childhood Phase II, n = 1446 total subjects, n = 763 asthmatic patients) data set to identify putative causal single nucleotide polymorphisms (SNPs) in the locus. Top asthma-associated polymorphisms were analyzed for allele-specific effects on transcription factor binding and promoter activity in vitro and gene expression in PBMCs after stimulation ex vivo. RESULTS: Two haplotypes (H1 and H2) were significantly associated with asthma in the cross-sectional (P = 9.9 × 10(-5) and P = .0035, respectively) and case-control (P = 3.15 × 10(-8) and P = .0021, respectively) populations. Polymorphisms rs8076131 and rs4065275 were identified to drive these effects. For rs4065275, a quantitative difference in transcription factor binding was found, whereas for rs8076131, changes in upstream stimulatory factor 1 and 2 transcription factor binding were observed in vitro by using different cell lines and PBMCs. This might contribute to detected alterations in luciferase activity paralleled with changes in ORMDL3 gene expression and IL-4 and IL-13 cytokine levels ex vivo in response to innate and adaptive stimuli in an allele-specific manner. Both SNPs were in strong linkage disequilibrium with asthma-associated 17q21 SNPs previously related to altered ORMDL3 gene expression. CONCLUSION: Polymorphisms in a putative promoter region of ORMDL3, which are associated with childhood asthma, alter transcriptional regulation of ORMDL3, correlate with changes in TH2 cytokines levels, and therefore might contribute to the childhood asthma susceptibility signal from 17q21. AU - Schedel, M.* AU - Michel, S.* AU - Gaertner, V.D.* AU - Toncheva, A.A.* AU - Depner, M.* AU - Binia, A.* AU - Schieck, M.* AU - Rieger, M.T.* AU - Klopp, N. AU - von Berg, A.* AU - Bufe, A.* AU - Laub, O.* AU - Rietschel, E.* AU - Heinzmann, A.* AU - Simma, B.* AU - Vogelberg, C.* AU - Genuneit, J.* AU - Illig, T. AU - Kabesch, M.* C1 - 44573 C2 - 37011 SP - 893-903 TI - Polymorphisms related to ORMDL3 are associated with asthma susceptibility, alterations in transcriptional regulation of ORMDL3, and changes in TH2 cytokine levels. JO - J. Allergy Clin. Immunol. VL - 136 IS - 4 PY - 2015 SN - 0091-6749 ER - TY - JOUR AB - Population-based birth cohorts on asthma and allergies increasingly provide new insights into the development and natural history of the diseases. More than 130 birth cohorts focusing on asthma and allergy have been initiated in the last 30 years. A National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; Mechanisms of the Development of Allergy (MeDALL; Framework Programme 7 of the European Commission) joint workshop was held in Bethesda, Maryland, on September 11-12, 2012, with 3 objectives: (1) documenting the knowledge that asthma/allergy birth cohorts have provided, (2) identifying the knowledge gaps and inconsistencies, and (3) developing strategies for moving forward, including potential new study designs and the harmonization of existing asthma birth cohort data. The meeting was organized around the presentations of 5 distinct workgroups: (1) clinical phenotypes, (2) risk factors, (3) immune development of asthma and allergy, (4) pulmonary development, and (5) harmonization of existing birth cohorts. This article presents the workgroup reports and provides Web links (AsthmaBirthCohorts.niaid.nih.gov or www.medall-fp7.eu), where the reader will find tables describing the characteristics of the birth cohorts included in this report, the type of data collected at differing ages, and a selected bibliography provided by the participating birth cohorts. AU - Bousquet, J.* AU - Gern, J.E.* AU - Martinez, F.D.* AU - Antò, J.M.* AU - Johnson, C.C.* AU - Holt, P.G.* AU - Lemanske Jr., R.F.* AU - Le Souëf, P.N.* AU - Tepper, R.S.* AU - von Mutius, E.* AU - Arshad, S.H.* AU - Bacharier, L.B.* AU - Becker, A.* AU - Belanger, K.* AU - Bergström, A.* AU - Bernstein, D.I.* AU - Cabana, M.D.* AU - Carroll, K.N.* AU - Castro, M.* AU - Cooper, P.J.* AU - Gillman, M.W.* AU - Gold, D.R.* AU - Henderson, J.* AU - Heinrich, J. AU - Hong, S.-J.* AU - Jackson, D.J.* AU - Keil, T.* AU - Kozyrskyj, A.L.* AU - Carlsen, K.L.* AU - Miller, R.L.* AU - Momas, I.* AU - Morgan, W.J.* AU - Noel, P.* AU - Ownby, D.R.* AU - Pinart, M.* AU - Ryan, P.H.* AU - Schwaninger, J.M.* AU - Sears, M.R.* AU - Simpson, A.* AU - Smit, H.A.* AU - Stern, D.A.* AU - Subbarao, P.* AU - Valenta, R.* AU - Wang, X.* AU - Weiss, S.T.* AU - Wood, R.D.* AU - Wright, A.L.* AU - Wright, R.J.* AU - Togias, A.* AU - Gergen, P.J.* C1 - 30803 C2 - 33973 CY - New York SP - 1535-1546 TI - Birth cohorts in asthma and allergic diseases: Report of a NIAID/NHLBI/MeDALL joint workshop. JO - J. Allergy Clin. Immunol. VL - 133 IS - 6 PB - Mosby-elsevier PY - 2014 SN - 0091-6749 ER - TY - JOUR AU - Cifuentes, L.* AU - Blank, S. AU - Pennino, D.* AU - Michel, J.* AU - Darsow, U.* AU - Ring, J.* AU - Ollert, M.* C1 - 31933 C2 - 34899 CY - New York SP - 494-495 TI - Reply. JO - J. Allergy Clin. Immunol. VL - 134 IS - 2 PB - Mosby-elsevier PY - 2014 SN - 0091-6749 ER - TY - JOUR AB - Background Evidence on the long-term effects of air pollution exposure on childhood allergy is limited. Objective We investigated the association between air pollution exposure and allergic sensitization to common allergens in children followed prospectively during the first 10 years of life. Methods Five European birth cohorts participating in the European Study of Cohorts for Air Pollution Effects project were included: BAMSE (Sweden), LISAplus and GINIplus (Germany), MAAS (Great Britain), and PIAMA (The Netherlands). Land-use regression models were applied to assess the individual residential outdoor levels of particulate matter with an aerodynamic diameter of less than 2.5 μm (PM2.5), the mass concentration of particles between 2.5 and 10 μm in size, and levels of particulate matter with an aerodynamic diameter of less than 10 μm (PM10), as well as measurement of the blackness of PM2.5 filters and nitrogen dioxide and nitrogen oxide levels. Blood samples drawn at 4 to 6 years of age, 8 to 10 years of age, or both from more than 6500 children were analyzed for allergen-specific serum IgE against common allergens. Associations were assessed by using multiple logistic regression and subsequent meta-analysis. Results The prevalence of sensitization to any common allergen within the 5 cohorts ranged between 24.1% and 40.4% at the age of 4 to 6 years and between 34.8% and 47.9% at the age of 8 to 10 years. Overall, air pollution exposure was not associated with sensitization to any common allergen, with odds ratios ranging from 0.94 (95% CI, 0.63-1.40) for a 1 × 10 -5 â̂™ m-1 increase in measurement of the blackness of PM2.5 filters to 1.26 (95% CI, 0.90-1.77) for a 5 μg/m3 increase in PM2.5 exposure at birth address. Further analyses did not provide consistent evidence for a modification of the air pollution effects by sex, family history of atopy, or moving status. Conclusion No clear associations between air pollution exposure and development of allergic sensitization in children up to 10 years of age were revealed. AU - Gruzieva, O.* AU - Gehring, U.* AU - Aalberse, R.* AU - Agius, R.M.* AU - Beelen, R.* AU - Behrendt, H. AU - Bellander, T.* AU - Birk, M. AU - de Jongste, J.C.* AU - Fuertes, E. AU - Heinrich, J. AU - Hoek, G.* AU - Klümper, C.* AU - Koppelman, G.* AU - Korek, M.* AU - Krämer, U.* AU - Lindley, S.* AU - Mölter, A.* AU - Simpson, A.* AU - Standl, M. AU - van Hage, M.* AU - von Berg, A.* AU - Wijga, A.* AU - Brunekreef, B.* AU - Pershagen, G.* C1 - 30781 C2 - 33862 CY - New York SP - 767-776 TI - Meta-analysis of air pollution exposure association with allergic sensitization in European birth cohorts. JO - J. Allergy Clin. Immunol. VL - 133 IS - 3 PB - Mosby-elsevier PY - 2014 SN - 0091-6749 ER - TY - JOUR AB - Background Previous studies suggested that maternal farm exposure during pregnancy modulates early immune development toward an allergy-protective status potentially mediated by TH1 or regulatory T (Treg) cells. However, the underlying mechanisms might involve immune modulation of additional T-cell populations, such as TH17 cells, influenced by genetic predisposition. Objective We examined the role of maternal farm exposure and genetic predisposition on TH17 cell responses to innate and adaptive immune stimulation in cord blood. Methods Eighty-four pregnant mothers were recruited before delivery. Detailed questionnaires (60 nonfarming mother, 22 farming mothers, and 2 exclusions) assessed farming exposures. Cord blood was stimulated with lipid A, peptidoglycan (Ppg), or PHA. TH17 lineage (retinoic acid receptor-related orphan receptor C [RORC], retinoic acid receptor-related orphan receptor α [RORA], IL-23 receptor [IL23R], IL17, IL17F, and IL22) and Treg cell markers (forkhead box protein 3 [FOXP3], lymphocyte activation gene 3 [LAG3], and glucocorticoid-induced TNF receptor [GITR]) were assessed at the mRNA level. TH17/Treg/T H1/TH2 cytokines and 7 single nucleotide polymorphisms within the TH17 lineage (RORC, IL23R, and IL17) were examined. Results TH17 lineage mRNA markers were expressed at birth at low concentrations independent of maternal farm exposure. A positive correlation between TH17 lineage markers and FOXP3 (mRNA) was observed on stimulation (nonfarming mothers: lipid A, Ppg, and PHA; farming mothers: Ppg and PHA), influenced by maternal farming. Specific single nucleotide polymorphisms within the TH17 lineage genes influenced gene expression of T H17 and Treg cell markers and cytokine secretion. Conclusions Gene expression of TH17 lineage markers in cord blood was not influenced by maternal farming. Yet TH17 and Treg cell markers were positively correlated and influenced by maternal farm exposure. Our data suggest that prenatal exposures and genetic predisposition play a role during early T H17 immune maturation, potentially regulating the development of immune-mediated diseases, such as childhood asthma. AU - Lluis, A.* AU - Ballenberger, N.* AU - Illi, S.* AU - Schieck, M.* AU - Kabesch, M.* AU - Illig, T. AU - Schleich, I.* AU - von Mutius, E.* AU - Schaub, B.* C1 - 30780 C2 - 33863 CY - New York SP - 864-871 TI - Regulation of TH17 markers early in life through maternal farm exposure. JO - J. Allergy Clin. Immunol. VL - 133 IS - 3 PB - Mosby-elsevier PY - 2014 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Evidence on the longitudinal association of airway responsiveness with respiratory diseases is scarce. The best indicator of responsiveness is still undetermined. OBJECTIVE: We investigated the association of airway responsiveness with the incidence of asthma, chronic obstructive pulmonary disease (COPD), and allergic rhinitis. METHODS: We studied 3851 subjects who underwent spirometry and methacholine challenge tests both at baseline (1991-1993), when they were 20 to 44 years old, and at follow-up (1999-2002) in the European Community Respiratory Health Survey. Airway responsiveness was defined based on the methacholine dose-response slope on both occasions. Incidence rate ratios for the association of airway responsiveness with disease occurrence were computed by using Poisson regression. RESULTS: With respect to reference (slope of the fourth quintile or greater), subjects with the greatest degree of airway responsiveness (slope less than the first quintile) showed the greatest risk of developing asthma, COPD, and allergic rhinitis (incidence rate ratios of 10.82, 5.53, and 4.84, respectively; all P < .01). A low slope predicted disease occurrence, even in subjects who did not reach a 20% decrease in FEV1 at the cumulative dose of 1 mg of methacholine (PD20 >1 mg). A decrease in slope over time was an independent predictor of disease risk. CONCLUSION: Airway responsiveness predicted new-onset asthma, COPD, and allergic rhinitis. Our study supports the use of a continuous noncensored indicator of airway responsiveness, such as the slope of the methacholine dose-response curve, in clinical practice and research because it showed clear advantages over PD20. AU - Marcon, A.* AU - Cerveri, I.* AU - Wjst, M. AU - Anto, J.* AU - Heinrich, J. AU - Janson, C.* AU - Jarvis, D.* AU - Leynaert, B.* AU - Probst-Hensch, N.* AU - Svanes, C.* AU - Torén, K.* AU - Burney, P.* AU - de Marco, R.* C1 - 26180 C2 - 32109 SP - 104-110 TI - Can an airway challenge test predict respiratory diseases? A population-based international study. JO - J. Allergy Clin. Immunol. VL - 133 IS - 1 PB - Mosby-Elsevier PY - 2014 SN - 0091-6749 ER - TY - JOUR AU - Schieck, M.* AU - Michel, S.* AU - Suttner, K. AU - Illig, T. AU - Zeilinger, S. AU - Franke, A.* AU - von Berg, A.* AU - Bufe, A.* AU - Heinzmann, A.* AU - Laub, O.* AU - Rietschel, E.* AU - Frischer, T.* AU - Genuneit, J.* AU - Kerzel, S.* AU - Kabesch, M.* C1 - 28244 C2 - 33028 CY - New York SP - 888-891 TI - Genetic variation in TH17 pathway genes, childhood asthma, and total serum IgE levels. JO - J. Allergy Clin. Immunol. VL - 133 IS - 3 PB - Mosby-Elsevier PY - 2014 SN - 0091-6749 ER - TY - JOUR AU - Scholtens, S.* AU - Postma, D.S.* AU - Moffatt, M.F.* AU - Panasevich, S.* AU - Granell, R.* AU - Henderson, A.J.* AU - Melén, E.* AU - Nyberg, F.* AU - Pershagen, G.* AU - Jarvis, D.* AU - Ramasamy, A.* AU - Wjst, M. AU - Svanes, C.* AU - Bouzigon, E.* AU - Demenais, F.* AU - Kauffmann, F.* AU - Siroux, V.* AU - von Mutius, E.* AU - Ege, M.J.* AU - Braun-Fahrländer, C.* AU - Genuneit, J.* AU - GABRIELA Study Group (*) AU - Brunekreef, B.* AU - Smit, H.A.* AU - Wijga, A.H.* AU - Kerkhof, M.* AU - Curjuric, I.* AU - Imboden, M.* AU - Thun, G.A.* AU - Probst-Hensch, N.* AU - Freidin, M.B.* AU - Bragina, E.I.* AU - Deev, I.A.* AU - Puzyrev, V.P.* AU - Daley, D.* AU - Park, J.* AU - Becker, A.* AU - Chan-Yeung, M.* AU - Kozyrskyj, A.L.* AU - Pare, P.* AU - Marenholn, I.* AU - Lau, S.* AU - Keil, T.* AU - Lee, Y.A.* AU - Kabesch, M.* AU - Wijmenga, C.* AU - Franke, L.* AU - Nolte, I.M.* AU - Vonk, J.M.* AU - Kumar, A.* AU - Farrall, M.* AU - Cookson, W.O.* AU - Strachan, D.P.* AU - Koppelman, G.H.* AU - Boezen, H.M.* C1 - 28637 C2 - 33509 CY - New York SP - 885-888 TI - Novel childhood asthma genes interact with in utero and early-life tobacco smoke exposure. JO - J. Allergy Clin. Immunol. VL - 133 IS - 3 PB - Mosby-Elsevier PY - 2014 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: The fraction of exhaled nitric oxide (Feno) value is a biomarker of eosinophilic airway inflammation and is associated with childhood asthma. Identification of common genetic variants associated with childhood Feno values might help to define biological mechanisms related to specific asthma phenotypes. OBJECTIVE: We sought to identify the genetic variants associated with childhood Feno values and their relation with asthma. METHODS: Feno values were measured in children age 5 to 15 years. In 14 genome-wide association studies (N = 8,858), we examined the associations of approximately 2.5 million single nucleotide polymorphisms (SNPs) with Feno values. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci in genome-wide expression data sets of lymphoblastoid cell lines (n = 1,830) and were related to asthma in a previously published genome-wide association data set (cases, n = 10,365; control subjects: n = 16,110). RESULTS: We identified 3 SNPs associated with Feno values: rs3751972 in LYR motif containing 9 (LYRM9; P = 1.97 × 10-10) and rs944722 in inducible nitric oxide synthase 2 (NOS2; P = 1.28 × 10-9), both of which are located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB; P = 1.88 × 10-8) at 17q12-q21. We found a cis expression quantitative trait locus for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. rs8069176 at 17q12-q21, but not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma. CONCLUSION: This study identified 3 variants associated with Feno values, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight into the regulation of Feno values. This study highlights that both shared and distinct genetic factors affect Feno values and childhood asthma. AU - van der Valk, R.J.* AU - Duijts, L.* AU - Timpson, N.J.* AU - Salam, M.T.* AU - Standl, M. AU - Curtin, J.A.* AU - Genuneit, J.* AU - Kerhof, M.* AU - Kreiner-Møller, E.* AU - Cáceres, A.* AU - Gref, A.* AU - Liang, L.L.* AU - Taal, H.R.* AU - Bouzigon, E.* AU - Demenais, F.* AU - Nadif, R.* AU - Ober, C.* AU - Thompson, E.E.* AU - Estrada, K.* AU - Hofman, A.* AU - Uitterlinden, A.G.* AU - van Duijn, C.M.* AU - Rivadeneira, F.* AU - Li, X.* AU - Eckel, S.P.* AU - Berhane, K.* AU - Gauderman, W.J.* AU - Granell, R.* AU - Evans, D.M* AU - St Pourcain, B.* AU - McArdle, W.* AU - Kemp, J.P.* AU - Smith, G.D.* AU - Tiesler, C.M. AU - Flexeder, C. AU - Simpson, A.* AU - Murray, C.S.* AU - Fuchs, O.* AU - Postma, D.S.* AU - Bønnelykke, K.* AU - Torrent, M.* AU - Andersson, M.* AU - Sleiman, P.M.* AU - Hakonarson, H.* AU - Cookson, W.O.* AU - Moffatt, M.F.* AU - Paternoster, L.* AU - Melén, E.* AU - Sunyer, J.* AU - Bisgaard, H.* AU - Koppelman, G.H.* AU - Ege, M.* AU - Custovic, A.* AU - Heinrich, J. AU - Gilliland, F.D.* AU - Henderson, A.J.* AU - Jaddoe, V.W.* AU - de Jongste, J.C.* AU - EUMODIC Consortium (*) C1 - 28622 C2 - 33494 CY - New York SP - 46-55 TI - Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variants. JO - J. Allergy Clin. Immunol. VL - 134 IS - 1 PB - Mosby-Elsevier PY - 2014 SN - 0091-6749 ER - TY - JOUR AU - Cifuentes, L.* AU - Vosseler, S.* AU - Blank, S.* AU - Seismann, H.* AU - Pennino, D. AU - Darsow, U.* AU - Bredehorst, R.* AU - Ring, J.* AU - Mempel, M.* AU - Spillner, E.* AU - Ollert, M.* C1 - 28605 C2 - 33477 CY - New York SP - 909–910 TI - Identification of Hymenoptera venom-allergic patients with negative specific IgE to venom extract by using recombinant allergens. JO - J. Allergy Clin. Immunol. VL - 133 IS - 3 PB - Mosby-Elsevier PY - 2013 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: There is conflicting evidence on whether allergen-specific memory is primed prenatally, whether this priming affects persistent immunologic effects, and whether it is modulated by the first environmental exposures in infancy. OBJECTIVE: We sought to explore the course of atopic sensitization between birth and 12 months of age. METHODS: Specific IgE levels for 6 food and 13 common inhalant allergens were assessed in cord blood and 1-year blood samples in the Protection against Allergy-Study in Rural Environments (PASTURE) birth cohort including 793 children from rural regions of 5 European countries. Detailed information on children's health, nutrition, and farm-related exposures was gathered by using a pregnancy questionnaire, 2 questionnaires at 2 and 12 months of age, and a diary covering the time in between. RESULTS: Sensitization was more common at 12 months of age than at birth for almost all specificities. On an individual level, persistent sensitization to the same allergens was rare (1%), whereas transient (only at birth, 11%) and incident (only at 12 months, 34%) sensitization was seen in substantial proportions of children. Associations of transient sensitization with maternal sensitization differed with the allergen specificities, with the strongest associations for food allergens (odds ratio [OR], 10.6; 95% CI, 6.0-18.6) and the weakest associations for seasonal allergens (OR, 1.64; 95% CI, 0.94-2.86). Associations of maternal sensitization with incident sensitization were also seen. Incident sensitization was related to distinct prenatal and postnatal environmental exposures of mother and child, such as consumption of cereals for incident sensitization to seasonal allergens (OR, 0.66; 95% CI, 0.50-0.88). CONCLUSION: IgE sensitization patterns change between birth and 12 months and are related to maternal and environmental influences. AU - Depner, M.* AU - Ege, M.J.* AU - Genuneit, J.* AU - Pekkanen, J.* AU - Roponen, M.* AU - Hirvonen, M.R.* AU - Dalphin, J.-C.* AU - Kaulek, V.* AU - Krauss-Etschmann, S. AU - Riedler, J.* AU - Braun-Fahrländer, C.* AU - Roduit, C.* AU - Lauener, R.* AU - Pfefferle, P.I.* AU - Weber, J.* AU - von Mutius, E.* C1 - 11878 C2 - 30836 SP - 781-788 TI - Atopic sensitization in the first year of life. JO - J. Allergy Clin. Immunol. VL - 131 IS - 3 PB - Mosby-Elsevier PY - 2013 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Associations between traffic-related air pollution (TRAP) and allergic rhinitis remain inconsistent, possibly because of unexplored gene-environment interactions. OBJECTIVE: In a pooled analysis of 6 birth cohorts (Ntotal = 15,299), we examined whether TRAP and genetic polymorphisms related to inflammation and oxidative stress predict allergic rhinitis and sensitization. METHODS: Allergic rhinitis was defined with a doctor diagnosis or reported symptoms at age 7 or 8 years. Associations between nitrogen dioxide, particulate matter 2.5 (PM2.5) mass, PM2.5 absorbance, and ozone, estimated for each child at the year of birth, and single nucleotide polymorphisms within the GSTP1, TNF, TLR2, or TLR4 genes with allergic rhinitis and aeroallergen sensitization were examined with logistic regression. Models were stratified by genotype and interaction terms tested for gene-environment associations. RESULTS: Point estimates for associations between nitrogen dioxide, PM2.5 mass, and PM2.5 absorbance with allergic rhinitis were elevated, but only that for PM2.5 mass was statistically significant (1.37 [1.01, 1.86] per 5 μg/m(3)). This result was not robust to single-cohort exclusions. Carriers of at least 1 minor rs1800629 (TNF) or rs1927911 (TLR4) allele were consistently at an increased risk of developing allergic rhinitis (1.19 [1.00, 1.41] and 1.24 [1.01, 1.53], respectively), regardless of TRAP exposure. No evidence of gene-environment interactions was observed. CONCLUSION: The generally null effect of TRAP on allergic rhinitis and aeroallergen sensitization was not modified by the studied variants in the GSTP1, TNF, TLR2, or TLR4 genes. Children carrying a minor rs1800629 (TNF) or rs1927911 (TLR4) allele may be at a higher risk of allergic rhinitis. AU - Fuertes, E. AU - Brauer, M.* AU - MacIntyre, E.A. AU - Bauer, M.* AU - Bellander, T.* AU - von Berg, A.* AU - Berdel, D.* AU - Brunekreef, B.* AU - Chan-Yeung, M.* AU - Gehring, U.* AU - Herbarth, O.* AU - Hoffmann, B.* AU - Kerkhof, M.* AU - Klümper, C.* AU - Koletzko, S.* AU - Kozyrskyj, A.* AU - Kull, I.* AU - Heinrich, J. AU - Melén, E.* AU - Pershagen, G.* AU - Postma, D.* AU - Tiesler, C.M. AU - Carlsten, C.* AU - TAG Consortium (*) C1 - 26144 C2 - 32091 SP - 342-352 TI - Childhood allergic rhinitis, traffic-related air pollution, and variability in the GSTP1, TNF, TLR2, and TLR4 genes: Results from the TAG study. JO - J. Allergy Clin. Immunol. VL - 132 IS - 2 PB - Mosby-Elsevier PY - 2013 SN - 0091-6749 ER - TY - JOUR AU - Pandey, R.C.* AU - Michel, S.* AU - Tesse, R.* AU - Binia, A.* AU - Schedel, M.* AU - Liang, L.M.* AU - Klopp, N. AU - Franke, A.* AU - von Berg, A.* AU - Bufe, A.* AU - Rietschel, E.* AU - Heinzmann, A.* AU - Laub, O.* AU - Simma, B.* AU - Frischer, T.* AU - Genuneit, J.* AU - Illig, T. AU - Kabesch, M.* C1 - 23146 C2 - 31013 SP - 602-605 TI - Genetic variation in the toll-like receptor signaling pathway is associated with childhood asthma. JO - J. Allergy Clin. Immunol. VL - 131 IS - 2 PB - Elsevier PY - 2013 SN - 0091-6749 ER - TY - JOUR AB - Asthma susceptibility loci determined by genome-wide association studies explain only a fraction of asthma's hereditability. Pathway analysis has emerged as a next step toward mining hidden genetic factors in complex diseases. A recent study investigating the association between polymorphisms in Toll-like receptor signaling pathways and asthma revealed that 2 members of the mitogen-activated protein kinase (MAPK) pathway (MAP kinase kinase 3 and extracellular signal-regulated kinase 2 [ERK2]) showed strong association with the disease AU - Pandey, R.C.* AU - Michel, S.* AU - Schieck, M.* AU - Binia, A.* AU - Liang, L.M.* AU - Klopp, N. AU - Franke, A.* AU - von Berg, A.* AU - Bufe, A.* AU - Rietschel, E.* AU - Heinzmann, A.* AU - Laub, O.* AU - Simma, B.* AU - Frischer, T.* AU - Genuneit, J.* AU - Illig, T. AU - Kabesch, M.* C1 - 24325 C2 - 31519 SP - 1245-1247 TI - Polymorphisms in extracellular signal-regulated kinase family influence genetic susceptibility to asthma. JO - J. Allergy Clin. Immunol. VL - 131 IS - 4 PB - Mosby-Elsevier PY - 2013 SN - 0091-6749 ER - TY - JOUR AB - Background: IL-22 controls tissue homeostasis by both proinflammatory and anti-inflammatory effects. However, the anti-inflammatory mechanisms of IL-22 remain poorly investigated. Objective: We sought to investigate the anti-inflammatory role for IL-22 in human asthma. Methods: T-cell lines derived from lung biopsy specimens of asthmatic patients were characterized by means of flow cytometry. Human bronchial epithelial cells from healthy and asthmatic subjects were stimulated with IL-22, IFN-gamma, or the combination of both cytokines. Effects of cytokine stimulation were investigated by using whole-genome analysis, ELISA, and flow cytometry. The functional consequence of cytokine stimulation was evaluated in an in vitro wound repair model and T cell-mediated cytotoxicity experiments. In vivo cytokine expression was measured by using immunohistochemistry and Luminex assays in bronchoalveolar lavage fluid of healthy and asthmatic patients. Results: The current study identifies a tissue-restricted antagonistic interplay of IL-22 and the proinflammatory cytokine IFN-gamma. On the one hand, IFN-gamma antagonized IL-22-mediated induction of the antimicrobial peptide S100A7 and epithelial cell migration in bronchial epithelial cells. On the other hand, IL-22 decreased epithelial susceptibility to T cell-mediated cytotoxicity by inhibiting the IFN-gamma-induced expression of MHC-I, MHC-II, and CD54/intercellular adhesion molecule 1 molecules. Likewise, IL-22 inhibited IFN-gamma-induced secretion of the proinflammatory chemokines CCL5/RANTES and CXCL10/interferon-inducible protein 10 in vitro. Consistently, the IL-22 expression in bronchoalveolar lavage fluid of asthmatic patients inversely correlated with the expression of CCL5/RANTES and CXCL10/interferon-inducible protein 10 in vivo. Conclusions: IL-22 might control the extent of IFN-gamma-mediated lung inflammation and therefore play a tissue-restricted regulatory role. AU - Pennino, D. AU - Bhavsar, P.K.* AU - Effner, R. AU - Avitabile, S.* AU - Venn, P.* AU - Quaranta, M. AU - Marzaioli, V. AU - Cifuentes, L. AU - Durham, S.R.* AU - Cavani, A.* AU - Eyerich, K.* AU - Chung, K.F.* AU - Schmidt-Weber, C.B. AU - Eyerich, S. C1 - 23148 C2 - 31012 SP - 562-570 TI - IL-22 suppresses IFN-γ-mediated lung inflammation in asthmatic patients. JO - J. Allergy Clin. Immunol. VL - 131 IS - 2 PB - Elsevier PY - 2013 SN - 0091-6749 ER - TY - JOUR AB - Background: IL10 encodes for IL-10, an important anti-inflammatory cytokine with pleiotropic effects. It is crucial for development of immune tolerance, downregulates expression of T(H)1 cytokines, and is relevant for T-cell regulation. Several IL10 single nucleotide polymorphisms (SNPs) were associated with inflammatory diseases, such as atopic diseases, which might have their onset during early immune maturation. Objective: We hypothesized that IL10 SNPs are associated with decreased regulatory T (Treg) cell numbers, T(H)2-skewed immune responses, and decreased IFN-gamma levels in cord blood parallel with increased proinflammatory markers, subsequently leading to increased atopic diseases until 3 years. Methods: Eight genetic IL10 variants, represented by 4 linkage disequilibrium blocks (R-2 > 0.80) and 2 distal promoter SNPs, were genotyped in cord blood mononuclear cells of 200 healthy neonates. Cord blood mononuclear cells were cultured unstimulated or after stimulation with lipid A, peptidoglycan, PHA, house dust mite (Der p 1), or Der p 1 plus lipid A. mRNA expression of Treg cell-associated genes (forkhead box protein P3 [FOXP3], glucocorticoid-induced TNF receptor [GITR], lymphocyte activation gene 3 [LAG3]), T(H)1/T(H)2 cytokines, TNF-alpha, and GM-CSF were assessed. Atopic and respiratory outcomes (atopic dermatitis [AD] and wheeze) were assessed by means of questionnaire at age 3 years. Results: Carriers of 3 IL10 SNP blocks and both distal promoter SNPs showed reduced expression of Treg cell markers, reduced IL-5 levels, proinflammatory TNF-alpha and GM-CSF, and partially increased IFN-gamma levels. The same SNPs presented as determinant for AD, wheeze, or symptoms of AD, wheeze, or both at age 3 years. Conclusions: Polymorphisms in IL10 influenced Treg cell marker expression and T(H)1/T(H)2 and proinflammatory cytokine secretion early in life. This was relevant for further development of immune-mediated diseases, such as AD and wheeze, in early childhood. AU - Rädler, D.* AU - Illi, S.* AU - Pinto, L.A.* AU - von Mutius, E.* AU - Illig, T. AU - Kabesch, M.* AU - Schaub, B.* C1 - 23640 C2 - 31267 SP - 789-796 TI - IL10 polymorphisms influence neonatal immune responses, atopic dermatitis, and wheeze at age 3 years. JO - J. Allergy Clin. Immunol. VL - 131 IS - 3 PB - Mosby-Elsevier PY - 2013 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: The causal link between body mass index (BMI) or obesity and asthma in children is still being debated. Analyses of large longitudinal studies with a sufficient number of incident cases and in which the time-dependent processes of both excess weight and asthma development can be validly analyzed are lacking. OBJECTIVE: We sought to investigate whether the course of BMI predicts incident asthma in childhood. METHODS: Data from 12,050 subjects of 8 European birth cohorts on asthma and allergies were combined. BMI and doctor-diagnosed asthma were modeled during the first 6 years of life with latent growth mixture modeling and discrete time hazard models. Subpopulations of children were identified with similar standardized BMI trajectories according to age- and sex-specific "World Health Organization (WHO) child growth standards" and "WHO growth standards for school aged children and adolescents" for children up to age 5 years and older than 5 years, respectively (BMI-SDS). These types of growth profiles were analyzed as predictors for incident asthma. RESULTS: Children with a rapid BMI-SDS gain in the first 2 years of life had a higher risk for incident asthma up to age 6 years than children with a less pronounced weight gain slope in early childhood. The hazard ratio was 1.3 (95% CI, 1.1-1.5) after adjustment for birth weight, weight-for-length at birth, gestational age, sex, maternal smoking in pregnancy, breast-feeding, and family history of asthma or allergies. A rapid BMI gain at 2 to 6 years of age in addition to rapid gain in the first 2 years of life did not significantly enhance the risk of asthma. CONCLUSION: Rapid growth in BMI during the first 2 years of life increases the risk of asthma up to age 6 years. AU - Rzehak, P. AU - Wijga, A.H.* AU - Keil, T.* AU - Eller, E.* AU - Bindslev-Jensen, C.* AU - Smit, H.A.* AU - Weyler, J.* AU - Dom, S.* AU - Sunyer, J.* AU - Mendez, M.* AU - Torrent, M.* AU - Vall, O.* AU - Bauer, C.P.* AU - Berdel, D.* AU - Schaaf, B.* AU - Chen, C.-M. AU - Bergström, A.* AU - Fantini, M.P.* AU - Mommers, M.* AU - Wahn, U.* AU - Lau, S.* AU - Heinrich, J. C1 - 24847 C2 - 31704 SP - 1528-1536 TI - Body mass index trajectory classes and incident asthma in childhood: Results from 8 European birth cohorts - a Global Allergy and Asthma European Network initiative. JO - J. Allergy Clin. Immunol. VL - 131 IS - 6 PB - Mosby-Elsevier PY - 2013 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Atopic dermatitis (AD) is a major inflammatory condition of the skin caused by inherited skin barrier deficiency, with mutations in the filaggrin gene predisposing to development of AD. Support for barrier deficiency initiating AD came from flaky tail mice, which have a frameshift mutation in Flg and also carry an unknown gene, matted, causing a matted hair phenotype. OBJECTIVE: We sought to identify the matted mutant gene in mice and further define whether mutations in the human gene were associated with AD. METHODS: A mouse genetics approach was used to separate the matted and Flg mutations to produce congenic single-mutant strains for genetic and immunologic analysis. Next-generation sequencing was used to identify the matted gene. Five independently recruited AD case collections were analyzed to define associations between single nucleotide polymorphisms (SNPs) in the human gene and AD. RESULTS: The matted phenotype in flaky tail mice is due to a mutation in the Tmem79/Matt gene, with no expression of the encoded protein mattrin in the skin of mutant mice. Matt(ft) mice spontaneously have dermatitis and atopy caused by a defective skin barrier, with mutant mice having systemic sensitization after cutaneous challenge with house dust mite allergens. Meta-analysis of 4,245 AD cases and 10,558 population-matched control subjects showed that a missense SNP, rs6694514, in the human MATT gene has a small but significant association with AD. CONCLUSION: In mice mutations in Matt cause a defective skin barrier and spontaneous dermatitis and atopy. A common SNP in MATT has an association with AD in human subjects. AU - Saunders, S.P.* AU - Goh, C.S.* AU - Brown, S.J.* AU - Palmer, C.N.* AU - Porter, R.M.* AU - Cole, C.* AU - Campbell, L.E.* AU - Gierlinski, M.* AU - Barton, G.J.* AU - Schneider, G.* AU - Balmain, A.* AU - Prescott, A.R.* AU - Weidinger, S.* AU - Baurecht, H.* AU - Kabesch, M.* AU - Gieger, C. AU - Lee, Y.A.* AU - Tavendale, R.* AU - Mukhopadhyay, S.* AU - Turner, S.W.* AU - Madhok, V.B.* AU - Sullivan, F.M.* AU - Relton, C.* AU - Burn, J.* AU - Meggitt, S.* AU - Smith, C.H.* AU - Allen, M.A.* AU - Barker, J.N.* AU - Reynolds, N.J.* AU - Cordell, H.J.* AU - Irvine, A.D.* AU - McLean, W.H.* AU - Sandilands, A.* AU - Fallon, P.G.* C1 - 27829 C2 - 32831 SP - 1121-1129 TI - Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in human subjects. JO - J. Allergy Clin. Immunol. VL - 132 IS - 5 PB - Mosby-Elsevier PY - 2013 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: The pruritic cytokine IL-31 has been shown to be expressed by murine activated effector T Lymphocytes of a TH2 phenotype. Like IL-17 and IL-22, IL-31 is a tissue-signaling cytokine the receptor of which is mainly found on nonimmune cells. An overabundance of IL-31 has been shown in patients with atopic disorders, including dermatitis, as well as asthma, and therefore represents a promising drug target, although its regulation in the context of the human TH2 clusters is not yet known. OBJECTIVE: We sought to address the gene regulation of human IL-31 and to test whether IL-31 possesses a similar proallergic function as members of the human TH2 cytokine family, such as IL-4, IL-5, and IL-13. METHODS: Polyclonal and purified protein derivative of tuburculin-specific T-cell clones were generated. TH phenotype was determined, and IL-31 was measured by means of ELISA. Gene expression of primary bronchial epithelial cells treated with IL-31 was also measured. RESULTS: IL-31 was expressed by all of the TH2 clones and not by TH1, TH17, or TH22. This expression was dependent on autocrine IL-4 expression from these clones because it could be reduced if blocking antibodies to IL-4 were present. Interestingly, TH1 clones were able to express IL-31 if IL-4 was added to culture. This IL-31 expression was transient and did not affect the phenotype of the TH1 clones. IL-31 was able to induce proinflammatory genes, such as CCL2 and granulocyte colony-stimulating factor. CONCLUSION: IL-31 is not a TH2 cytokine in the classical sense but is likely to be expressed by a number of cells in an allergic situation in which IL-4 is present and possibly contribute to the allergic reaction. AU - Stott, B.* AU - Lavender, P.* AU - Lehmann, S. AU - Pennino, D. AU - Durham, S.* AU - Schmidt-Weber, C.B. C1 - 26246 C2 - 32142 SP - 446-454 TI - Human IL-31 is induced by IL-4 and promotes TH2-driven inflammation. JO - J. Allergy Clin. Immunol. VL - 132 IS - 2 PB - Mosby-Elsevier PY - 2013 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: The long-term effect of nutritional intervention with hydrolysate infant formulas on allergic manifestations in high-risk children is uncertain. OBJECTIVE: We sought to investigate the effect of hydrolysate infant formulas on allergic phenotypes in children with family history of allergies at school age. METHODS: We analyzed data from participants of the prospective German Infant Nutritional Intervention study after 10 years of follow-up. At birth, children were randomly assigned to receive, for the first 4 months, one of 4 blinded formulas as breast milk substitute, if necessary: partially hydrolyzed whey formula (pHF-W), extensively hydrolyzed whey formula (eHF-W), extensively hydrolyzed casein formula (eHF-C), or standard cow's milk formula. Outcomes were parent-reported, physician-diagnosed allergic diseases. Log-binomial regression models were used for statistical analysis. RESULTS: The relative risk for the cumulative incidence of any allergic disease in the intention-to-treat analysis (n = 2252) was 0.87 (95% CI, 0.77-0.99) for pHF-W, 0.94 (95% CI, 0.83-1.07) for eHF-W, and 0.83 (95% CI, 0.72-0.95) for eHF-C compared with standard cow's milk formula. The corresponding figures for atopic eczema/dermatits (AD) were 0.82 (95% CI, 0.68-1.00), 0.91 (95% CI, 0.76-1.10), and 0.72 (95% CI, 0.58-0.88), respectively. In the per-protocol analysis (n = 988) effects were stronger. The period prevalence of AD at 7 to 10 years was significantly reduced with eHF-C in this analysis, but there was no preventive effect on asthma or allergic rhinitis. CONCLUSION: The significant preventive effect on the cumulative incidence of allergic diseases, particularly AD, with pHF-W and eHF-C persisted until 10 years without rebound, whereas eHF-W showed no significant risk reduction. There is insufficient evidence of ongoing preventive activity at 7 to 10 years of age. AU - von Berg, A.* AU - Filipiak-Pittroff, B.* AU - Krämer, U.* AU - Hoffmann, B.* AU - Link, E.* AU - Beckmann, C.* AU - Hoffmann, U. AU - Reinhardt, D.* AU - Grubl, A.* AU - Heinrich, J. AU - Wichmann, H.-E. AU - Bauer, C.P.* AU - Koletzko, S.* AU - Berdel, D.* C1 - 25498 C2 - 31865 SP - 1565-1573 TI - Allergies in high-risk schoolchildren after early intervention with cow's milk protein hydrolysates: 10-year results from the German Infant Nutritional Intervention (GINI) study. JO - J. Allergy Clin. Immunol. VL - 131 IS - 6 PB - Mosby-Elsevier PY - 2013 SN - 0091-6749 ER - TY - JOUR AU - von Berg, A.* AU - Koletzko, S.* AU - Filipiak-Pittroff, B.* AU - Heinrich, J. AU - Bauer, C.P.* AU - Krämer, U.* AU - Hoffmann, B.* AU - Berdel, D.* AU - GINIplus Study Group (Heinrich, J. AU - Wichmann, H.-E.) C1 - 26298 C2 - 32158 SP - 770-771 TI - Reply. JO - J. Allergy Clin. Immunol. VL - 132 IS - 3 PB - Mosby-Elsevier PY - 2013 SN - 0091-6749 ER - TY - JOUR AB - Mechanisms of the Development of Allergy (MeDALL), a Seventh Framework Program European Union project, aims to generate novel knowledge on the mechanisms of initiation of allergy. Precise phenotypes of IgE-mediated allergic diseases will be defined in MeDALL. As part of MeDALL, a scientific seminar was held on January 24, 2011, to review current knowledge on the IgE-related phenotypes and to explore how a multidisciplinary effort could result in a new integrative translational approach. This article provides a summary of the meeting. It develops challenges in IgE-related phenotypes and new clinical and epidemiologic approaches to the investigation of allergic phenotypes, including cluster analysis, scale-free models, candidate biomarkers, and IgE microarrays; the particular case of severe asthma was reviewed. Then novel approaches to the IgE-associated phenotypes are reviewed from the individual mechanisms to the systems, including epigenetics, human in vitro immunology, systems biology, and animal models. The last chapter deals with the understanding of the population-based IgE-associated phenotypes in children and adolescents, including age effect in terms of maturation, observed effects of early-life exposures and shift of focus from early life to pregnancy, gene-environment interactions, cohort effects, and time trends in patients with allergic diseases. This review helps to define phenotypes of allergic diseases in MeDALL. AU - Antò, J.M.* AU - Pinart, M.* AU - Akdis, M.* AU - Auffray, C.* AU - Bachert, C.* AU - Basagana, X.* AU - Carlsen, K.H.* AU - Guerra, S.* AU - von Hertzen, L.* AU - Illi, S.* AU - Kauffmann, F.* AU - Keil, T.* AU - Kiley, J.P.* AU - Koppelman, G.H.* AU - Lupinek, C.* AU - Martinez, F.D.* AU - Nawijn, M.C.* AU - Postma, D.S.* AU - Siroux, V.* AU - Smit, H.A.* AU - Sterk, P.J.* AU - Sunyer, J.* AU - Valenta, R.* AU - Valverde, S.* AU - Akdis, C.A.* AU - Annesi-Maesano, I.* AU - Ballester, F.* AU - Benet, M.* AU - Cambon-Thomsen, A.* AU - Chatzi, L.* AU - Coquet, J.* AU - Demoly, P.* AU - Gan, W.* AU - Garcia-Aymerich, J.* AU - Gimeno-Santos, E.* AU - Guihenneuc-Jouyaux, C.* AU - Haahtela, T.* AU - Heinrich, J. AU - Herr, M.* AU - Hohmann, C.* AU - Jacquemin, B.* AU - Just, J.* AU - Kerkhof, M.* AU - Kogevinas, M.* AU - Kowalski, M.L.* AU - Lambrecht, B.N.* AU - Lau, S.* AU - Lødrup Carlsen, K.C.* AU - Maier, D.* AU - Momas, I.* AU - Noel, P.* AU - Oddie, S.* AU - Palkonen, S.* AU - Pin, I.* AU - Porta, D.* AU - Punturieri, A.* AU - Ranciere, F.* AU - Smith, R.A.* AU - Stanic, B.* AU - Stein, R.T.* AU - van de Veen, W.* AU - van Oosterhout, A.J.* AU - Varraso, R.* AU - Wickman, M.* AU - Wijmenga, C.* AU - Wright, J.* AU - Yaman, G.* AU - Zuberbier, T.* AU - Bousquet, J.* AU - WHO Collaborating Centre on Asthma and Rhinitis (Montpellier)* C1 - 7952 C2 - 29931 SP - 943-954 TI - Understanding the complexity of IgE-related phenotypes from childhood to young adulthood: A Mechanisms of the Development of Allergy (MeDALL) seminar. JO - J. Allergy Clin. Immunol. VL - 129 IS - 4 PB - Mosby-Elsevier PY - 2012 SN - 0091-6749 ER - TY - JOUR AB - Allergic rhinitis (AR) and asthma represent global health problems for all age groups. Asthma and rhinitis frequently coexist in the same subjects. Allergic Rhinitis and its Impact on Asthma (ARIA) was initiated during a World Health Organization workshop in 1999 (published in 2001). ARIA has reclassified ARas mild/moderate-severe and intermittent/persistent. This classification closely reflects patients' needs and underlines the close relationship between rhinitis and asthma. Patients, clinicians, and other health care professionals are confronted with various treatment choices for the management of AR. This contributes to considerable variation in clinical practice, and worldwide, patients, clinicians, and other health care professionals are faced with uncertainty about the relative merits and downsides of the various treatment options. In its 2010 Revision, ARIA developed clinical practice guidelines for the management of AR and asthma comorbidities based on the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system. ARIA is disseminated and implemented in more than 50 countries of the world. Ten years after the publication of the ARIAWorld Health Organization workshop report, it is important to make a summary of its achievements and identify the still unmet clinical, research, and implementation needs to strengthen the 2011 European Union Priority on allergy and asthma in children. (J Allergy Clin Immunol 2012;130:1049-62.) AU - Bousquet, J.* AU - Schünemann, H.J.* AU - Samolinski, B.* AU - Demoly, P.* AU - Baena-Cagnani, C.E.* AU - Bachert, C.* AU - Bonini, S.* AU - Boulet, L.P.* AU - Bousquet, P.J.* AU - Brozek, J.L.* AU - Canonica, G.W.* AU - Casale, T.B.* AU - Cruz, A.A.* AU - Fokkens, W.J.* AU - Fonseca, J.A.* AU - van Wijk, R.G.* AU - Grouse, L.* AU - Haahtela, T.* AU - Khaltaev, N.* AU - Kuna, P.* AU - Lockey, R.F.* AU - Carlsen, K.C.L.* AU - Mullol, J.* AU - Naclerio, R.* AU - O'Hehir, R.E.* AU - Ohta, K.* AU - Palkonen, S.* AU - Papadopoulos, N.G.* AU - Passalacqua, G.* AU - Pawankar, R.* AU - Price, D.* AU - Ryan, D.* AU - Simons, F.E.R.* AU - Togias, A.* AU - Williams, D.* AU - Yorgancioglu, A.* AU - Yusuf, O.M.* AU - Aberer, W.* AU - Adachi, M.* AU - Agache, I.* AU - Ait-Khaled, N.* AU - Akdis, C.A.* AU - Andrianarisoa, A.* AU - Annesi-Maesano, I.* AU - Ansotegui, I.J.* AU - Baiardini, I.* AU - Bateman, E.D.* AU - Bedbrook, A.* AU - Beghe, B.* AU - Beji, M.* AU - Bel, E.H.* AU - Ben Kheder, A.* AU - Bennoor, K.S.* AU - Bergmann, K.C.* AU - Berrissoul, F.* AU - Bieber, T.* AU - Jensen, C.B.* AU - Blaiss, M.S.* AU - Boner, A.L.* AU - Bouchard, J.* AU - Braido, F.* AU - Brightling, C.E.* AU - Bush, A.* AU - Caballero, F.* AU - Calderon, M.A.* AU - Calvo, M.A.* AU - Camargos, P.A.M.* AU - Caraballo, L.R.* AU - Carlsen, K.H.* AU - Carr, W.* AU - Cepeda, A.M.* AU - Cesario, A.* AU - Chavannes, N.H.* AU - Chen, Y.Z.* AU - Chiriac, A.M.* AU - Perez, T.C.* AU - Chkhartishvili, E.* AU - Ciprandi, G.* AU - Costa, D.J.* AU - Cox, L.* AU - Custovic, A.* AU - Dahl, R.* AU - Darsow, U. AU - de Blay, F.* AU - Deleanu, D.* AU - Denburg, J.A.* AU - Devillier, P.* AU - Didi, T.* AU - Dokic, D.* AU - Dolen, W.K.* AU - Douagui, H.* AU - Dubakiene, R.* AU - Durham, S.R.* AU - Dykewicz, M.S.* AU - El-Gamal, Y.* AU - El-Meziane, A.* AU - Emuzyte, R.* AU - Fiocchi, A.* AU - Fletcher, M.* AU - Fukuda, T.* AU - Gamkrelidze, A.* AU - Gereda, J.E.* AU - Diaz, S.G.* AU - Gotua, M.* AU - Guzman, M.A.* AU - Hellings, P.W.* AU - Hellquist-Dahl, B.* AU - Horak, F.* AU - Hourihane, J.O.* AU - Howarth, P.* AU - Humbert, M.* AU - Ivancevich, J.C.* AU - Jackson, C.* AU - Just, J.* AU - Kalayci, O.* AU - Kaliner, M.A.* AU - Kalyoncu, A.F.* AU - Keil, T.* AU - Keith, P.K.* AU - Khayat, G.* AU - Kim, Y.Y.* AU - N'Goran, B.K.* AU - Koppelman, G.H.* AU - Kowalski, M.L.* AU - Kull, I.* AU - Kvedariene, V.* AU - Larenas-Linnemann, D.* AU - Le, L.T.* AU - Lemiere, C.* AU - Li, J.* AU - Lieberman, P.* AU - Lipworth, B.* AU - Mahboub, B.* AU - Makela, M.J.* AU - Martin, F.* AU - Marshall, G.D.* AU - Martinez, F.D.* AU - Masjedi, M.R.* AU - Maurer, M.* AU - Mavale-Manuel, S.* AU - Mazon, A.* AU - Melén, E.* AU - Meltzer, E.O.* AU - Mendez, N.H.* AU - Merk, H.* AU - Mihaltan, F.* AU - Mohammad, Y.* AU - Morais-Almeida, M.* AU - Muraro, A.* AU - Nafti, S.* AU - Namazova-Baranova, L.* AU - Nekam, K.* AU - Neou, A.* AU - Niggemann, B.* AU - Niżankowska-Mogilnicka, E.* AU - Nyembue, T.D.* AU - Okamoto, Y.* AU - Okubo, K.* AU - Orru, M.P.* AU - Ouedraogo, S.* AU - Ozdemir, C.* AU - Panzner, P.* AU - Pali-Scholl, I.* AU - Park, H.S.* AU - Pigearias, B.* AU - Pohl, W.* AU - Popov, T.A.* AU - Postma, D.S.* AU - Potter, P.* AU - Rabe, K.F.* AU - Ratomaharo, J.* AU - Reitamo, S.* AU - Ring, J.* AU - Roberts, R.* AU - Rogala, B.* AU - Romano, A.* AU - Rodriguez, M.R.* AU - Rosado-Pinto, J.* AU - Rosenwasser, L.* AU - Rottem, M.* AU - Sanchez-Borges, M.* AU - Scadding, G.K.* AU - Schmid-Grendelmeier, P.* AU - Sheikh, A.* AU - Sisul, J.C.* AU - Sole, D.* AU - Sooronbaev, T.* AU - Spicak, V.* AU - Spranger, O.* AU - Stein, R.T.* AU - Stoloff, S.W.* AU - Sunyer, J.* AU - Szczeklik, A.* AU - Todo-Bom, A.* AU - Toskala, E.* AU - Tremblay, Y.* AU - Valenta, R.* AU - Valero, A.L.* AU - Valeyre, D.* AU - Valiulis, A.* AU - Valovirta, E.* AU - van Cauwenberge, P.* AU - Vandenplas, O.* AU - van Weel, C.* AU - Vichyanond, P.* AU - Viegi, G.* AU - Wang, D.Y.* AU - Wickman, M.* AU - Wohrl, S.* AU - Wright, J.* AU - Yawn, B.P.* AU - Yiallouros, P.K.* AU - Zar, H.J.* AU - Zernotti, M.E.* AU - Zhong, N.* AU - Zidarn, M.* AU - Zuberbier, T.* C1 - 11258 C2 - 30595 SP - 1049-1062 TI - Allergic Rhinitis and its Impact on Asthma (ARIA): Achievements in 10 years and future needs. JO - J. Allergy Clin. Immunol. VL - 130 IS - 5 PB - Mosby-Elsevier PY - 2012 SN - 0091-6749 ER - TY - JOUR AB - Comment on: Differentiation stage determines pathologic and protective allergen-specific CD4+ T-cell outcomes during specific immunotherapy. [J. Allergy Clin. Immunol. 2012] AU - Gilles, S. AU - Traidl-Hoffmann, C. C1 - 7252 C2 - 29612 SP - 552-554 TI - CD27 expression on allergen-specific T cells: A new surrogate for successful allergen-specific immunotherapy? JO - J. Allergy Clin. Immunol. VL - 129 IS - 2 PB - Elsevier PY - 2012 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Atopy and plasma IgE concentration are genetically complex traits, and the specific genetic risk factors that lead to IgE dysregulation and clinical atopy are an area of active investigation. OBJECTIVE: We sought to ascertain the genetic risk factors that lead to IgE dysregulation. METHODS: A genome-wide association study (GWAS) was performed in 6819 participants from the Framingham Heart Study (FHS). Seventy of the top single nucleotide polymorphisms (SNPs) were selected based on P values and linkage disequilibrium among neighboring SNPs and evaluated in a meta-analysis with 5 independent populations from the Cooperative Health Research in the Region of Augsburg cohort, the British 1958 Birth Cohort, and the Childhood Asthma Management Program cohort. RESULTS: Thirteen SNPs located in the region of 3 genes, FCER1A, signal transducer and activator of transcription 6 (STAT6), and IL13, were found to have genome-wide significance in the FHS cohort GWAS. The most significant SNPs from the 3 regions were rs2251746 (FCER1A, P = 2.11 × 10(-12)), rs1059513 (STAT6, P = 2.87 × 10(-8)), and rs1295686 (IL13, P = 3.55 × 10(-8)). Four additional gene regions, HLA-G, HLA-DQA2, HLA-A, and Duffy blood group, chemokine receptor (DARC), reached genome-wide statistical significance in a meta-analysis combining the FHS and replication cohorts, although the DARC association did not appear independent of SNPs in the nearby FCER1A gene. CONCLUSION: This GWAS of the FHS cohort has identified genetic loci in HLA genes that might have a role in the pathogenesis of IgE dysregulation and atopy. It also confirmed the association of the known susceptibility loci FCER1A, STAT6, and IL13 for the dysregulation of total IgE. AU - Granada, M.* AU - Wilk, J.B.* AU - Tuzova, M.* AU - Strachan, D.P.* AU - Weidinger, S.* AU - Albrecht, E. AU - Gieger, C. AU - Heinrich, J. AU - Himes, B.E.* AU - Hunninghake, G.M.* AU - Celedón, J.C.* AU - Weiss, S.T.* AU - Cruikshank, W.W.* AU - Farrer, L.A.* AU - Center, D.M.* AU - O'Connor, G.T.* C1 - 7447 C2 - 29716 SP - 840-845 TI - A genome-wide association study of plasma total IgE concentrations in the Framingham Heart Study. JO - J. Allergy Clin. Immunol. VL - 129 IS - 3 PB - Mosby-Elsevier PY - 2012 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Genome-wide association studies have identified determinants of chronic obstructive pulmonary disease, asthma, and lung function level; however, none have addressed decline in lung function. OBJECTIVE: We conducted the first genome-wide association study on the age-related decrease in FEV(1) and its ratio to forced vital capacity (FVC) stratified a priori by asthma status. METHODS: Discovery cohorts included adults of European ancestry (1,441 asthmatic and 2,677 nonasthmatic participants: the Epidemiological Study on the Genetics and Environment of Asthma, the Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults, and the European Community Respiratory Health Survey). The associations of FEV(1) and FEV(1)/FVC ratio decrease with 2.5 million single nucleotide polymorphisms (SNPs) were estimated. Thirty loci were followed up by in silico replication (1,160 asthmatic and 10,858 nonasthmatic participants: Atherosclerosis Risk in Communities, the Framingham Heart Study, the British 1958 Birth Cohort, and the Dutch Asthma Study). RESULTS: Main signals identified differed between asthmatic and nonasthmatic participants. None of the SNPs reached genome-wide significance. The association between the height-related gene DLEU7 and FEV(1) decrease suggested for nonasthmatic participants in the discovery phase was replicated (discovery, P = 4.8 × 10(-6); replication, P = .03), and additional sensitivity analyses point to a relation to growth. The top ranking signal, TUSC3, which is associated with FEV(1)/FVC ratio decrease in asthmatic participants (P = 5.3 × 10(-8)), did not replicate. SNPs previously associated with cross-sectional lung function were not prominently associated with decline. CONCLUSIONS: Genetic heterogeneity of lung function might be extensive. Our results suggest that genetic determinants of longitudinal and cross-sectional lung function differ and vary by asthma status. AU - Imboden, M.* AU - Bouzigon, E.* AU - Curjuric, I.* AU - Ramasamy, A.* AU - Kumar, A.* AU - Hancock, D.B.* AU - Wilk, J.B.* AU - Vonk, J.M.* AU - Thun, G.A. AU - Siroux, V.* AU - Nadif, R.* AU - Monier, F.* AU - Gonzalez, J.R.* AU - Wjst, M. AU - Heinrich, J. AU - Loehr, L.R.* AU - Franceschini, N.* AU - North, K.E.* AU - Altmüller, J.* AU - Koppelman, G.H.* AU - Guerra, S.* AU - Kronenberg, F.* AU - Lathrop, M* AU - Moffatt, M.F.* AU - O'Connor, G.T.* AU - Strachan, D.P.* AU - Postma, D.S.* AU - London, S.J.* AU - Schindler, C. AU - Kogevinas, M.* AU - Kauffmann, F.* AU - Jarvis, D.L.* AU - Demenais, F.* AU - Probst-Hensch, N.M.* C1 - 7490 C2 - 29750 SP - 1218-1228 TI - Genome-wide association study of lung function decline in adults with and without asthma. JO - J. Allergy Clin. Immunol. VL - 129 IS - 5 PB - Mosby-Elsevier PY - 2012 SN - 0091-6749 ER - TY - JOUR AB - no Abstract AU - Koletzko, S.* AU - Filipiak-Pittroff, B. AU - Koletzko, B.* AU - von Berg, A.* AU - Krämer, U.* AU - Berdel, D.* AU - Heinrich, J. C1 - 7211 C2 - 29563 SP - 262-262.e2 TI - No reason to change the current guidelines on allergy prevention. JO - J. Allergy Clin. Immunol. VL - 129 IS - 1 PB - Elsevier PY - 2012 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Cat exposure during childhood has been shown to increase the risk of developing cat sensitization, while the effect of cat exposure in adulthood has not yet been established. OBJECTIVE: To evaluate new-onset sensitization to cat in adulthood in relation to changes in cat keeping. METHODS: A total of 6292 European Community Respiratory Health Survey I (ECRHS I) participants aged 20 to 44 years from 28 European centers, who were not sensitized to cat, were reevaluated 9 years later in ECRHS II. Present and past cat ownership and total and specific IgE levels were assessed in both surveys. Allergen-specific sensitization was defined as a specific serum IgE level of 0.35 kU/L or more. RESULTS: A total of 4468 subjects did not have a cat in ECRHS I or ECRHS II, 473 had a cat only at baseline, 651 acquired a cat during the follow-up, and 700 had a cat at both evaluations. Two hundred thirty-one subjects (3.7%) became sensitized to cat. In a 2-level multivariable Poisson regression model, cat acquisition during follow-up was significantly associated with new-onset cat sensitization (relative risk = 1.85, 95% CI 1.23-2.78) when compared with those without a cat at both surveys. Preexisting sensitization to other allergens, a history of asthma, nasal allergies and eczema, and high total IgE level were also significant risk factors for developing cat sensitization, while cat ownership in childhood was a significant protective factor. CONCLUSION: Our data support that acquiring a cat in adulthood nearly doubles the risk of developing cat sensitization. Hence, cat avoidance should be considered in adults, especially in those sensitized to other allergens and reporting a history of allergic diseases. AU - Olivieri, M.* AU - Zock, J.P.* AU - Accordini, S.* AU - Heinrich, J. AU - Jarvis, D.* AU - Künzli, N.* AU - Antò, J.M.* AU - Norbäck, D.* AU - Svanes, C.* AU - Verlato, G* AU - European Community Respiratory Health Survey II (*) C1 - 7249 C2 - 29609 SP - 420-425 TI - Risk factors for new-onset cat sensitization among adults: A population-based international cohort study. JO - J. Allergy Clin. Immunol. VL - 129 IS - 2 PB - Elsevier PY - 2012 SN - 0091-6749 ER - TY - JOUR AU - Olivieri, M.* AU - Jarvis, D.* AU - Zock, J.P.* AU - Heinrich, J. AU - Antò, J.M.* AU - Verlato, G.* C1 - 7984 C2 - 29911 SP - 1690-1691 TI - Is cat-keeping the main determinant of new-onset adulthood cat sensitization? Reply JO - J. Allergy Clin. Immunol. VL - 129 IS - 6 PB - Mosby-Elsevier PY - 2012 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Enhanced apoptosis of keratinocytes is the main cause of eczema and spongiosis in patients with the common inflammatory skin disease atopic dermatitis (AD). OBJECTIVE: The aim of the study was to investigate molecular mechanisms of AD-related apoptosis of keratinocytes. METHODS: Primary keratinocytes isolated from patients with AD and healthy donors were used to study apoptosis by using annexin V/7-aminoactinomycin D staining. Illumina mRNA Expression BeadChips, quantitative RT-PCR, and immunofluorescence were used to study gene expression. In silico analysis of candidate genes was performed on genome-wide single nucleotide polymorphism data. RESULTS: We demonstrate that keratinocytes of patients with AD exhibit increased IFN-γ-induced apoptosis compared with keratinocytes from healthy subjects. Further mRNA expression analyses revealed differential expression of apoptosis-related genes in AD keratinocytes and skin and the upregulation of immune system-related genes in skin biopsy specimens of chronic AD lesions. Three apoptosis-related genes (NOD2, DUSP1, and ADM) and 8 genes overexpressed in AD skin lesions (CCDC109B, CCL5, CCL8, IFI35, LYN, RAB31, IFITM1, and IFITM2) were induced by IFN-γ in primary keratinocytes. The protein expression of IFITM1, CCL5, and CCL8 was verified in AD skin. In line with the functional studies and AD-related mRNA expression changes, in silico analysis of genome-wide single nucleotide polymorphism data revealed evidence of an association between AD and genetic markers close to or within the IFITM cluster or RAB31, DUSP1, and ADM genes. CONCLUSION: Our results demonstrate increased IFN-γ responses in skin of patients with AD and suggest involvement of multiple new apoptosis- and inflammation-related factors in the development of AD. AU - Rebane, A.* AU - Zimmermann, M.* AU - Aab, A.* AU - Baurecht, H.* AU - Koreck, A.* AU - Karelson, M.* AU - Abram, K.* AU - Metsalu, T.* AU - Pihlap, M.* AU - Meyer, N.* AU - Fölster-Holst, R.* AU - Nagy, N.* AU - Kemeny, L.* AU - Kingo, K.* AU - Vilo, J.* AU - Illig, T. AU - Akdis, M.* AU - Franke, A.* AU - Novak, N.* AU - Weidinger, S.* AU - Akdis, C.A.* C1 - 7497 C2 - 29757 SP - 1297-1306 TI - Mechanisms of IFN-γ-induced apoptosis of human skin keratinocytes in patients with atopic dermatitis. JO - J. Allergy Clin. Immunol. VL - 129 IS - 5 PB - Mosby-Elsevier PY - 2012 SN - 0091-6749 ER - TY - JOUR AU - Thyssen, J.P.* AU - Thuesen, B.* AU - Huth, C. AU - Standl, M. AU - Carson, C.G.* AU - Heinrich, J. AU - Krämer, U.* AU - Kratzsch, J.* AU - Berg, N.D.* AU - Menne, T.* AU - Johansen, J.D.* AU - Carlsen, B.C.* AU - Schwab, S. AU - Thorand, B. AU - Munk, M.* AU - Wallaschofski, H.* AU - Heickendorff, L.* AU - Meldgaard, M.* AU - Szecsi, P.B.* AU - Stender, S.* AU - Bonnelykke, K.* AU - Weidinger, S.* AU - Bisgaard, H.* AU - Linneberg, A.* C1 - 11264 C2 - 30590 SP - 1204-1207 TI - Skin barrier abnormality caused by filaggrin (FLG) mutations is associated with increased serum 25-hydroxyvitamin D concentrations. JO - J. Allergy Clin. Immunol. VL - 130 IS - 5 PB - Mosby-Elsevier PY - 2012 SN - 0091-6749 ER - TY - JOUR AB - Background: Bronchial asthma is a chronic inflammatory disease resulting from complex gene-environment interactions. Natural microbial exposure has been identified as an important environmental condition that provides asthma protection in a prenatal window of opportunity. Epigenetic regulation is an important mechanism by which environmental factors might interact with genes involved in allergy and asthma development. Objective: This study was designed to test whether epigenetic mechanisms might contribute to asthma protection conferred by early microbial exposure. Methods: Pregnant maternal mice were exposed to the farm-derived gram-negative bacterium Acinetobacter lwoffii F78. Epigenetic modifications in the offspring were analyzed in T(H)1- and T(H)2-relevant genes of CD4(+) T cells. Results: Prenatal administration of A lwoffii F78 prevented the development of an asthmatic phenotype in the progeny, and this effect was IFN-gamma dependent. Furthermore, the IFNG promoter of CD4(+) T cells in the offspring revealed a significant protection against loss of histone 4 (H4) acetylation, which was closely associated with IFN-gamma expression. Pharmacologic inhibition of H4 acetylation in the offspring abolished the asthma-protective phenotype. Regarding T(H)2-relevant genes only at the IL4 promoter, a decrease could be detected for H4 acetylation but not at the IL5 promoter or the intergenic T(H)2 regulatory region conserved noncoding sequence 1 (CNS1). Conclusion: These data support the hygiene concept and indicate that microbes operate by means of epigenetic mechanisms. This provides a new mechanism in the understanding of gene-environment interactions in the context of allergy protection. (J Allergy Clin Immunol 2011;128:618-25.) AU - Brand, S.* AU - Teich, R.* AU - Dicke, T.* AU - Harb, H.* AU - Yildirim, A.Ö. AU - Tost, J.* AU - Schneider-Stock, R.* AU - Waterland, R.A. * AU - Bauer, U.M.* AU - von Mutius, E.* AU - Garn, H.* AU - Pfefferle, P.I.* AU - Renz, H.* C1 - 6248 C2 - 29060 SP - 618-625 TI - Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes. JO - J. Allergy Clin. Immunol. VL - 128 IS - 3 PB - Mosby-Elsevier PY - 2011 SN - 0091-6749 ER - TY - JOUR AB - Allergic rhinitis symptoms of itching, sneezing, rhinorrhea, and nasal obstruction significantly decrease patients' quality of life. Compared with histamine and leukotriene receptor antagonists, the petasol butenoate complex Ze 339 displays pharmacologically distinct properties. In vitro it inhibits the biosynthesis of leukotrienes and mediator release from activated eosinophils. OBJECTIVE: This study aimed to assess the efficacy and mode of action of Ze 339, desloratadine, and placebo on allergic rhinitis symptoms, nasal airflow, and local mediator levels after unilateral nasal allergen provocation. METHODS: In this double-blind, randomized, crossover study 18 subjects with allergic rhinitis to grass pollen received Ze 339, desloratadine, and placebo for 5 days before nasal allergen challenge with grass pollen extract. Rhinomanometry, symptom assessment, and local inflammatory mediator measurement were performed during the 24 hours after allergen challenge. RESULTS: With Ze 339, the patient's time to recovery (5.4 ± 1.6 hours) from nasal obstruction after allergen challenge (time for return to 90% of baseline value ± SEM) was significantly shorter than with placebo (9.1 ± 2.3 hours, P = .035) and desloratadine (10.7 ± 2.5 hours, P = .022). Likewise, Ze 339's standardized symptom assessment for nasal obstruction (3.2 ± 1.3 hours) showed significantly faster relief (time for return to baseline value ± SEM compared with placebo, 8.3 ± 2.4 hours; P = .027) and desloratadine (4.5 ± 1.2 hours, P = .030). One interesting finding was that Ze 339 significantly reduced IL-8 and leukotriene B(4) levels in nasal secretions before challenge.CONCLUSION: When compared with desloratadine and placebo, Ze 339 shows better efficacy in relieving nasal obstruction symptoms and inhibiting critical components of the chemokine network and as such represents a novel symptomatic and possible prophylactic treatment for allergic rhinitis. AU - Dumitru, A.F.* AU - Shamji, M.* AU - Wagenmann, M.* AU - Hindersin, S.* AU - Scheckenbach, K.* AU - Greve, J.* AU - Klenzner, T.* AU - Hess, L.* AU - Nebel, S.* AU - Zimmermann, C.* AU - Zahner, C.* AU - Schmidt-Weber, C.B. AU - Chaker, A.* C1 - 6394 C2 - 28604 SP - 1515-1521 TI - Petasol butenoate complex (Ze 339) relieves allergic rhinitis-induced nasal obstruction more effectively than desloratadine. JO - J. Allergy Clin. Immunol. VL - 127 IS - 6 PB - Mosby, Inc. PY - 2011 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: It was reported that in infants with eczema and food sensitization, the presence of a filaggrin (FLG) null mutation predicts future asthma with a specificity and positive predictive value of 100%. OBJECTIVES: We sought to evaluate the predictive value of food sensitization and food allergy, FLG haploinsufficiency, and their combination in infants with early-onset eczema for persistent eczema and childhood asthma. METHODS: The German Infant Nutritional Intervention (GINI) and Influence of Lifestyle-related Factors on the Immune System and the Development of Allergies in Childhood (LISA) birth cohorts, as well as a collection of 65 cases of early-onset eczema with and without food allergy were investigated. RESULTS: The risk for asthma was significantly increased by food sensitization (positive diagnostic likelihood ratios [PLRs] of 1.9 [95% CI, 1.1-3.4] in the GINI cohort and 5.5 [95% CI, 2.8-10.8] in the LISA cohort) and the presence of an FLG mutation (PLRs of 2.9 [95% CI, 1.2-6.6] in the GINI cohort and 2.8 [95% CI, 1.0-7.9] in the LISA cohort) with a rather high specificity (79.1% and 92.9% in the GINI cohort and 89.0% and 91.7% in the LISA cohort, respectively) but low sensitivity (40.0% and 39.3% in the GINI cohort and 31.6% and 23.5% in the LISA cohort, respectively). Likewise, the risk for persistent eczema was increased. In the clinical cases neither food allergy nor FLG mutations had a significant effect. The combination of both parameters did not improve prediction and reached positive predictive values of 52.3% (GINI cohort), 66.9% (LISA cohort), and 30.6% (clinical cases), assuming an asthma prevalence in children with early eczema of 30%. CONCLUSION: Early food sensitization and the presence of an FLG mutation in infants with early eczema increase the risk for later asthma, but the combination of the 2 factors does not represent a clinically useful approach to reliably identify children at risk. AU - Filipiak-Pittroff, B. AU - Schnopp, C.* AU - Berdel, D.* AU - Naumann, A.* AU - Sedlmeier, S.* AU - Onken, A.* AU - Rodriguez, E.* AU - Fölster-Holst, R.* AU - Baurecht, H.* AU - Ollert, M.* AU - Ring, J.* AU - Cramer, C.* AU - von Berg, A.* AU - Bauer, C.P.* AU - Herbarth, O.* AU - Lehmann, I.* AU - Schaaf, B.* AU - Koletzko, S.* AU - Wichmann, H.-E. AU - Heinrich, J. AU - Weidinger, S.* AU - GINIplus Study Group (Schoetzau, A. AU - Mosetter, M. AU - Gehring, U. AU - Thaqi, A. AU - Sausenthaler, S. AU - Wichmann, H.-E. AU - Heinrich, J. AU - Popescu, M. AU - Schindler, J. AU - Franke, K. AU - Laubereau, B. AU - Zirngibl, A. AU - Zutavern, A.) AU - LISAplus Study Group (Schindler, J. AU - Höhnke, A. AU - Franke, K. AU - Laubereau, B. AU - Wichmann, H.-E. AU - Heinrich, J. AU - Bolte, G. AU - Belcredi, P. AU - Jacob, B. AU - Schoetzau, A. AU - Mosetter, M. AU - Sausenthaler, S. AU - Thaqi, A. AU - Zirngibl, A. AU - Zutavern, A.) C1 - 6808 C2 - 29292 SP - 1235-1241 TI - Predictive value of food sensitization and filaggrin mutations in children with eczema. JO - J. Allergy Clin. Immunol. VL - 128 IS - 6 PB - Mosby-Elsevier PY - 2011 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Water-soluble components from pollen modulate dendritic cell (DC) functions, such as IL-12 secretion and 3'-5'-cyclic adenosine monophosphate (cAMP) signaling and migration, possibly contributing to the establishment of a T(H)2-dominated immune response against pollen. Because these effects could not solely be attributed to the previously identified pollen-associated lipid mediators, the pollen metabolome was analyzed for candidate immunomodulatory substances. OBJECTIVE: We sought to perform an analysis of the effect of pollen-associated adenosine on DC function and T(H) cell differentiation. METHODS: Fractions of aqueous pollen extracts (APEs) were generated by means of ultrafiltration and were subjected simultaneously to biological tests and metabolome analysis (ultra-high-resolution mass spectrometry) and ultraperformance liquid chromatography. Effects of pollen-derived adenosine on monocyte-derived DC cAMP signaling, cytokine response, and capacity to differentiate T(H) cells were studied. RESULTS: The less than 3-kd fraction of APEs comprised thousands of substances, including adenosine in micromolar concentrations. Pollen-derived adenosine mediated A₂ receptor-dependent induction of cAMP and inhibition of IL-12p70 in DCs. APEs digested with adenosine deaminase failed to mediate IL-12 inhibition. DCs of nonatopic donors exposed to APEs showed an adenosine-dependent reduced capacity to differentiate T(H)1 cells and an enhanced capacity to induce regulatory T cells and IL-10. DCs of atopic donors failed to induce IL-10 but instead induced IL-5 and IL-13. CONCLUSION: This study identifies adenosine out of thousands of metabolites as a potent immunoregulatory substance in pollen. It acts on the level of the DC, with differential effects in atopic and nonatopic donors. AU - Gilles, S. AU - Fekete, A. AU - Zhang, X. AU - Beck, I. AU - Blume, C. AU - Ring, J.* AU - Schmidt-Weber, C.B. AU - Behrendt, H. AU - Schmitt-Kopplin, P. AU - Traidl-Hoffmann, C. C1 - 6391 C2 - 28601 SP - 454-461 TI - Pollen metabolome analysis reveals adenosine as a major regulator of dendritic cell-primed TH cell responses. JO - J. Allergy Clin. Immunol. VL - 127 IS - 2 PB - Elsevier PY - 2011 SN - 0091-6749 ER - TY - JOUR AB - Excessive extracellular matrix deposition occurs as a result of repetitive injury-repair cycles and plays a central role in the pathogenesis of chronic inflammatory diseases, such as allergic asthma. The molecular mechanism leading to aberrant collagen deposition is not fully understood. We sought to test the hypothesis that increased nerve growth factor (NGF) production contributes to collagen deposition in the airways during chronic allergic airway inflammation. Antibody-blocking experiments were performed in an in vivo model for chronic allergic airway inflammation (allergic asthma), which is accompanied by matrix deposition in the subepithelial compartment of the airways, to study the profibrotic effect of NGF. The signaling pathways were delineated with in vivo and in vitro studies in primary lung fibroblasts. Functional blocking of NGF in chronically affected mice markedly prevented subepithelial fibrosis. Transgenic overexpression of NGF in murine airways resulted in altered airway wall morphology with increased peribronchial collagen deposition and impaired lung physiology in the absence of inflammation. NGF exerted a direct effect on collagen expression in murine lung fibroblasts, which was mainly mediated through the activation of the receptor tropomyosin-related kinase A. NGF-induced collagen expression was dependent on downstream activation of p38 mitogen-activated protein kinase independent of the TGF-β1/mothers against decapentaplegic homolog (SMAD) pathway. AU - Kılıç, A.* AU - Sonar, S.S.* AU - Yildirim, A.Ö. AU - Fehrenbach, H.* AU - Nockher, W.A.* AU - Renz, H.* C1 - 6644 C2 - 29024 CY - New York, NY SP - 1058-1066 TI - Nerve growth factor induces type III collagen production in chronic allergic airway inflammation. JO - J. Allergy Clin. Immunol. VL - 128 IS - 5 PB - Elsevier PY - 2011 SN - 0091-6749 ER - TY - JOUR AU - Koletzko, S.* AU - Filipiak-Pittroff, B. AU - von Berg, A.* AU - Grubl, A.* AU - Heinrich, J. AU - Krämer, U.* AU - Wichmann, H.-E. AU - Bauer, C.-P.* AU - Reinhardt, D.* AU - Berdel, D.* C1 - 5941 C2 - 28419 CY - New York SP - 836-838 TI - Supplementation with cow's milk at birth is not recommended. JO - J. Allergy Clin. Immunol. VL - 127 IS - 3 PB - Mosby-Elsevier PY - 2011 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Rhinitis is an increasingly common condition with a heavy health care burden, but relatively little is known about its risk factors. OBJECTIVE: To examine the association between early-life factors and the development of rhinitis in the European Community Respiratory Health Study (ECRHS). METHODS: In 1992-1994, community-based samples of 20-44-year-old people were recruited from 48 centers in 22 countries. On average, 8.9 years later, 28 centers reinvestigated their samples. Onset of rhinitis was reported by 8486 participants in interviewer-led questionnaires. Cox regression was used to assess independent predictors of rhinitis at ages ≤5, 6-10, 11-20, and ≥21 years. RESULTS: The crude lifelong incidence of rhinitis was 7.00/1000/year (men) and 7.95/1000/year (women) (P = .002). Women developed less rhinitis in later childhood (hazard ratios [HR], 0.63; 95% CI, 0.47-0.85) and more rhinitis in adulthood (HR, 1.36; 95% CI, 1.11-1.66) than did men. In atopic subjects, siblings were associated with lower risk of rhinitis throughout life (pooled HR, 0.94; 95% CI, 0.91-0.98 per 1 sibling). Early contact with children in the family or day care was associated with less incidence of rhinitis, predominantly before age 5 years (HR, 0.84; 95% CI, 0.72-0.99). Early childhood pets or growing up on a farm was associated with less incidence of rhinitis in adolescence (HR, 0.50; 95% CI, 0.37-0.68). Combining these factors showed evidence of a dose-response relationship (trend P = .0001). CONCLUSIONS: Gender is a strong risk factor for rhinitis, with age patterns varying according to atopic status. Protective effects of early contact with children and animals were suggested for incident rhinitis, with risk patterns varying by age window and atopic status. AU - Matheson, M.C.* AU - Dharmage, S.C.* AU - Abramson, M.J.* AU - Walters, E.H.* AU - Sunyer, J.* AU - de Marco, R.* AU - Leynaert, B.* AU - Heinrich, J. AU - Jarvis, D.* AU - Norbäck, D.* AU - Raherison, C.* AU - Wjst, M. AU - Svanes, C.* C1 - 6571 C2 - 28883 SP - 816-823 TI - Early-life risk factors and incidence of rhinitis: Results from the European Community Respiratory Health Study - an international population-based cohort study. JO - J. Allergy Clin. Immunol. VL - 128 IS - 4 PB - American Academy of Allergy, Asthma & Immunology. PY - 2011 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Based on a recent positional cloning approach, it was claimed that the collagen 29A1 gene (COL29A1), which encodes an epidermal collagen, represents a major risk gene for eczema underlying a previously reported linkage to chromosome 3q21. However, thus far, not a single replication attempt has been published, and no definitive functional data have been provided. OBJECTIVES: We aimed to determine whether COL29A1 polymorphisms contribute to eczema susceptibility and whether COL29A1 expression is altered in eczema. METHODS: We investigated the reported association of COL29A1 variants with eczema, subtypes of eczema, and eczema-related traits in 5 independent and large study populations comprehensively phenotyped for allergic diseases: a set of 1687 German patients with eczema and 2387 population control subjects, a collection of 274 German families with eczema-diseases children, a cross-sectional population of German children (n = 3099), the Swedish population-based birth cohort Children Allergy and Milieu in Stockholm, an Epidemiologic Study (BAMSE) (n = 2033), and the European cross-sectional Prevention of Allergy-Risk Factors for Sensitization Related to Farming and Anthroposophic Lifestyle (PARSIFAL) study (n = 3113). An additional set of 19 COL29A1 coding single nucleotide polymorphisms was analyzed in BAMSE and PARSIFAL. COL29A1 expression was investigated by using in situ hybridization. RESULTS: We found no evidence for a relationship between COL29A1 polymorphisms and eczema. The equivalence test rejected the hypothesis of association even excluding small effects. In situ hybridization carried out on biopsy specimens from lesional and nonlesional skin of patients with eczema and from healthy control subjects did not show any differences in the cellular distribution pattern of COL29A1 expression at the mRNA level. CONCLUSIONS: Our results suggest that COL29A1 is unlikely to contain genetic variants that have a major effect on eczema or atopy susceptibility. AU - Naumann, A.* AU - Söderhäll, C.* AU - Fölster-Holst, R.* AU - Baurecht, H.* AU - Harde, V.* AU - Müller-Wehling, K.* AU - Rodriguez, E.* AU - Ruether, A.* AU - Franke, A.* AU - Wagenpfeil, S.* AU - Novak, N.* AU - Mempel, M.* AU - Kalali, BN.* AU - Allgaeuer, M.* AU - Koch, J.* AU - Gerhard, M.* AU - Melén, E.* AU - Wahlgren, C.F.* AU - Kull, I.* AU - Stahl, C.* AU - Pershagen, G.* AU - Lauener, R.* AU - Riedler, J.* AU - Doekes, G.* AU - Scheynius, A.* AU - Illig, T. AU - von, Mutius, E.* AU - Schreiber, S.* AU - Kere, J.* AU - Kabesch, M.* AU - Weidinger, S. C1 - 4061 C2 - 28571 SP - 1187-1194 TI - A comprehensive analysis of the COL29A1 gene does not support a role in eczema. JO - J. Allergy Clin. Immunol. VL - 127 IS - 5 PB - Mosby-Elsevier PY - 2011 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Hay fever or seasonal allergic rhinitis (AR) is a chronic disorder associated with IgE sensitization to grass. The underlying genetic variants have not been studied comprehensively. There is overwhelming evidence that those who have older siblings have less AR, although the mechanism for this remains unclear. OBJECTIVE: We sought to identify common genetic variant associations with prevalent AR and grass sensitization using existing genome-wide association study (GWAS) data and to determine whether genetic variants modify the protective effect of older siblings. METHOD: Approximately 2.2 million genotyped or imputed single nucleotide polymorphisms were investigated in 4 large European adult cohorts for AR (3,933 self-reported cases vs 8,965 control subjects) and grass sensitization (2,315 cases vs 10,032 control subjects). RESULTS: Three loci reached genome-wide significance for either phenotype. The HLA variant rs7775228, which cis-regulates HLA-DRB4, was strongly associated with grass sensitization and weakly with AR (P(grass) = 1.6 × 10(-9); P(AR) = 8.0 × 10(-3)). Variants in a locus near chromosome 11 open reading frame 30 (C11orf30) and leucine-rich repeat containing 32 (LRRC32), which was previously associated with atopic dermatitis and eczema, were also strongly associated with both phenotypes (rs2155219; P(grass) = 9.4 × 10(-9); P(AR) = 3.8 × 10(-8)). The third genome-wide significant variant was rs17513503 (P(grass) = 1.2 × 10(-8); PAR = 7.4 × 10(-7)) which was located near transmembrane protein 232 (TMEM232) and solute carrier family 25, member 46 (SLC25A46). Twelve further loci with suggestive associations were also identified. Using a candidate gene approach, where we considered variants within 164 genes previously thought to be important, we found variants in 3 further genes that may be of interest: thymic stromal lymphopoietin (TSLP), Toll-like receptor 6 (TLR6) and nucleotide-binding oligomerization domain containing 1 (NOD1/CARD4). We found no evidence for variants that modified the effect of birth order on either phenotype. CONCLUSIONS: This relatively large meta-analysis of GWASs identified few loci associated with AR and grass sensitization. No birth order interaction was identified in the current analyses. AU - Ramasamy, A.* AU - Curjuric, I.* AU - Coin, L.J.* AU - Kumar, A.* AU - McArdle, W.L.* AU - Imboden, M.* AU - Leynaert, B.* AU - Kogevinas, M.* AU - Schmid-Grendelmeier, P.* AU - Pekkanen, J.* AU - Wjst, M. AU - Bircher, A.J.* AU - Sovio, U.* AU - Rochat, T.* AU - Hartikainen, A.L.* AU - Balding, D.J.* AU - Jarvelin, M.R.* AU - Probst-Hensch, N.* AU - Strachan, D.P.* AU - Jarvis, D.L.* C1 - 5452 C2 - 29328 SP - 996-1005 TI - A genome-wide meta-analysis of genetic variants associated with allergic rhinitis and grass sensitization and their interaction with birth order. JO - J. Allergy Clin. Immunol. VL - 128 IS - 5 PB - Mosby PY - 2011 SN - 0091-6749 ER - TY - JOUR AB - Several studies showed a protective effect of elder siblings on eczema development, which is in line with the hygiene hypothesis. However, findings are not consistent, and there might exist different causal pathways for the development of eczema. Especially barrier disturbances as found in children with mutations in the filaggrin gene (FLG) seem to play an important role.OBJECTIVES: To investigate the interaction between FLG mutations and the presence of elder siblings on the development of eczema in 2 independent birth cohorts.METHODS: We used data from 2 German birth cohorts (LISAplus, GINIplus) up to the age of 6 years. Genotyping for FLG mutations (R501X, 2282del4) was performed in 1039 (LISAplus) and 1828 (GINIplus) children. Data on eczema (diagnosis and symptoms) and elder siblings were obtained by parental questionnaires. The association among eczema, FLG mutations, and elder siblings was analyzed longitudinally by using generalized estimating equations.RESULTS: We found no protective effect of elder siblings on eczema development. On the contrary, children with FLG mutations had a significantly higher risk for eczema if they had elder siblings. Attending day care centers lessened this effect. After excluding 303 children who attended early day care, the odds ratio for interaction between FLG mutations and elder siblings was 3.27 (95% CI, 1.14-9.36) in LISAplus and 2.41 (95% CI, 1.06-5.48) in GINIplus.CONCLUSION: Our findings did not confirm a protective sibling effect. The prevalence of eczema in children with filaggrin deficiency was higher if elder siblings were present. Our results give evidence for complex skin-driven pathogenic mechanisms that might be different depending on children's genetic backgrounds. AU - Cramer, C.* AU - Link, E.* AU - Horster, M.* AU - Koletzko, S.* AU - Bauer, C.P.* AU - Berde, l. D.* AU - von Berg, A.* AU - Lehmann, I.* AU - Herbarth, O.* AU - Borte, M.* AU - Schaaf, B.* AU - Behrendt, H. AU - Chen, C.M. AU - Sausenthaler, S. AU - Illig, T. AU - Wichmann, H.-E. AU - Heinrich, J. AU - Krämer, U.* C1 - 2035 C2 - 27888 SP - 1254-1260 TI - Elder siblings enhance the effect of filaggrin mutations on childhood eczema: Results from the 2 birth cohort studies LISAplus and GINIplus. JO - J. Allergy Clin. Immunol. VL - 125 IS - 6 PB - Mosby PY - 2010 SN - 0091-6749 ER - TY - JOUR AB - Background: Traditional farming represents a unique model situation to investigate the relationship of early-life farm-related exposure and allergy protection. Objectives: To investigate associations between maternal farm exposures and cytokine production in cord blood (CB) mononuclear cells in a prospective multinational birth cohort of 299 farm and 326 nonfarm children and their families. Methods: Supernatants from phorbol 12-myristate 13-acetate/ionomycin-stimulated CB mononuclear cells were assessed for the production of IFN-gamma, TNF-alpha, IL-5, IL-10, and IL-12. Results: Significantly higher levels of IFN-gamma and TNF-alpha in farm compared with nonfarm children were found, whereas IL-5, IL-10, and IL-12 levels did not differ between study groups. Maternal contact with different farm animal species and barns and consumption of farm-produced butter during pregnancy enhanced the production of proinflammatory CB cytokines, whereas maternal consumption of farm-produced yogurt resulted in significant lower levels of IFN-gamma and TNF-alpha in umbilical blood. Conclusion: Maternal exposure to farming activities and farm dairy products during pregnancy modulated cytokine production patterns of offspring at birth. AU - Pfefferle, P.I.* AU - Büchele, G.* AU - Blümer, N.* AU - Roponen, M.* AU - Ege, M.J.* AU - Krauss-Etschmann, S. AU - Genuneit, J.* AU - Hyvärinen, A.* AU - Hirvonen, M.R.* AU - Lauener, R.* AU - Pekkanen, J.* AU - Riedler, J.* AU - Dalphin, J.-C.* AU - Brunekeef, B.* AU - Braun-Fahrländer, C.* AU - von Mutius, E.* AU - Renz, H.* C1 - 4728 C2 - 28210 CY - New York SP - 108-115 TI - Cord blood cytokines are modulated by maternal farming activities and consumption of farm dairy products during pregnancy: The PASTURE study. JO - J. Allergy Clin. Immunol. VL - 125 IS - 1 PB - Mosby-Elsevier PY - 2010 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Severe side effects during venom immunotherapy (VIT) are associated with a variety of risk factors. OBJECTIVE: Our aim was to evaluate the association of baseline serum tryptase concentration (BTC) and of other parameters, which are routinely recorded during patient evaluation, with the frequency of severe reactions requiring an emergency intervention during the buildup phase of VIT. METHODS: In this observational prospective multicenter study, we enrolled 680 patients with established honeybee or vespid venom allergy who underwent VIT. Data were collected on tryptase concentration, age, sex, culprit insect, cardiovascular medication, degree of preceding sting reaction, preventive antiallergic medication before therapy, time between last preceding sting reaction and VIT, venom specific IgE concentration, and type of buildup procedure. Relative rates were calculated with generalized additive models. RESULTS: Fifty-seven patients (8.4%) required an emergency intervention during buildup because of a severe systemic reaction. The frequency of interventions increased significantly with higher BTC (log-linear association; adjusted odds ratio, 1.56; 95% CI, 1.15-2.11; P < .005). The predictive power of BTC was markedly greater when VIT was performed for vespid venom allergy than for bee venom (for bee VIT, no significant association; for vespid VIT, log-linear association; adjusted odds ratio, 2.33; 95% CI, 1.28-4.26; P = .005). The most important other factor significantly associated with severe reactions during the buildup phase of VIT was bee venom allergy. CONCLUSION: Before vespid VIT, measurement of baseline serum tryptase concentration should be used to identify patients with a high risk for side effects. Patients with bee venom allergy require a particularly high degree of surveillance during VIT. AU - Rueff, F.* AU - Przybilla, B.* AU - Bilo, M.B.* AU - Müller, U.* AU - Scheipl, F.* AU - Aberer, W.* AU - Birnbaum, J.* AU - Bodzenta-Lukaszyk, A.* AU - Bonifazi, F.* AU - Bucher, C.* AU - Campi, P.* AU - Darsow, U. AU - Egger, C.* AU - Haeberli, G.* AU - Hawranek, T.* AU - Kucharewicz, I.* AU - Küchenhoff, H.* AU - Lang, R.* AU - Quercia, O.* AU - Reider, N.* AU - Severino, M.* AU - Sticherling, M.* AU - Sturm, G.J.* AU - Wüthrich, B.* C1 - 2841 C2 - 27538 SP - 105-111 TI - Predictors of side effects during the buildup phase of venom immunotherapy for Hymenoptera venom allergy: The importance of baseline serum tryptase. JO - J. Allergy Clin. Immunol. VL - 126 IS - 1 PB - Mosby-Elsevier PY - 2010 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Cross-sectional studies suggest an association between eczema and mental health problems, but the temporal relationship is unclear. OBJECTIVE: To assess the association between infant-onset eczema and mental health problems in a prospective study. METHODS: Between 1995 and 1998, a birth cohort study was recruited and followed until age 10 years. Physician-diagnosed eczema, comorbidities, and a broad set of environmental exposures were assessed at age 1, 2, 3, 4, 6, and 10 years. First, we investigated the association between infant-onset eczema (age 1-2 years) and mental health problems at age 10 years according to the Strengths and Difficulties Questionnaire. Second, we analyzed the likelihood of mental health problems at age 10 years in relation to the course of eczema. RESULTS: A total of 2916 infants were eligible for analysis. Compared with participants never diagnosed as having eczema, children with infant-onset eczema had a significantly increased risk for possible/probable mental health problems (Strengths and Difficulties Questionnaire total score) at age 10 years (odds ratio, 1.49; 95% CI, 1.13-1.96) and for emotional symptoms (odds ratio, 1.62; 95% CI, 1.25-2.09). Eczema limited to infancy predicted a significantly higher risk for conduct problems at age 10 years. The strength of the association between eczema and emotional problems at age 10 years increased with increasing eczema persistence. CONCLUSION: Infants with eczema are at increased risk for mental health problems at age 10 years. Even if cleared afterward, eczema at age 1 to 2 years may cause persistent emotional and behavioral difficulties. AU - Schmitt, J.* AU - Apfelbacher, C.* AU - Chen, C.-M. AU - Romanos, M.* AU - Sausenthaler, S. AU - Koletzko, S.* AU - Bauer, C.P.* AU - Hoffmann, U.* AU - Krämer, U.* AU - Berdel, D.* AU - von Berg, A.* AU - Wichmann, H.-E. AU - Heinrich, J. C1 - 215 C2 - 27163 SP - 404-410 TI - Infant-onset eczema in relation to mental health problems at age 10 years: Results from a prospective birth cohort study (German Infant Nutrition Intervention plus). JO - J. Allergy Clin. Immunol. VL - 125 IS - 2 PB - American Academy of Allergy PY - 2010 SN - 0091-6749 ER - TY - JOUR AU - Schnabel, E. AU - Heinrich, J. C1 - 5498 C2 - 27920 SP - 1071-1073 TI - Respiratory tract infections and not paracetamol medication during infancy are associated with asthma development in childhood. JO - J. Allergy Clin. Immunol. VL - 126 IS - 5 PB - Mosby Inc. PY - 2010 SN - 0091-6749 ER - TY - JOUR AU - Suttner, K.* AU - Depner, M.* AU - Wetzke, M.* AU - Klopp, N. AU - von Mutius, E.* AU - Illig, T. AU - Sparwasser, T.* AU - Kabesch, M.* C1 - 1446 C2 - 27365 SP - 1395-1399 TI - Genetic variants harbored in the forkhead box protein 3 locus increase hay fever risk. JO - J. Allergy Clin. Immunol. VL - 125 IS - 6 PB - Mosby-Elsevier PY - 2010 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Patients with atopic eczema (AE) regularly experience colonization with Staphylococcus aureus that is directly correlated with the severity of eczema. Recent studies show that an impaired IL-17 immune response results in diseases associated with chronic skin infections. OBJECTIVE: We sought to elucidate the effect of IL-17 on antimicrobial immune responses in AE skin. METHODS: T cells infiltrating atopy patch test (APT) reactions were characterized for IL-17 secretion to varying stimuli. IL-17-dependent induction of the antimicrobial peptide human beta-defensin 2 (HBD-2) in keratinocytes was investigated. RESULTS: Approximately 10% of APT-infiltrating T cells secreted IL-17 after phorbol 12-myristate 13-acetate (PMA)/ionomycin stimulation. Among these, 33% belonged to the newly characterized subtype T(H)2/IL-17. Despite the capacity to secrete IL-17, specific T-cell clones released only low amounts of IL-17 on cognate allergen stimulation, whereas IL-4, IFN-gamma, or both were efficiently induced. IL-17 secretion was not enhanced by IL-23, IL-1 beta, or IL-6 but was enhanced by the S aureus-derived superantigen staphylococcal enterotoxin B. Both healthy and AE keratinocytes upregulated HBD-2 in response to IL-17, but coexpressed IL-4/IL-13 partially inhibited this effect. In vivo, additional application of staphylococcal enterotoxin B induced IL-17 in APT reactions, whereas IL-4, IFN-gamma, and IL-10 were marginally regulated. Induced IL-17 upregulated HBD-2 in human keratinocytes in vivo. CONCLUSION: IL-17-capable T cells, in particular T(H)2/IL-17 cells, infiltrate acute AE reactions. Although IL-17 secretion by specific T cells is tightly regulated, it can be triggered by bacteria-derived superantigens. The ineffective IL-17-dependent upregulation of HBD-2 in patients with AE is due to a partial inhibition by the type 2 microenvironment, which could partially explain why patients with AE do not clear S aureus. AU - Eyerich, K.* AU - Pennino, D.* AU - Scarponi, C.* AU - Förster, S.C. AU - Nasorri, F.* AU - Behrendt, H. AU - Ring, J. AU - Traidl-Hoffmann, C. AU - Albanesi, C.* AU - Cavani, A.* C1 - 996 C2 - 26101 SP - 59-66.e4 TI - IL-17 in atopic eczema: Linking allergen-specific adaptive and microbial-triggered innate immune response. JO - J. Allergy Clin. Immunol. VL - 123 IS - 1 PB - Elsevier PY - 2009 SN - 0091-6749 ER - TY - JOUR AU - Krauss-Etschmann, S. AU - Niedermaier, S. AU - Beyer, J.* AU - Campoy, C.* AU - Escolano, V.* AU - Decsi, T.* AU - Jakobik, V.* AU - Schendel, D.J. AU - Demmelmair, H.* AU - Heinrich, J. AU - Koletzko, B.V.* C1 - 900 C2 - 26134 SP - 1176-1178 TI - Current use of room disinfectants and allergic symptoms at the age of 4 years. JO - J. Allergy Clin. Immunol. VL - 123 IS - 5 PB - Mosby-Elsevier PY - 2009 SN - 0091-6749 ER - TY - JOUR AB - Background: The discovery of filaggrin (FLG) null mutations as a major risk factor for eczema represents a milestone toward the understanding of an important mechanism in this complex disease. However, published studies demonstrate differences concerning design and effect size, and conflicting results for asthma have been reported. Objectives: We sought to provide a more accurate estimate of FLG effect sizes and to better refine FLG risk profiles within the broad and inclusive eczema diagnosis. We also sought to provide a more detailed and conclusive estimate of the risk for asthma associated with FLG null alleles. Methods: We performed a meta-analysis of 24 studies on FLG mutations and eczema involving 5,791 cases, 26,454 control subjects, and 1,951 families as well as 17 studies on asthma involving 3,138 cases, 17,164 control subjects, and 1,511 offspring. Results: Both case-control and family studies showed strong associations with eczema. Case-control studies were heterogeneous, whereas family studies yielded more homogeneous results. Combined analysis showed that FLG haploinsufficiency strongly increases the eczema risk (odds ratio [OR], 3.12; 95% CI, 2.57-3.79) and is associated with more severe and dermatologist-diagnosed disease. FLG mutations are also significantly associated with asthma (OR, 1.48; 95% CI, 1.32-1.66). However, although strong effects for the compound phenotype asthma plus eczema (OR, 3.29; 95% CI, 2.84-3.82) were observed, there appears to be no association with asthma in the absence of eczema. Conclusions: This meta-analysis summarizes the strong evidence for a high eczema risk conferred by FLG mutations and refines their risk profiles, suggesting an association with more severe and secondary care disease. FLG mutations are also a robust risk factor for asthma and might help define the asthma endophenotype linked with eczema. AU - Rodriguez, E. AU - Baurecht, H. AU - Herberich, E.* AU - Wagenpfeil, S.* AU - Brown, S.J.* AU - Cordell, H.J.* AU - Irvine, A.D.* AU - Weidinger, S. C1 - 728 C2 - 26242 SP - 1361-1370 TI - Meta-analysis of filaggrin polymorphisms in eczema and asthma: Robust risk factors in atopic disease. JO - J. Allergy Clin. Immunol. VL - 123 IS - 6 PB - Mosby-Elsevier PY - 2009 SN - 0091-6749 ER - TY - JOUR AB - The IL-4/IL-13 pathway is central for IgE regulation. Signal transducer and activator of transcription 6 (STAT6) is the major transcription factor within this pathway. STAT6 polymorphisms were recently associated with elevated total IgE levels in a genome-wide association study. OBJECTIVE: This study aimed to assess biological mechanisms by which an IgE-associated genetic variation in STAT6 may potentially influence gene expression. METHODS: STAT6 intron 2 carrying either the wild-type C or the polymorphic T allele of the putatively causal single nucleotide polymorphism rs324011 was cloned into STAT6 promoter vectors to investigate their influence on STAT6 promoter activity by in vitro luciferase assays. Transcription factor binding depending on rs324011 was examined by electrophoretic mobility shift assays in Jurkat T cells and primary CD4(+) T cells. Allele-specific STAT6 gene expression of 3 splice variants was studied ex vivo by real-time PCR in 239 individuals. RESULTS: STAT6 intron 2 acts as a silencer regulatory element. The polymorphic T allele at rs324011 (in linkage disequilibrium with the genome-wide association signal and consistently associated with elevated IgE levels in 3 previous studies) increases STAT6 promoter activity significantly in vitro (P < .00001) and gene expression of STAT6 splice variants ex vivo (P < .01) compared with the wild-type C allele. These effects correlate with the creation of a novel, T-allele-specific binding site for the transcription factor nuclear factor-kappaB in T cells. CONCLUSION: The consistently replicated effects of genetic variance in STAT6 on IgE regulation may be explained in part by allele-specific alterations in nuclear factor-kappaB binding at rs324011 and consecutive changes in STAT6 gene expression. AU - Schedel, M.* AU - Frei, R.* AU - Bieli, C.* AU - Cameron, L.* AU - Adamski, J. AU - Lauener, R.* AU - Kabesch, M.* C1 - 1978 C2 - 26831 SP - 583-589 TI - An IgE-associated polymorphism in STAT6 alters NF-κB binding, STAT6 promoter activity, and MRNA expression. JO - J. Allergy Clin. Immunol. VL - 124 IS - 3 PY - 2009 SN - 0091-6749 ER - TY - JOUR AU - Suttner, K.* AU - Depner, M.* AU - Klopp, N. AU - Illig, T. AU - Vogelberg, C. AU - Adamski, J. AU - von Mutius, E.* AU - Kabesch, M.* C1 - 521 C2 - 26138 SP - 1179-1181 TI - Genetic variants in the GATA3 gene are not associated with asthma and atopic diseases in German children. JO - J. Allergy Clin. Immunol. VL - 123 IS - 5 PB - Mosby-Elsevier PY - 2009 SN - 0091-6749 ER - TY - JOUR AB - The T cell-specific T-box transcription factor (TBX21) plays a crucial role in the regulation of the immune system because this factor induces the differentiation of T(H)1 and blocks T(H)2 commitment together with the homeobox transcription factor HLX1. Objective: The role of genetic variants in TBX21 alone and in combination with HLX1 polymorphisms was investigated in the development of T(H)2-associated atopy and asthma. Methods: The TBX21 gene was resequenced in 37 adult volunteers. Polymorphisms identified were genotyped in a cross-sectional (N = 3099) and nested asthma case-control population (N = 1872) using mainly matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Effects of promoter polymorphisms on TBX21 gene expression were studied by reporter gene assays. Furthermore, the impact of combinations of TBX21 and HLX1 polymorphisms on the development of asthma was assessed by using a risk score model. Statistical analyses were performed by using SAS/Genetics. Results: Forty-three polymorphisms were identified in the TBX21 gene. Considering a minor allele frequency of at least 10%, single nucleotide polymorphisms were assigned to 7 linkage disequilibrium blocks. Three tagging single nucleotide polymorphisms increased childhood asthma risk significantly (odds ratio [OR], 2.60, 95% CI, 1.34-5.03, P = .003; OR, 1.39, 95% CI, 1.02-1.90, P = .039; and OR, 1.97,95% CI, 1.18-3.30, P = .009). TBX21 promoter polymorphisms contained in 2 blocks significantly influenced TBX21 promoter activity. In a risk score model, the combination of TBX21 and HLX1 polymorphisms increased the asthma risk by more than 3-fold. Conclusions: These data suggest that TBX21 polymorphisms contribute to the development of asthma, potentially by altering TBX21 promoter activity. A risk score model indicates that TBX21 and HLX1 polymorphisms may have synergistic effects on asthma risk. AU - Suttner, K.* AU - Rosenstiel, P.* AU - Depner, M.* AU - Schedel, M.* AU - Pinto, L.A.* AU - Ruether, A.* AU - Adamski, J. AU - Klopp, N. AU - Illig, T. AU - Vogelberg, C.* AU - Schreiber, S.* AU - von Mutius, E.* AU - Kabesch, M.* C1 - 522 C2 - 26139 SP - 1062-1068 TI - TBX21 gene variants increase childhood asthma risk in combination with HLX1 variants. JO - J. Allergy Clin. Immunol. VL - 123 IS - 5 PB - Mosby-Elsevier PY - 2009 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Major transcription factors controlling T(H)1 and T(H)2 development, such as T-box transcription factor and GATA3, might be centrally involved in asthma and atopic diseases. Only recently, the homeobox transcription factor H.20-like homeobox 1 (HLX1), interacting closely with T-box transcription factor, has been identified as an important regulator of T(H)1 differentiation and suppressor of T(H)2 commitment. OBJECTIVE: We investigated whether genetic variations in the HLX1 gene exist and whether these could affect the development of childhood asthma. METHODS: The HLX1 gene was resequenced in 80 chromosomes. Associations between identified polymorphisms, asthma, and atopic diseases were investigated in German children (total n = 3099) from the cross-sectional International Study of Asthma and Allergy in Childhood phase II. Functional properties of polymorphisms were studied by using luciferase reporter gene assays and electrophoretic mobility shift assays in T cells. All statistical analyses were performed with SAS/Genetics software (SAS Institute, Inc, Cary, NC). RESULTS: Nineteen polymorphisms were identified in the HLX1 gene, and 2 tagging single nucleotide polymorphisms representing 7 polymorphisms were associated with childhood asthma in our study population. Two promoter polymorphisms, C-1407T and C-742G, contained in 1 tagging block were associated with asthma (odds ratio, 1.44; 95% CI, 1.11-1.86; P = .0061), significantly decrease promoter transactivation, and disrupt specificity protein-transcription factor binding in in vitro experiments. CONCLUSIONS: Our data suggest that polymorphisms in the HLX1 gene increase the risk for childhood asthma. On the cellular level, altered binding of specificity protein-transcription factors to the HLX1 promoter and subsequent changes in HLX1 gene expression might contribute to these effects. AU - Suttner, K.* AU - Ruoss, I.* AU - Rosenstiel, P.* AU - Depner, M.* AU - Pinto, LA.* AU - Schedel, M.* AU - Adamski, J. AU - Illig, T. AU - Schreiber, S.* AU - von Mutius, E.* AU - Kabesch, M.* C1 - 2385 C2 - 25906 SP - 82-88 TI - HLX1 gene variants influence the development of childhood asthma. JO - J. Allergy Clin. Immunol. VL - 123 IS - 1 PB - Mosby, Inc. PY - 2009 SN - 0091-6749 ER - TY - JOUR AB - The question "What makes an allergen an allergen?" has puzzled generations of researchers, and we still do not have a conclusive answer. Despite increasing knowledge about the molecular and functional characteristics of allergens that have been identified, we still do not fully understand why some proteins are clinically relevant allergens and most are not. Different approaches have been taken to identify the structural and functional features of allergens, aiming at developing methods to predict allergenicity and thus to identify allergens. However, none of these methods has allowed a reliable discrimination between allergenic and nonallergenic compounds on its own. This review sums up diverse determinants that contribute to the phenomenon of allergenicity and outlines that in addition to the structure and function of the allergen, factors derived from allergen carriers, the environment, and the susceptible individual are of importance. AU - Traidl-Hoffmann, C. AU - Jakob, T.* AU - Behrendt, H. C1 - 34594 C2 - 41411 SP - 558-566 TI - Determinants of allergenicity. JO - J. Allergy Clin. Immunol. VL - 123 IS - 3 PY - 2009 SN - 0091-6749 ER - TY - JOUR AB - Professional use of hypochlorite (bleach) has been associated with respiratory symptoms. Bleach is capable of inactivating allergens, and there are indications that its domestic use may reduce the risk of allergies in children. OBJECTIVE: To study the associations between household use of bleach and atopic sensitization, allergic diseases, and respiratory health status in adults. METHODS: We identified 3626 participants of the European Community Respiratory Health Survey II in 10 countries who did the cleaning in their homes and for whom data on specific serum IgE to 4 environmental allergens were available. Frequency of bleach use and information on respiratory symptoms were obtained in face-to-face interviews. House dust mite and cat allergens in mattress dust were measured in a subsample. Associations between the frequency of bleach use and health outcomes were evaluated by using multivariable mixed logistic regression analyses. RESULTS: The use of bleach was associated with less atopic sensitization (odds ratio [OR], 0.75; 95% CI, 0.63-0.89). This association was apparent for specific IgE to both indoor (cat) and outdoor (grass) allergens, and was consistent in various subgroups, including those without any history of respiratory problems (OR, 0.85). Dose-response relationships (P < .05) were apparent for the frequency of bleach use and sensitization rates. Lower respiratory tract symptoms, but not allergic symptoms, were more prevalent among those using bleach 4 or more days per week (OR, 1.24-1.49). The use of bleach was not associated with indoor allergen concentrations. CONCLUSION: People who clean their homes with hypochlorite bleach are less likely to be atopic but more likely to have respiratory symptoms. AU - Zock, J.P.* AU - Plana, E.* AU - Antò, J.M.* AU - Benke, G.* AU - Blanc, P.D.* AU - Carosso, A.* AU - Dahlman-Höglund, A.* AU - Heinrich, J. AU - Jarvis, D.* AU - Kromhout, H.* AU - Lillienberg, L.* AU - Mirabelli, M.C.* AU - Norbäck, D.* AU - Olivieri, M.* AU - Ponzio, M.* AU - Radon, K.* AU - Soon, A.* AU - van Sprundel, M.* AU - Sunyer, J.* AU - Svanes, C.* AU - Torén, K.* AU - Verlato, G.* AU - Villani, S.* AU - Kogevinas, M.* C1 - 1630 C2 - 26559 SP - 731-738 TI - Domestic use of hypochlorite bleach, atopic sensitization, and respiratory symptoms in adults. JO - J. Allergy Clin. Immunol. VL - 124 IS - 4 PY - 2009 SN - 0091-6749 ER - TY - JOUR AB - Background: Previous cross-sectional surveys have suggested that maternal exposure to animal sheds during pregnancy exerted a protective effect on atopic sensitization in children lasting until school age. Objective: We sought to evaluate the effects of maternal exposure to animal sheds and other farm-related exposures during pregnancy on cord blood IgE levels in a prospective birth cohort. Methods: Pregnant women living in rural areas in Austria, Finland, France, Germany, and Switzerland were recruited in the third trimester of pregnancy. Information on maternal farm-related exposures, nutrition, and health during pregnancy was obtained by means of interviews. Specific IgE levels for food and common inhalant allergens were assessed in cord blood of 922 children and peripheral blood samples of their mothers. Results: Different sensitization patterns in cord blood of farm and nonfarm children were observed. In multivariable analysis consumption of boiled, but not unboiled, farm milk during pregnancy was positively associated with specific IgE to cow's milk independently from maternal IgE. In contrast, there was an inverse relationship between maternal exposure to animal sheds and cord blood IgE levels against seasonal allergens (adjusted odds ratio, 0.38; 95% CI, 0.21-0.70). This association was not confounded by maternal IgE levels. Maternal contact with hay enhanced the protective effect of exposure to animal sheds on IgE levels to grass pollen in cord blood. AU - Ege, M.J.* AU - Herzum, I.* AU - Büchele, G.* AU - Krauss-Etschmann, S. AU - Lauener, R.P.* AU - Roponen, M.* AU - Hyvärinen, A.* AU - Vuitton, D.A.* AU - Riedler, J.* AU - Brunekreef, B.* AU - Dalphin, J.-C.* AU - Braun-Fahrländer, C.* AU - Pekkanen, J.* AU - Renz, H.* AU - von Mutius, E.* AU - PASTURE Study Group (*) C1 - 3383 C2 - 25927 SP - 407-412 TI - Prenatal exposure to a farm environment modifies atopic sensitization at birth. JO - J. Allergy Clin. Immunol. VL - 122 IS - 2 PB - Mosby PY - 2008 SN - 0091-6749 ER - TY - JOUR AB - The association between allergic sensitization and eczema has been debated for years. OBJECTIVE: We sought to determine and compare the strength of the association between allergen skin sensitization and eczema in both developing and industrialized countries. METHODS: Twenty-eight thousand five hundred ninety-one randomly selected 8- to 12-year-old schoolchildren in 20 countries were physically examined for flexural eczema and received skin prick testing to Dermatophagoides pteronyssinus, Dermatophagoides farinae, cat hair, Alternaria tenuis, mixed tree and grass pollen, and allergens of local relevance. RESULTS: The age- and sex-adjusted odds ratios (ORs) for a positive association between flexural eczema and atopy ranged between 0.74 (95% CI, 0.31-1.81) and 4.53 (95% CI, 1.72-11.93), with a significantly stronger association in affluent compared with nonaffluent countries (combined age- and sex-adjusted OR(affluent) = 2.69 [95% CI, 2.31-3.13] and OR(nonaffluent) = 1.17 [95% CI, 0.81-1.70]). The combined population attributable fraction for atopy in flexural eczema was 27.9% for affluent and 1.2% for nonaffluent-country centers. Correlating gross national per-capita income with either ORs or population attributable fractions for atopy in flexural eczema confirmed a highly significant positive association (P = .006 and P < .001, respectively). CONCLUSIONS: The association between atopy and flexural eczema is weak and more variable than previously suggested, and the strength of this association is positively linked to gross national income. AU - Flohr, C.* AU - Weiland, S.K.* AU - Weinmayr, G.* AU - Björkstén, B.* AU - Bråbäck, L.* AU - Brunekreef, B.* AU - Büchele, G.* AU - Clausen, M.* AU - Cookson, W.O.* AU - von Mutius, E.* AU - Strachan, D.P.* AU - Williams, HC* AU - ISAAC Phase Two Study Group (*) C1 - 2854 C2 - 25292 SP - 141-147 TI - The role of atopic sensitization in flexural eczema: Findings from the International Study of Asthma and Allergies in Childhood Phase Two. JO - J. Allergy Clin. Immunol. VL - 121 IS - 1 PB - Mosby PY - 2008 SN - 0091-6749 ER - TY - JOUR AB - Primary cellular immunodeficiencies are a group of genetic disorders in which 1 or more components of the cellular immune system are lacking or dysfunctional. OBJECTIVE: We sought to identify novel mouse mutants that display primary cellular immunodeficiencies. METHODS: Genome-wide N-ethyl-N-nitrosourea mutagenesis was performed in mice, followed by a phenotype screen of immunologic blood parameters. RESULTS: We identified novel mouse mutants with isolated B-cell deficiency, combined block in early B- and T-cell development, combined T-cell and natural killer cell reduction, and 3 different forms of T-cell deficiencies. One of the mutants, designated DeltaT3, displayed a combined phenotype of increased IgE, absence of peripheral T cells, and block in late thymocyte differentiation. In addition, DeltaT3 mice were unable to mount specific humoral immune responses. Chromosomal mapping and sequencing of candidate genes revealed a novel point mutation in the kinase domain of the T-cell receptor zeta chain-associated protein kinase (Zap70). In contrast to Zap70-deficient mice, DeltaT3 mutants displayed normal Zap70 mRNA and residual Zap70 protein levels. Complementation studies with Zap70-deficient mice confirmed that the point mutation found in Zap70 was causative for the DeltaT3 phenotype, including increased IgE plasma levels, a phenotype that has not been associated with altered Zap70 function in the past. CONCLUSION: Random genome-wide mutagenesis combined with a phenotype screen can be used to generate novel mouse mutants with primary cellular immunodeficiencies. AU - Jakob, T. AU - Köllisch, G.V. AU - Howaldt, M.* AU - Bewersdorff, M. AU - Rathkolb, B.* AU - Müller, M.L.* AU - Sandholzer, N.* AU - Nitschke, L.* AU - Schiemann, M. AU - Mempel, M. AU - Ollert, M.* AU - Neubauer, A.* AU - Soewarto, D. AU - Kremmer, E. AU - Ring, J.* AU - Behrendt, H. AU - Flaswinkel, H.* C1 - 2675 C2 - 25594 SP - 179-184 TI - Novel mouse mutants with primary cellular immunodeficiencies generated by genome-wide mutagenesis. JO - J. Allergy Clin. Immunol. VL - 121 IS - 1 PB - Mosby PY - 2008 SN - 0091-6749 ER - TY - JOUR AB - Early exposure to microbes reduces the risk for asthma. Toll-like receptors (TLRs) represent a major group of receptors for the specific recognition of pathogen-associated molecular patterns of microbes capable of activating innate and adaptive immunity. OBJECTIVE: Because TLRs can influence key events in the induction and perpetuation of asthma and atopy, we sought to determine whether genetic alterations in TLR genes affect asthma risk. METHODS: We systematically evaluated putatively functional genetic variants in all 10 human TLR genes for their association with different asthma phenotypes in a case-control study (n = 1872) by using matrix-assisted laser desorption/ionization time-of-flight genotyping. For polymorphisms showing association with atopic asthma, effects on gene and protein expression were studied by means of RT-PCR and flow cytometry ex vivo. T-cell cytokine production was evaluated by means of ELISA after stimulation of the respective TLRs with specific ligands. RESULTS: Protective effects on atopic asthma were identified for single nucleotide polymorphisms in TLR1 (odds ratio [OR], 0.54; 95% CI, 0.37-0.81; P = .002), TLR6 (OR, 0.54; 95% CI, 0.37-0.79; P = .003), and TLR10 (OR, 0.58; 95% CI, 0.39-0.86; P = .006), all capable of forming heterodimers with TLR2. Effects remained significant after correction for multiple comparisons. PBMCs of minor allele carriers showed increased levels of the respective TLR mRNA and proteins, augmented inflammatory responses, increased T(H)1 cytokine expression, and reduced T(H)2-associated IL-4 production after specific stimulation. CONCLUSION: These results suggest that functional relevant TLR1 and TLR6 variants are directly involved in asthma development. AU - Kormann, M.S.D.* AU - Depner, M.* AU - Hartl, D.* AU - Klopp, N. AU - Illig, T. AU - Adamski, J. AU - Vogelberg, C.* AU - Weiland, S.K.* AU - von Mutius, E.* AU - Kabesch, M.* C1 - 2805 C2 - 25447 SP - 86-92 TI - Toll-like receptor heterodimer variants protect from childhood asthma. JO - J. Allergy Clin. Immunol. VL - 122 IS - 1 PB - Mosby PY - 2008 SN - 0091-6749 ER - TY - JOUR AB - Altered intakes of n-3 and n-6 polyunsaturated fatty acids were suggested to modulate allergic disease, but intervention trials yielded inconclusive results. Because allergies are primed in early infancy and in utero, the fetus might be more accessible to nutritional intervention strategies. OBJECTIVE: We sought to investigate how supplementation of pregnant women with a fish oil (FO) preparation modulates allergy-related immune parameters in mothers and offspring. METHODS: We performed a multicenter, randomized, double-blind, placebo-controlled trial. Three hundred eleven pregnant women received daily either FO with 0.5 g of docosahexaenoic acid and 0.15 g of eicosapentaenoic acid, 400 mug of methyl-tetra-hydrofolic acid, both, or placebo from the 22nd gestational week. T(H)1/T(H)2-related molecules were quantified in 197 maternal and 195 cord blood samples by using real-time RT-PCR. Data are given as geometric means [95% CIs]. RESULTS: FO supplementation was associated with increased TGF-beta mRNA in maternal (0.85 [0.8-0.89]; placebo: 0.68 [0.64-0.72]) and cord blood (0.85 [0.81-0.9]; placebo: 0.75 [0.71-0.79]). IL-1 (0.69 [0.66-0.73]; placebo: 0.83 [0.79-0.88]) and IFN-gamma (0.54 [0.51-0.57]; placebo: 0.65 [0.61-0.69]) were decreased in mothers only (P < .001). Cord blood mRNA levels of IL-4 (0.54 [0.52-0.57]; placebo: 0.64 [0.61-0.68]), IL-13 (0.61 [0.58-0.65]; placebo: 0.85 [0.80-0.89]), CCR4 (0.70 [0.67-0.73]; placebo: 0.88 [0.84-0.92]; all P < .001), and natural killer (P < .001) and CCR3+CD8+ T cells (P < .04) were decreased in the FO group. CONCLUSION: Supplementation with FO during pregnancy is associated with decreased mRNA levels of T(H)2-related molecules in the fetus and decreased maternal inflammatory cytokines. We speculate that both effects are mediated by TGF-beta. AU - Krauss-Etschmann, S. AU - Hartl, D. AU - Rzehak, P. AU - Heinrich, J. AU - Shadid, R. AU - Del Carmen Ramírez-Tortosa, M.* AU - Campoy, C.* AU - Pardillo, S.* AU - Schendel, D.J. AU - Decsi, T.* AU - Demmelmair, H.* AU - Koletzko, B.V.* AU - Nutraceuticals for Healthier Life Study Group (*) C1 - 633 C2 - 25275 SP - 464-470 TI - Decreased cord blood IL-4, IL-13, and CCR4 and increased TGF-β levels after fish oil supplementation of pregnant women. JO - J. Allergy Clin. Immunol. VL - 121 IS - 2 PB - Mosby PY - 2008 SN - 0091-6749 ER - TY - JOUR AB - Background: It is currently discussed whether allergic sensitization may start in utero under the influence of the maternal immune system and environmental determinants. Objective: To investigate the relationship between allergen-specific cord blood (CB) IgE levels, parental sensitization, CB cytokine production, and environmental influences. Methods: As part of an ongoing multicenter birth cohort study, allergen-specific IgE antibodies against 20 common seasonal, perennial, and food allergens were measured in blood samples from 922 neonates, 922 mothers, and 835 fathers. Supernatants from stimulated CB cells were assessed for the production of IL-5, IFN-gamma, IL-10, and TNF-alpha. Results: Allergen-specific IgE antibodies were detectable in 23.9% of newborns. Contamination with maternal serum was excluded by several means of analyses, including the absence of IgA antibodies. Clear correlation between maternal and fetal IgE was found only for hen's egg, cow's milk, and soybean allergen. Fetal IgE correlated negatively with the level of IFN-gamma production, but not with IL-5 and IL-10. Conclusion: Allergen-specific IgE antibodies most probably of fetal origin are detectable in CB and correlate with a lowered CB IFN-gamma production. AU - Pfefferle, P.I.* AU - Sel, S.* AU - Ege, M.J.* AU - Büchele, G.* AU - Blümer, N.* AU - Krauss-Etschmann, S. AU - Herzum, I.* AU - Albers, C.E.* AU - Lauener, R.P.* AU - Roponen, M.* AU - Hirvonen, M.R.* AU - Vuitton, D.A.* AU - Riedler, J.* AU - Brunekreef, B.* AU - Dalphin, J.-C.* AU - Braun-Fahrländer, C.* AU - Pekkanen, J.* AU - von Mutius, E.* AU - Renz, H* AU - PASTURE Study Group (*) C1 - 4516 C2 - 25928 SP - 711-716 TI - Cord blood allergen-specific IgE is associated with reduced IFN-gamma production by cord blood cells: The Protection against Allergy-Study in Rural Environments (PASTURE) study. JO - J. Allergy Clin. Immunol. VL - 122 IS - 4 PB - Mosby PY - 2008 SN - 0091-6749 ER - TY - JOUR AB - Cross-linking of mast cell-bound IgE releases proinflammatory mediators, cytokines, and proteolytic enzymes and is a key event in allergic inflammation. OBJECTIVE: We sought to study the effect of proteases released on effector cell activation on receptor-bound IgE and their possible role in the regulation of allergic inflammation. METHODS: Using molar ratios of purified recombinant tryptase and human IgE, we studied whether tryptase can cleave IgE. Similar experiments were performed with mast cell lysates in the presence or absence of protease inhibitors. IgE cleavage products were detected in supernatants of allergen cross-linked, cultivated mast cells and in tissue fluids collected from patients' skin after IgE-mediated degranulation. The effects of protamine, an inhibitor of heparin-dependent proteases on IgE-mediated allergic in vivo skin inflammation in human subjects were studied. RESULTS: We show that beta-tryptase, a major protease released during mast cell activation, cleaves IgE. IgE degradation products were detected in tryptase-containing tissue fluids collected from sites of allergic inflammation. The biologic significance of this mechanism is demonstrated by in vivo experiments showing that protease inhibition enhances allergic skin inflammation. CONCLUSION: We suggest that IgE cleavage by effector cell proteases is a natural mechanism for controlling allergic inflammation. AU - Rauter, I.* AU - Krauth, M.T.* AU - Westritschnig, K.* AU - Horak, F.* AU - Flicker, S.* AU - Gieras, A.* AU - Repa, A.* AU - Balic, N.* AU - Spitzauer, S.* AU - Huss-Marp, J. AU - Brockow, K. AU - Darsow, U. AU - Behrendt, H. AU - Ring, J. AU - Kricek, F.* AU - Valent, P.* AU - Valenta, R.* C1 - 1983 C2 - 25722 SP - 197-202 TI - Mast cell-derived proteases control allergic inflammation through cleavage of IgE. JO - J. Allergy Clin. Immunol. VL - 121 IS - 1 PB - Mosby PY - 2008 SN - 0091-6749 ER - TY - JOUR AB - There is limited information on potential changes in respiratory health when women enter the menopausal transition. OBJECTIVE: We sought to investigate whether the menopausal transition is related to lung function and asthma and whether body mass index (BMI) modifies associations. METHODS: Four thousand two hundred fifty-nine women from 21 centers (ECRHS II, 2002) responded to a questionnaire concerning women's health. Women aged 45 to 56 years not using exogenous sex hormones (n = 1274) were included in the present analysis. Lung function measurements (n = 1120) and serum markers of hormonal status (follicle-stimulating hormone, luteinizing hormone, and estradiol; n = 710) were available. Logistic and linear regression analyses were adjusted for BMI, age, years of education, smoking status, center, and height. RESULTS: Women not menstruating for the last 6 months (n = 432, 34%) had significantly lower FEV(1) values (-120 mL [95% CI, -177 to -63]), lower forced vital capacity values (-115 mL [95% CI, -181 to -50]), and more respiratory symptoms (odds ratio [OR], 1.82 [95% CI, 1.27-2.61]) than those menstruating regularly. Results were similar when restricting analyses to those who never smoked. Associations were significantly stronger in women with BMIs of less than 23 kg/m(2) (respiratory symptoms: OR, 4.07 [95% CI, 1.88-8.80]; FEV(1) adjusted difference: -166 [95% CI, -263 to -70]) than in women with BMIs of 23 to 28 kg/m(2) (respiratory symptoms: OR, 1.10 [95% CI, 0.61-1.97], P(interaction): .04; FEV(1) adjusted difference, -54 [95% CI, -151 to 43], P(interaction) = .06). CONCLUSIONS: Menopause is associated with lower lung function and more respiratory symptoms, especially among lean women. AU - Real, F.G.* AU - Svanes, C.* AU - Omenaas, E.R.* AU - Antò, J.M.* AU - Plana, E.* AU - Jarvis, D.* AU - Janson, C.* AU - Neukirch, F.* AU - Zemp, E.* AU - Dratva, J.* AU - Wjst, M. AU - Svanes, K.* AU - Leynaert, B.* AU - Sunyer, J.* C1 - 649 C2 - 25289 SP - 72-80 TI - Lung function, respiratory symptoms, and the menopausal transition. JO - J. Allergy Clin. Immunol. VL - 121 IS - 1 PB - Mosby PY - 2008 SN - 0091-6749 ER - TY - JOUR AU - Schnopp, C.* AU - Grosch, J.* AU - Ring, J. AU - Ollert, M.* AU - Mempel, M. C1 - 2676 C2 - 25597 SP - 267-268 TI - Microbial allergen-specific IgE is not suitable to identify the intrinsic form of atopic eczema in children. JO - J. Allergy Clin. Immunol. VL - 121 IS - 1 PB - Mosby PY - 2008 SN - 0091-6749 ER - TY - JOUR AB - The long-term effect of nutritional intervention with hydrolyzed infant formulas on allergy development has not been sufficiently evaluated. OBJECTIVE: We performed a follow-up of the German Infant Nutritional Intervention study until 6 years of life to investigate the long-term allergy-preventive effect of 3 hydrolyzed infant formulas compared with cow's milk formula (CMF) in a randomized, double-blind trial. METHODS: Between 1995 and 1998, 2252 newborns with atopic heredity were randomly assigned at birth to receive one of 4 blinded formulas: partially or extensively hydrolyzed whey formula, extensively hydrolyzed casein formula, or CMF as milk substitute for the first 4 months when breast-feeding was insufficient. The cohort was followed from birth until 6 years of age with yearly questionnaires. Outcomes were physician-diagnosed allergic diseases (atopic dermatitis, food allergy, allergic urticaria, asthma, and hay fever/allergic rhinitis). Log-binomial regression modeled with generalized estimation equations was used for the statistical analysis. RESULTS: In the intent-to-treat analysis the relative risk of a physician's diagnosis of allergic manifestation (AM) compared with CMF was 0.82 (95% CI, 0.70-0.96) for partially hydrolyzed whey formula, 0.90 (95% CI, 0.78-1.04) for extensively hydrolyzed whey formula, and 0.80 (95% CI, 0.69-0.93) for extensively hydrolyzed casein formula. The corresponding figures for atopic eczema were 0.79 (95% CI, 0.64-0.97), 0.92 (95% CI, 0.76-1.11), and 0.71 (95% CI, 0.58-0.88), respectively. In the per-protocol analysis all effects were stronger and significant. No significant effect on other AMs was found. CONCLUSION: The data confirm a long-term allergy-preventive effect of hydrolyzed infant formulas on AM and atopic eczema until 6 years of age. AU - von Berg, A.* AU - Filipiak-Pittroff, B.* AU - Krämer, U.* AU - Link, E.* AU - Bollrath, C.* AU - Brockow, I. AU - Koletzko, S.* AU - Grubl, A.* AU - Heinrich, J. AU - Wichmann, H.-E. AU - Bauer, C.P.* AU - Reinhardt, D.* AU - Berdel, D* AU - GINIplus Study Group (Heinrich, J. AU - Wichmann, H.-E.) C1 - 4574 C2 - 25487 SP - 1442-1447 TI - Preventive effect of hydrolyzed infant formulas persists until age 6 years: Long-term results from the German Infant Nutritional Intervention Study (GINI). JO - J. Allergy Clin. Immunol. VL - 121 IS - 6 PB - Mosby PY - 2008 SN - 0091-6749 ER - TY - JOUR AB - Mutations in the filaggrin gene (FLG) have been shown to play a significant role in ichthyosis vulgaris and eczema, 2 common chronic skin diseases. However, their role in the development of other atopic diseases such as asthma and rhinitis has not yet been clarified in large population-based studies. OBJECTIVES: To study the effect of FLG mutations at the population level and their effect on other atopic phenotypes. METHODS: Association analysis of the 2 common FLG-null mutations R501X and 2282del4 and 3 recently identified rare FLG variants (R2447X, S3247X, 3702delG) was performed on our cross-sectional population of German children (n = 3099) recruited as part of the International Study of Asthma and Allergies in Childhood II in Munich (n = 1159) and Dresden (n = 1940). RESULTS: FLG variants increased the risk for eczema more than 3-fold (odds ratio [OR], 3.12; 95% CI, 2.33-4.173; P = 2.5 x 10(-14); population-attributable risk, 13.5%). Independent of eczema, FLG mutations conferred a substantial risk for allergic rhinitis (OR, 2.64; 95% CI, 1.76-4.00; P = 2.5 x 10(-6); population-attributable risk, 10.8%). Nasal biopsies demonstrated strong filaggrin expression in the cornified epithelium of the nasal vestibular lining, but not the transitional and respiratory nasal epithelia. In contrast, the association with asthma (OR, 1.79; 95% CI, 1.19-2.68; P = .0048) was restricted to asthma occurring in the context of eczema, and there was a strong association with the complex phenotype eczema plus asthma (OR, 3.49; 95% CI, 2.00-6.08; P = 1.0 x 10(-5)). CONCLUSION: Our results suggest that FLG mutations are key organ specific factors predominantly affecting the development of eczema and confer significant risks of allergic sensitization and allergic rhinitis as well as asthma in the context of eczema. AU - Weidinger, S. AU - O'Sullivan, M.* AU - Illig, T. AU - Baurecht, H. AU - Depner, M.* AU - Rodriguez, E. AU - Ruether, A.* AU - Klopp, N. AU - Vogelberg, C.* AU - Weiland, S.K.* AU - McLean, W.H.* AU - von Mutius, E.* AU - Irvine, A.D.* AU - Kabesch, M.* C1 - 778 C2 - 25386 SP - 1203-1209 TI - Filaggrin mutations, atopic eczema, hay fever, and asthma in children. JO - J. Allergy Clin. Immunol. VL - 121 IS - 5 PB - Mosby PY - 2008 SN - 0091-6749 ER - TY - JOUR AB - Polymorphisms in the serine protease inhibitor gene serine peptidase inhibitor Kazal type 5 (SPINK5) and the serine protease kallikrein-related peptidase 7 gene (KLK7) appear to confer risk to eczema in some cohorts, but these findings have not been widely replicated. These genes encode proteins thought to be involved in the regulation of posttranslation processing of filaggrin (FLG), the strongest identified genetic risk factor for eczema to date. OBJECTIVES: We sought to clarify the individual risk of eczema conferred by the SPINK5 polymorphism rs2303067 (Glu420Lys) and a previously described insertion in the 3' untranslated region of KLK7 and to examine potential epistatic effects between these variants and FLG mutations. METHODS: Initially, we examined the effects of these polymorphisms and FLG in 486 unrelated patients from a German family-based study, an additional 287 German patients, and 418 unrelated Irish/English patients with eczema (n for 3 genes studied = 1191 vs 4544 control subjects). We then additionally studied the SPINK5 polymorphism and FLG mutations in 1583 patients with eczema from the Avon Longitudinal Study of Parents and Children cohort (sample size for 2 genes studied = 2774 vs 10,607 control subjects). RESULTS: No association was seen with the SPINK5 or KLK7 variants in the case-control analysis; however, a weaker effect was observed for the SPINK5 variant with maternal transmission in the family-based study. No interactions were seen between the polymorphisms in KLK7, SPINK5, and FLG. CONCLUSION: The SPINK5 420LysSer mutation confers a risk of eczema when maternally inherited but is not a major eczema risk factor. The KLK7 insertion appears to confer no risk of eczema. We found no interaction between the SPINK5 risk allele or the putative KLK7 risk allele and FLG mutations. AU - Weidinger, S. AU - Baurecht, H. AU - Wagenpfeil, S.* AU - Henderson, J.* AU - Novak, N.* AU - Sandilands, A.* AU - Chen, H.* AU - Rodriguez, E. AU - O'Regan, G.M.* AU - Watson, R.* AU - Liao, H.* AU - Zhao, Y.* AU - Barker, J.N.* AU - Allen, M.* AU - Reynolds, N.* AU - Meggitt, S.* AU - Northstone, K.* AU - Smith, G.D.* AU - Strobl, C.* AU - Stahl, C.* AU - Kneib, T.* AU - Klopp, N.* AU - Bieber, T.* AU - Behrendt, H. AU - Palmer, C.N.* AU - Wichmann, H.-E. AU - Ring, J. AU - Illig, T. AU - McLean, W.H.* AU - Irvine, A.D.* C1 - 2545 C2 - 25725 SP - 560-568 TI - Analysis of the individual and aggregate genetic contributions of previously identified serine peptidase inhibitor Kazal type 5 (SPINK5), kallikrein-related peptidase 7 (KLK7), and filaggrin (FLG) polymorphisms to eczema risk. JO - J. Allergy Clin. Immunol. VL - 122 IS - 3 PB - Mosby PY - 2008 SN - 0091-6749 ER - TY - JOUR AU - Wjst, M. C1 - 4515 C2 - 25805 SP - 1065-1066 TI - Allergy risk of vitamin D supplements has been described in various settings. JO - J. Allergy Clin. Immunol. VL - 121 IS - 4 PB - Mosby PY - 2008 SN - 0091-6749 ER - TY - JOUR AB - With an impressive series of replication studies, filaggrin (FLG) has become the gene with the most widely replicated association to atopic eczema (AE). However, studies published to date demonstrate differences concerning study design and strength of associations. OBJECTIVES: We sought to provide a general and overall estimate of FLG effect sizes and to estimate allele and carrier frequencies. METHODS: We searched Medline and Institute for Scientific Information Web of Knowledge databases for relevant studies and abstracts from professional societies that were published through June 30, 2007. Initially, we accounted for different study types and evaluated an overall estimate for case-control and family studies. In a second step, we combined those 2 study types and used a random-effects analysis approach to calculate overall odds ratios (ORs). Tests of asymmetry were applied to detect potential publication bias. RESULTS: Nine studies that met the inclusion criteria were included in the meta-analysis. For the combined genotype (R501X or 2282del4), we found an overall OR of 4.09 (95% CI, 2.64-6.33) from the case-control studies and a summary OR of 2.06 (95% CI, 1.76-2.42) from the family studies. CONCLUSION: The powerful effect of FLG variation on AE risk exceeds that of any other investigated candidate gene for AE thus far and makes FLG one of the strongest genes known to date for complex diseases. CLINICAL IMPLICATIONS: These results underline the importance of a genetically determined epidermal barrier disruption in AE. AU - Baurecht, H. AU - Irvine, A.D.* AU - Novak, N.* AU - Illig, T. AU - Bühler, B. AU - Ring, J. AU - Wagenpfeil, S.* AU - Weidinger, S. C1 - 2290 C2 - 25009 SP - 1406-1412 TI - Toward a major risk factor for atopic eczema: Meta-analysis of filaggrin polymorphism data. JO - J. Allergy Clin. Immunol. VL - 120 IS - 6 PB - Mosby PY - 2007 SN - 0091-6749 ER - TY - JOUR AU - Belloni, B.* AU - Ziai, M.* AU - Lim, A.* AU - Lemercier, B.* AU - Sbornik, M.* AU - Weidinger, S.* AU - Andres, C.* AU - Schnopp, C.* AU - Ring, J.* AU - Hein, R.* AU - Ollert, M.* AU - Mempel, M.* C1 - 1288 C2 - 25068 SP - 1223-1225 TI - Low-dose anti-IgE therapy in patients with atopic eczema with high serum IgE levels. JO - J. Allergy Clin. Immunol. VL - 120 IS - 5 PB - Mosby PY - 2007 SN - 0091-6749 ER - TY - JOUR AB - The influence of cat allergen exposure in early childhood on the development of sensitization and allergic diseases is complex. Little is known about the natural course of the sensitization development within individuals.We investigated the association between cat allergen exposure in infancy and cat ownership and cat contact during childhood and the development of cat sensitization and allergic diseases up to age 6 years using a longitudinal analysis approach.Overall, 2166 children from an ongoing birth cohort study were included in the analysis. House dust samples were collected 3 months after birth. Cat allergen levels were extracted. Blood samples were collected when the children were 2 and 6 years old. Information on the allergic symptoms of children and doctor-diagnosed allergic disease were collected at each follow-up using questionnaires.Cat allergen exposure in infancy was positively associated with sensitization at age 2 years but not at age 6 years. No associations existed between cat allergen exposure in infancy and allergic symptoms and diseases up to age 6 years. Cumulative allergen exposure from cat ownership and regular cat contact increased the risk of cat sensitization up to age 6 years.Cat allergen exposure in infancy increases the risk of sensitization development in early childhood but not in school-age children. Cumulative allergen exposure from cat ownership and regular cat contact during childhood contribute to sensitization development up to school age. Clinical implications Cat allergen avoidance at home alone might be not effective to prevent the development of allergic sensitization in young children. AU - Chen, C.M. AU - Rzehak, P. AU - Zutavern, A. AU - Fahlbusch, B.* AU - Bischof, W.* AU - Herbarth, O.* AU - Borte, M.* AU - Lehmann, I.* AU - Behrendt, H. AU - Krämer, U.* AU - Wichmann, H.-E. AU - Heinrich, J. AU - LISAplus Study Group (Wichmann, H.-E. AU - Heinrich, J. AU - Bolte, G. AU - Belcredi, P. AU - Jacob, B. AU - Schoetzau, A. AU - Mosetter, M. AU - Schindler, J. AU - Höhnke, A.) C1 - 5196 C2 - 24505 SP - 1148-1155 TI - Longitudinal study on cat allergen exposure and the development of allergy in young children. JO - J. Allergy Clin. Immunol. VL - 119 IS - 5 PB - Mosby PY - 2007 SN - 0091-6749 ER - TY - JOUR AB - We recently demonstrated that pollen not only function as allergen carriers but also as rich sources of bioactive lipids, such as phytoprostanes, that modulate human dendritic cell (DC) function in a way that results in an enhanced T(H)2 polarization in vitro. OBJECTIVE: Here we analyzed the immunomodulatory capacities of Betula alba (white birch) aqueous pollen extracts (Bet-APEs) and pollen-associated phytoprostanes in the murine system in vitro and in vivo. METHODS: DC function was analyzed in vitro by using BALB/c bone marrow-derived DCs. T-cell responses were analyzed with DO11.10 peptide 323-339 from chicken ovalbumin (OVA)-specific CD4 T cells as responder cells. For in vivo studies, OVA-specific CD4 T cells were adoptively transferred into BALB/c mice. Twenty-four hours later, mice were challenged by means of intranasal application of OVA in the absence or presence of Bet-APEs or phytoprostanes. Polarization of T-cell responses in vivo was analyzed in draining lymph node cells. RESULTS: In vitro Bet-APEs and E(1)-phytoprostanes dose-dependently inhibited LPS-induced IL-12p70 of DCs. In addition, Bet-APEs induced a T(H)2 polarization in vitro. Similarly, intranasal instillation of Bet-APEs in vivo, together with the antigen, lead to increased IL-4, IL-5, and IL-13 secretion and decreased IFN-gamma secretion from antigen-specific T cells in the draining lymph nodes. In contrast, intranasal E1- and F1-phytoprostanes downregulated both T(H)1 and T(H)2 cytokine production in vivo. CONCLUSION: Pollen release water-soluble factors that display T(H)2-polarizing capacities in vivo independently of E(1)- and F(1)-phytoprostanes. CLINICAL IMPLICATIONS: Identification of the underlying mechanisms might open new approaches for pharmacologic intervention. AU - Gutermuth, J. AU - Bewersdorff, M.* AU - Traidl-Hoffmann, C. AU - Ring, J.* AU - Mueller, M.J. AU - Behrendt, H. AU - Jakob, T. C1 - 4022 C2 - 24727 SP - 293-299 TI - Immunomodulatory effects of aqueous birch pollen extracts and phytoprostanes on primary immune responses in vivo. JO - J. Allergy Clin. Immunol. VL - 120 IS - 2 PB - Mosby PY - 2007 SN - 0091-6749 ER - TY - JOUR AB - Asthma is characterized by a T(H)2 immune response. CD4(+)CD25(hi) regulatory T cells (Tregs) have been proposed to prevent allergic diseases through suppression of T(H)2 responses. OBJECTIVE: We sought to investigate the role of CD4(+)CD25(hi) T cells in children with asthma. METHODS: CD4(+)CD25(hi) Tregs and forkhead/winged-helix transcription factor FOXP3 mRNA levels were quantified in peripheral blood and bronchoalveolar lavage fluid (BALF) of 18 children with asthma, 10 children with chronic cough, and 13 control subjects without lung diseases. CD4(+)CD25(hi) T cells were isolated from peripheral blood and BALF of asthmatic patients and control subjects, and their capacity to suppress proliferation and cytokine/chemokine production of autologous responder T cells was analyzed. RESULTS: CD4(+)CD25(hi) T cells were decreased in BALF of asthmatic children compared with values in children with cough or control subjects. In children with asthma, inhaled corticosteroid treatment was associated with increased percentages of CD4(+)CD25(hi) T cells in peripheral blood and BALF. Isolated BALF and peripheral blood CD4(+)CD25(hi) T cells from nonasthmatic subjects suppressed proliferation and cytokine/chemokine production by CD4(+)CD25(-) responder T cells. BALF CD4(+)CD25(hi) T cells from asthmatic subjects failed to suppress proliferation and production of T(H)2-associated cytokines and chemokines by CD4(+)CD25(-) responder T cells, which was restored after use of inhaled corticosteroids. CONCLUSION: These findings provide the first evidence that pulmonary CD4(+)CD25(hi) Tregs are impaired in pediatric asthma. CLINICAL IMPLICATIONS: Pulmonary Tregs might represent a therapeutic target in pediatric asthma. AU - Hartl, D.* AU - Koller, B. AU - Mehlhorn, A.T.* AU - Reinhardt, D.* AU - Nicolai, T.* AU - Schendel, D.J. AU - Griese, M.* AU - Krauss-Etschmann, S. C1 - 3172 C2 - 24751 SP - 1258-1266 TI - Quantitative and functional impairment of pulmonary CD4⁺CD25hi regulatory T cells in pediatric asthma. JO - J. Allergy Clin. Immunol. VL - 119 IS - 5 PB - Mosby PY - 2007 SN - 0091-6749 ER - TY - JOUR AU - Huss-Marp, J. AU - Krämer, U.* AU - Eberlein, B. AU - Pfab, F. AU - Ring, J.* AU - Behrendt, H. AU - Gulyas, A.F.* C1 - 1289 C2 - 25070 SP - 1227-1228 TI - Exhaled nitric oxide in children with asthma at high altitude - Reply JO - J. Allergy Clin. Immunol. VL - 120 IS - 5 PB - Mosby PY - 2007 SN - 0091-6749 ER - TY - JOUR AU - Huss-Marp, J. AU - Krämer, U.* AU - Eberlein, B. AU - Pfab, F. AU - Ring, J.* AU - Behrendt, H. AU - Gulyas, A.F.* C1 - 4021 C2 - 24721 SP - 470-471 TI - Reduced exhaled nitric oxide values in children with asthma after inpatient rehabilitation at high altitude. JO - J. Allergy Clin. Immunol. VL - 120 IS - 2 PB - Mosby PY - 2007 SN - 0091-6749 ER - TY - JOUR AB - Exposure to allergen may induce a modified T(H)2 response characterized by high IgG(4) levels, absence of IgE sensitization, and a decreased risk of allergic respiratory symptoms. OBJECTIVE: To assess the association of IgG(4) level with allergic respiratory symptoms in a community-based sample of adults. METHODS: Information on exposure to cats, respiratory symptoms, and mattress allergen levels was obtained from 2780 adults. Levels of cat and house dust mite (HDM) specific IgE, IgG, and IgG(4) were measured. The association of exposure to allergen with IgG(4) and of IgG(4) with symptoms was assessed. RESULTS: Geometric mean (GM) cat specific IgG and IgG(4) was higher in subjects who had a cat that was allowed in the bedroom than in subjects without a cat (adjusted ratio of GM IgG(4), 1.41; 95% CI, 1.25-1.57). Levels of HDM specific IgG and IgG(4) were similar in subjects with undetectable and high (>20.22 microg/g) mattress Der 1 levels (adjusted ratio of GM IgG(4), 1.02; 95% CI, 0.89-1.17). There was no evidence that high cat or HDM specific IgG(4) levels were associated with less IgE sensitization or with fewer symptoms. CONCLUSION: In this community-based sample of adults, high IgG(4) levels to cat or HDM were not associated with a lower risk of allergic respiratory symptoms. CLINICAL IMPLICATIONS: In adults, high cat allergen exposure does not protect against respiratory symptoms. AU - Jarvis, D.* AU - Zock, J.P.* AU - Heinrich, J. AU - Svanes, C.* AU - Verlato, G.* AU - Olivieri, M.* AU - Villani, S.* AU - Ponzio, M.* AU - Leynaert, B.* AU - Sunyer, J.* AU - Dahlman-Höglund, A.* AU - Chinn, S.* AU - Luczynska, C.* AU - Norbäck, D.* AU - Burney, P.* C1 - 1784 C2 - 24948 SP - 697-704 TI - Cat and dust mite allergen levels, specific IgG and IgG4, and respiratory symptoms in adults. JO - J. Allergy Clin. Immunol. VL - 119 IS - 3 PB - Mosby PY - 2007 SN - 0091-6749 ER - TY - JOUR AU - Kerzl, R.* AU - Simonowa, A.* AU - Ring, J.* AU - Ollert, M. AU - Mempel, M. C1 - 4442 C2 - 24720 SP - 507-508 TI - Life-threatening anaphylaxis to kiwi fruit: Protective sublingual allergen immunotherapy effect persists even after discontinuation. JO - J. Allergy Clin. Immunol. VL - 119 PB - Mosby PY - 2007 SN - 0091-6749 ER - TY - JOUR AB - Patients with atopic diseases are characterized by high levels of specific IgE production. However, little is known about the composition of their B-cell repertoires. OBJECTIVES: We sought to analyze the complete PBMC-derived IgE repertoire and to compare clonal expansions between different patients. METHODS: We have analyzed the IgE-bearing B-cell receptor repertoire in highly atopic patients (>1000 IU/mL) using quantitative RT-PCR, complementarity determining region 3 spectratyping, and sequence analysis. Three representative patients were additionally followed during anti-IgE therapy. RESULTS: Atopic patients exhibited 100 to 1000 times more IgE-specific transcripts than control individuals. These patients used a variable region of the heavy immunoglobulin chain (VH) epsilon repertoire highly similar to their IgM and IgG repertoires, with preference of VH3b, VH4, VH3a, and VH1 segments. Each patient harbored individual clonal expansions, most probably as correlation of allergen-specific IgE production. Common expansions within the complementary determining region 3 shared by several individuals with similar sensitization patterns were found in spectratyping analysis. However, these antigen-driven expansions showed differences on the sequence level. In omalizumab-treated patients the clinical improvement was paralleled by a clear increase in the ratio of IgG/IgE transcripts. CONCLUSION: The IgE repertoire in atopic patients follows the VH use patterns seen for other immunoglobulins and seems to preferentially recruit individual rearrangements rather than public expansions. CLINICAL IMPLICATIONS: The detailed analysis of the IgE B-cell repertoire is highly suitable to follow changes in IgE uses during different therapy modalities. AU - Lim, A. AU - Luderschmidt, S.* AU - Weidinger, A.* AU - Schnopp, C.* AU - Ring, J.* AU - Hein, R.* AU - Ollert, M.* AU - Mempel, M. C1 - 1383 C2 - 24719 SP - 696-706 TI - The IgE repertoire in PBMCs of atopic patients is characterized by individual rearrangements without variable region of the heavy immunoglobulin chain bias. JO - J. Allergy Clin. Immunol. VL - 120 IS - 3 PB - Mosby PY - 2007 SN - 0091-6749 ER - TY - JOUR AB - Oligomenorrhea was associated with more asthma (Respiratory Health in Northern Europe study), but a possible association with lung function has not been investigated previously. OBJECTIVE: To investigate whether oligomenorrhea was related to lung function and asthma, and whether body mass index and physical activity modified associations. METHODS: Women age 28 to 44 years (n = 1631) participating in the European Community Respiratory Health Survey were included. Women who were taking exogenous sex hormones, were pregnant, or had recently given birth were excluded. RESULTS: Long or irregular menstrual cycles were reported by 313 women (19%). Oligomenorrhea was significantly associated with more asthma symptoms (odds ratio [OR], 1.76; 95% CI, 1.29-2.40), allergic asthma (OR, 2.46; 95% CI, 1.43-4.23), and lower forced vital capacity (FVC; adjusted difference, 63 mL; 95% CI, -124 to -1). When excluding women using asthma medication, very lean women, or women exercising daily, these associations remained significant. Effects of oligomenorrhea were additive to those of body mass index (BMI) on asthma and FVC. Asthma symptoms increased significantly with BMI. FVC and FEV(1) increased with BMI until 25 kg/m(2) and thereafter decreased with increasing BMI. Excluding women exercising daily, asthma symptoms increased significantly with decreasing physical activity (OR, 1.09; 95% CI, 1.001-1.19) per category of physical activity) independently of oligomenorrhea. Among women exercising daily, oligomenorrhea predicted very high risk for asthma symptoms (OR, 12.6; 95% CI, 3.7-43). CONCLUSION: Women with oligomenorrhea have reduced lung function and more asthma, particularly allergic asthma, independent of BMI and physical activity. Airways pathology may have not only a hormonal but also a metabolic component. CLINICAL IMPLICATIONS: Women with oligomenorrhea should be investigated with regard to asthma and lung function. Underlying metabolic disturbance should be considered in asthma. AU - Real, F.G.* AU - Svanes, C.* AU - Omenaas, E.R.* AU - Antò, J.M.* AU - Plana, E.* AU - Janson, C.* AU - Jarvis, D.* AU - Zemp, E.* AU - Wjst, M. AU - Leynaert, B.* AU - Sunyer, J.* C1 - 5894 C2 - 24877 SP - 557-564 TI - Menstrual irregularity and asthma and lung function. JO - J. Allergy Clin. Immunol. VL - 120 IS - 3 PB - Mosby PY - 2007 SN - 0091-6749 ER - TY - JOUR AB - Recommendations for primary prevention of allergic diseases in high-risk children include feeding with hydrolyzed formulas if breast-feeding is insufficient. The primary objective of the German Infant Nutritional Intervention study was to investigate the allergy preventive effect of 3 hydrolyzed formulas compared with cow's milk formula in the first 3 years of life in a randomized, double-blind trial. Between 1995 and 1998, 2252 newborns with atopic heredity were allocated to a group receiving cow's milk formula, partially or extensively hydrolyzed whey formula, or extensively hydrolyzed casein formula as a milk substitute for the first 4 months if breast-feeding was insufficient. Main outcome parameters were allergic manifestations, atopic dermatitis (AD), and asthma.Results After 3 years, 396 of 2252 children (17.6%) had dropped out. Breast-fed infants without formula feeding during the intervention (n = 889) were considered separately. A significant reduction of the incidence of AD was achieved with the extensively hydrolyzed casein formula in the intention-to-treat (ITT; n = 1363) and per protocol (PP; n = 904) analyses (ITT: population odds ratio [95% CI], 0.67 [0.45-0.99]; PP: adjusted odds ratio [ORadj], 0.53 [0.32-0.88]), and with the partially hydrolyzed whey formula in the PP analysis (ITT: population odds ratio, 0.76 [0.52-1.11]; PP:ORadj, 0.60 [0.37-0.97]). None of the formulas reduced the incidence of asthma. Conclusion The risk for AD, but not for asthma, can be reduced with certain cow's milk hydrolyzates in high-risk infants when breast-feeding is insufficient. Clinical implications Early nutritional intervention in high-risk children has significant influence on the incidence of AD, but not of asthma. AU - von Berg, A.* AU - Koletzko, S.* AU - Filipiak-Pittroff, B. AU - Laubereau, B. AU - Grubl, A.* AU - Wichmann, H.-E. AU - Bauer, C.-P.* AU - Reinhardt, D.* AU - Berdel, D.* C1 - 5280 C2 - 24619 SP - 718-725 TI - Certain hydrolyzed formulas reduce the incidence of atopic dermatitis but not that of asthma: Three-year results of the German Infant Nutritional Intervention Study. JO - J. Allergy Clin. Immunol. VL - 119 IS - 3 PB - Mosby PY - 2007 SN - 0091-6749 ER - TY - JOUR AU - Alessandrini, F. AU - Schulz, S. AU - Takenaka, S. AU - Lentner, B. AU - Karg, E.W. AU - Behrendt, H. AU - Jakob, T. C1 - 4939 C2 - 23900 SP - 824-830 TI - Effects of ultrafine carbon particle inhalation on allergic inflammation of the lung. JO - J. Allergy Clin. Immunol. VL - 117 PY - 2006 SN - 0091-6749 ER - TY - JOUR AU - Hartl, D.* AU - Griese, M.* AU - Kappler, M.* AU - Zissel, G.* AU - Reinhardt, D.* AU - Rebhan, C.* AU - Schendel, D.J. AU - Krauss-Etschmann, S. C1 - 4254 C2 - 23297 SP - 204-211 TI - Pulmonary Th2 response in Pseudomonas aeruginosa-infected patients with cystic fibrosis. JO - J. Allergy Clin. Immunol. VL - 117 PY - 2006 SN - 0091-6749 ER - TY - JOUR AB - Background: Cat allergen level in settled house dust and its determinants in Europe are unknown. Objective: The aim of this study is to quantify the level of cat allergens in mattress dust, to study its determinants, and to analyze the relationship with cat specific IgE on community level across European centers. Methods: Trained field workers collected dust from approximately 3000 mattresses during home visits in 22 European Community Respiratory Health Survey II centers. Sieved dust extracts were assayed for cat allergen using a mAb ELISA assay. Results: The overall geometric mean cat allergen was 0.94 μg/g, ranging from 0.12 μg/g in Huelva, Spain, to 3.76 μg/g in Antwerp, Belgium. Current cat owners' homes showed substantially higher levels than past cat owners' and never cat owners' homes (geometric mean and 95% CI, 61.4 μg/g [48.4-77.9] vs 1.37 μg/g [0.97-1.9] vs 0.29 μg/g [0.27-0.31]). Community prevalence of cat ownership was moderately correlated with cat allergen levels in noncat owners (r s = 0.50), but not for past or current cat owners. The multilevel model identified community prevalence of cat keeping as the only statistically significant determinant of mattress cat allergen levels for noncat owners. However, averaged cat allergen levels per center were not related to community prevalence of detectable specific IgE to cat. Conclusion: Not having a cat in the home is associated with substantially lower Fel d 1 concentration, but does not protect against high Fel d 1 exposure in communities where cat ownership is common. Clinical implications: People (including patients with cat allergy) who do not own cats may be exposed to high levels of cat allergen in their home, particularly if they live in communities with high levels of cat ownership. © 2006 American Academy of Allergy, Asthma and Immunology. AU - Heinrich, J. AU - Bedada, G.B. AU - Zock, J.P.* AU - Chinn, S.* AU - Norbäck, D.* AU - Olivieri, M.* AU - Svanes, C.* AU - Ponzio, M.* AU - Verlato, G.* AU - Villani, S.* AU - Jarvis, D.* AU - Luczynska, C* AU - European Community Respiratory Health Survey II (*) C1 - 3862 C2 - 24049 SP - 674-681 TI - Cat allergen level: Its determinants and relationship to specific IgE to cat across European centers. JO - J. Allergy Clin. Immunol. VL - 118 IS - 3 PY - 2006 SN - 0091-6749 ER - TY - JOUR AB - Background: Asthma and allergy might influence the choice of keeping pets, leading to apparent protective effects of pets on allergic disease. Objective: We investigated the effects of asthma and allergy on subsequent pet keeping in childhood and adulthood. Methods: Information about asthma and pet keeping at ages 0 to 4, 5 to 15, 20 to 44, and 26 to 56 years was provided by 9812 subjects participating in the 9-year follow-up of the European Community Respiratory Health Survey. Results: In childhood asthma debut at younger than 5 years was associated with less cat keeping at 5 to 15 years (odds ratio [OR], 0.60; 95% CI, 0.44-0.82), an effect only observed when the parents did not have asthma or allergy (P interaction = .045). Childhood asthma did not influence adult pet ownership, unless there were adult symptoms. Adults less often acquired cats at follow-up if they had 3 or more asthma symptoms (OR, 0.78; 95% CI, 0.64-0.95), were taking asthma medication (OR, 0.48; 95% CI, 0.31-0.74), had hay fever (OR, 0.75; 95% CI, 0.62-0.91), had atopy (OR, 0.75; 95% CI, 0.61-0.91), or had specific IgE to cat (OR, 0.57; 95% CI, 0.39-0.82) at baseline. Adults who already had pets usually continued keeping the same type of pet, except that the presence of 3 or more asthma symptoms was associated with less subsequent dog keeping (OR, 0.69; 95% CI, 0.53-0.89). Pet removal between surveys to reduce allergen was reported by 4.7%. Conclusion: Selective avoidance subsequent to asthma or allergy was observed for childhood cat keeping and adult cat acquisition. Avoidance would produce an apparent protective effect of cats on childhood asthma (large OR, 0.83). Avoidance was generally not observed for dogs or birds. Clinical implications: A part of the protective effects of childhood cats on asthma and allergy can be attributed to selective avoidance. © 2006 American Academy of Allergy, Asthma and Immunology. AU - Svanes, C.* AU - Zock, J.P.* AU - Antò, J.M.* AU - Dharmage, S.* AU - Norbäck, D.* AU - Wjst, M. AU - Heinrich, J. AU - Jarvis, D.* AU - de Marco, R.* AU - Plana, E.* AU - Raherison, C.* AU - Sunyer, J.* AU - European Community Respiratory Health Survey II (*) C1 - 5082 C2 - 24242 SP - 691-698 TI - Do asthma and allergy influence subsequent pet keeping? An analysis of childhood and adulthood. JO - J. Allergy Clin. Immunol. VL - 118 IS - 3 PY - 2006 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: The role of regulatory T cells has been widely reported in the suppression of T-cell activation. A dysfunction in CD4(+)CD25(+) T-regulatory cell-specific transcription factor FoxP3 leads to immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome, often associated with atopic dermatitis. Increasing the number and activity of regulatory T cells in affected organs has been suggested as a remedy in various inflammatory diseases, including allergy. OBJECTIVE: To determine the presence and function of regulatory T cells in atopic dermatitis. METHODS: Immunohistochemistry of lesional atopic dermatitis skin and control skin conditions was used to demonstrate regulatory cells and cytokines in situ. The role of effector and regulatory T cells as well as their specific cytokines in apoptosis in human keratinocyte cultures and artificial skin equivalents was investigated. RESULTS: Human T-regulatory type 1 cells, their suppressive cytokines, IL-10 and TGF-beta, as well as receptors for these cytokines were significantly expressed, whereas CD4(+)CD25(+)FoxP3(+) T-regulatory cells were not found in lesional and atopy patch test atopic dermatitis or psoriasis skin. Both subsets of regulatory T cells suppress the allergen-specific activation of T(H)1 and T(H)2 cells. In coculture and artificial skin equivalent experiments, subsets of T-regulatory cells neither induced keratinocyte death nor suppressed apoptosis induced by skin T cells, T(H)1 cells, IFN-gamma, or TNF-alpha. CONCLUSION: A dysregulation of disease-causing effector T cells is observed in atopic dermatitis lesions, in association with an impaired CD4(+)CD25(+)FoxP3(+) T-cell infiltration, despite the expression of type 1 regulatory cells in the dermis.   AU - Verhagen, J.* AU - Akdis, M.* AU - Traidl-Hoffmann, C. AU - Schmid-Grendelmeier, P.* AU - Hijnen, D.* AU - Knol, E.F.* AU - Behrendt, H. AU - Blaser, K.* AU - Akdis, C.A.* C1 - 3663 C2 - 24235 SP - 176-183 TI - Absence of T-regulatory cell expression and function in atopic dermatitis skin. JO - J. Allergy Clin. Immunol. VL - 117 IS - 1 PY - 2006 SN - 0091-6749 ER - TY - JOUR AU - Weidinger, S. AU - Novak, N.* AU - Klopp, N. AU - Baurecht, H.* AU - Wagenpfeil, S.* AU - Rummler, L.* AU - Ring, J.* AU - Behrendt, H. AU - Illig, T. C1 - 3026 C2 - 23852 SP - 277-279 TI - Lack of association between toll-like receptor 2 and toll-like receptor 4 polymorphisms and atopic eczema. JO - J. Allergy Clin. Immunol. VL - 118 IS - 1 PY - 2006 SN - 0091-6749 ER - TY - JOUR AU - Weidinger, S. AU - Mayerhofer, A.* AU - Raemsch, R.* AU - Ring, J.* AU - Köhn, F.-M.* C1 - 3664 C2 - 24236 SP - 213-215 TI - Prostate-specific antigen as allergen in human seminal plasma allergy. Letter to the Editor. JO - J. Allergy Clin. Immunol. VL - 117 IS - 1 PY - 2006 SN - 0091-6749 ER - TY - JOUR AB - BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease with a strong genetic background. One of the characteristic features of AD and causative factor for the disease is an impaired epidermal skin barrier based on a primary defect of epidermal differentiation. OBJECTIVES: Recently, 2 loss-of-function mutations (R501X and 2282derl4) in the filaggrin gene (FLG) that cause ichthyosis vulgaris, one of the most common inherited skin disorders of keratinization, have been reported to be strong predisposing factors for AD. METHODS: We evaluated the association of the loss-of-function mutations R501X and 2282del4 within the FLG gene in a large collection of 476 well-characterized white German families with AD by using the transmission-disequilibrium test. RESULTS: Our family-based approach revealed prominent associations between the 2 loss-of-function FLG mutations and AD, as previously observed in a traditional Mendelian linkage analysis and case-control cohort analysis approach. In addition, we observed associations of the FLG mutations in particular with the extrinsic subtype of AD, which is characterized by high total serum IgE levels and concomitant allergic sensitizations. Furthermore, FLG mutations are significantly associated with palmar hyperlinearity in patients with AD, which represents a shared feature of AD and ichthyosis vulgaris. CONCLUSION: Together these data implicate that FLG is the first really strong genetic factor identified in a common complex disease. CLINICAL IMPLICATIONS: These findings underline the crucial role of the skin barrier in preventing allergic sensitization.   AU - Weidinger, S. AU - Illig, T. AU - Rodriguez, E. AU - Klopp, N. AU - Behrendt, H. C1 - 4851 C2 - 23849 SP - 214-219 TI - Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. JO - J. Allergy Clin. Immunol. VL - 118 IS - 1 PY - 2006 SN - 0091-6749 ER - TY - JOUR AB - Background: Several studies in European homes have described allergen levels from the house dust mite species Dermatophagoides pteronyssinus and to a lesser extent Dermatophagoides farinae, but geographic comparisons of exposure levels and risk factors have been hampered by a lack of standardized methods. Objective: To study the distribution and determinants of the major house dust mite allergens Der p 1 and Der f 1 in 10 European countries using a common protocol. Methods: During home visits with 3580 participants of the European Community Respiratory Health Survey II from 22 study centers, mattress dust was sampled and analyzed for Der p 1, Der f 1, and Der 2 allergen. Information on housing characteristics was obtained by both observations and interview. Results: Der 1 and Der 2 allergens were detectable (≥0.1 μg/g) in 68% and 53% of the samples, respectively. Large differences in allergen levels between study centers were observed, and geographic patterns for Der p 1 and Der f 1 were different. Low winter temperatures reduced Der p 1 rather than Der f 1. Important risk factors for high allergen levels included an older mattress, a lower floor level of the bedroom, limited ventilation of the bedroom, and dampness for Der p 1 but not for Der f 1. Conclusion: There are large qualitative and quantitative differences of house dust mite allergen levels in Europe, which can partly be explained by geographic and housing characteristics. Clinical implications: Mite allergen exposure may be reduced by replacing the mattress regularly and increasing ventilation of the bedroom, particularly in winter. © 2006 American Academy of Allergy, Asthma and Immunology. AU - Zock, J.P.* AU - Heinrich, J. AU - Jarvis, D.* AU - Verlato, G.* AU - Norbäck, D.* AU - Plana, E.* AU - Sunyer, J.* AU - Chinn, S.* AU - Olivieri, M.* AU - Soon, A.* AU - Villani, S.* AU - Ponzio, M.* AU - Dahlman-Höglund, A.* AU - Svanes, C.* AU - Luczynska, C* AU - European Community Respiratory Health Survey II (*) C1 - 4217 C2 - 24050 SP - 682-690 TI - Distribution and determinants of house dust mite allergens in Europe: The European Community Respiratory health survey II. JO - J. Allergy Clin. Immunol. VL - 118 IS - 3 PY - 2006 SN - 0091-6749 ER - TY - JOUR AU - Hartl, D.* AU - Griese, M.* AU - Nicolai, T.* AU - Zissel, G.* AU - Prell, C.* AU - Konstantopoulos, N.* AU - Gruber, R.* AU - Reinhardt, D.* AU - Schendel, D.J. AU - Krauss-Etschmann, S.* C1 - 5229 C2 - 22916 SP - 728-736 TI - Pulmonary chemokines and their receptors differentiate children with asthma and chronic cough. JO - J. Allergy Clin. Immunol. VL - 115 PY - 2005 SN - 0091-6749 ER - TY - JOUR AU - Jarvis, D.* AU - Heinrich, J. AU - Wjst, M. C1 - 3945 C2 - 23264 SP - 675-682 TI - Change in prevalence of IgE sensitization and mean total IgE with age and cohort. JO - J. Allergy Clin. Immunol. VL - 116 PY - 2005 SN - 0091-6749 ER - TY - JOUR AU - Pfab, F. AU - Hammes, M.* AU - Bäcker, M.* AU - Huss-Marp, J. AU - Athanasiadis, G.I.* AU - Tölle, T.R.* AU - Behrendt, H. AU - Ring, J.* AU - Darsow, U. C1 - 4318 C2 - 23154 SP - 1386-1388 TI - Preventive effect of acupuncture on histamine-induced itch: A blinded, randomized, placebo-controlled, crossover trial. JO - J. Allergy Clin. Immunol. VL - 116 PY - 2005 SN - 0091-6749 ER - TY - JOUR AU - Weidinger, S. AU - Klopp, N. AU - Heinrich, J. AU - Jakob, T. AU - Behrendt, H. AU - Wichmann, H.-E. AU - Ring, J. AU - Illig, T. C1 - 5513 C2 - 22958 SP - 177-184 TI - Association of NOD1 polymorphisms with atopic eczema and related phenotypes. JO - J. Allergy Clin. Immunol. VL - 116 PY - 2005 SN - 0091-6749 ER - TY - JOUR AU - Eberlein-König, B. AU - Ring, J.* C1 - 487 C2 - 21963 SP - 1223 TI - Diagnosis of IgE-mediated hymenoptera venom anaphylaxis in patients with negative skin tests and negative RAST using cellular in vvitro tests. JO - J. Allergy Clin. Immunol. VL - 113 PY - 2004 SN - 0091-6749 ER - TY - JOUR AU - Plötz, S.G. AU - Traidl-Hoffmann, C. AU - Feussner, I.* AU - Feser, A.* AU - Ring, J.* AU - Jakob, T. AU - Behrendt, H. C1 - 5334 C2 - 22532 SP - 1152-1160 TI - Chemotaxis and activation of human peripheral blood eosinophils induced by pollen-associated lipid mediators. JO - J. Allergy Clin. Immunol. VL - 113 PY - 2004 SN - 0091-6749 ER - TY - JOUR AU - Schedel, M.* AU - Carr, D.* AU - Klopp, N. AU - Woitsch, B.* AU - Illig, T. AU - Stachel, D.* AU - Schmid, I.* AU - Fritzsch, C.* AU - Weiland, S.K.* AU - von Mutius, E.* AU - Kabesch, M.* C1 - 5175 C2 - 22249 SP - 1100-1105 TI - A signal transducer and activator of transcription 6 haplotype influences the regulation of serum IgE levels. JO - J. Allergy Clin. Immunol. VL - 114 PY - 2004 SN - 0091-6749 ER - TY - JOUR AU - Weidinger, S.* AU - Krämer, U.* AU - Dunemann, L.* AU - Möhrenschlager, M.* AU - Ring, J.* AU - Behrendt, H. C1 - 396 C2 - 22558 SP - 457-459 TI - Body burden of mercury is associated with acute atopic eczema and total IgE in children from Southern Germany. JO - J. Allergy Clin. Immunol. VL - 114 PY - 2004 SN - 0091-6749 ER - TY - JOUR AU - Weidinger, S. AU - Schäfer, T.* AU - Malek, B.* AU - von Schmiedeberg, S.* AU - Schill, W.B.* AU - Ring, J.* AU - Köhn, F.M.* C1 - 3183 C2 - 21964 SP - 192-193 TI - Association between atopy and cryptorchidism. JO - J. Allergy Clin. Immunol. VL - 114 PY - 2004 SN - 0091-6749 ER - TY - JOUR AU - Mempel, M.* AU - Rakoski, J.* AU - Ring, J.* AU - Ollert, M. C1 - 10111 C2 - 21765 SP - 1406-1409 TI - Severe anaphylaxis to kiwi fruit : Immunologic changes related tu successful sublingual allergen immunotherapy. JO - J. Allergy Clin. Immunol. VL - 111 PY - 2003 SN - 0091-6749 ER - TY - JOUR AU - von Berg, A.* AU - Koletzko, S.* AU - Grubl, A.* AU - Filipiak-Pittroff, B. AU - Wichmann, H.-E. AU - Bauer, C.P.* AU - Reinhardt, D.* AU - Berdel, D.* C1 - 10113 C2 - 21614 SP - 533-540 TI - The effect of hydrolyzed cow's milk formula for allergy prevention in the first year of life : The Germany Infant Nutritional Intervention Study, a randomized double-blind trial. JO - J. Allergy Clin. Immunol. VL - 111 PY - 2003 SN - 0091-6749 ER - TY - JOUR AU - Werner, M. AU - Topp, R. AU - Wimmer, K. AU - Richter, K.* AU - Bischof, W.* AU - Wjst, M. AU - Heinrich, J. C1 - 10112 C2 - 21180 SP - 323-330 TI - TLR4 gene variants modify endotoxin effects on asthma. JO - J. Allergy Clin. Immunol. VL - 112 PY - 2003 SN - 0091-6749 ER - TY - JOUR AB - Background: Early exposure to bacterial endotoxin has been proposed to protect against allergy development in children. Whether endotoxin is able to direct T-cell differentiation into a predominance of type I immunity is still unresolved.Objective; We sought to compare the effects of endotoxin and mite and cat allergens on T-cell differentiation in infants.Methods; In a random population sample of 135 2-year-old children of an ongoing birth-cohort study, peripheral blood CD4(+) and CD8(+) T-cell subsets were defined by the expression of the chemokine receptors CCR5 and CCR3 as surrogate markers for type I and type 2 T cells, respectively. Endotoxin and mite and cat allergens were measured in house dust collected from the mother's mattress at the child's age of 3 months to assess early exposure.Results: In the CD4(+) T-cell subset, endotoxin levels were positively associated with high proportions of type 1 CCR5(+) cells (odds ratio for fourth exposure quartile [ORQ4], 7.68; 95% CI, 1.35-43.75), whereas cat allergen levels were associated with increased proportions of type 2 CCR3(+) cells (ORQ4, 4.07; 95% CI, 1.05-15.85). In contrast to endotoxin, allergen levels were associated with CD8+ T cells, showing an inverse relationship between mite allergen concentrations and high proportions of CCR5(+) or CCR3(+) cells (CCR5(+) cells: ORQ4, 0.14; 95% CI, 0.03-0.74; CCR3(+) cells: ORQ4, 0.16; 95% CI, 0.03-0.89) and a positive association of cat allergen levels with increased proportions of CCR5(+) cells (ORQ4, 9.24, 95% CI, 1.61-53.10), as well as CCR3(+) cells (ORQ3, 6.64; 95% CI, 1.21-36.51).Conclusion: Our results indicate that endotoxin has the potential to promote the development of type 1 CD4(+) T cells, where-as mite and cat allergens primarily modify the proportion of CD8(+) cells of both types. AU - Bolte, G. AU - Krauss-Etschmann, S. AU - Konstantopoulos, N. AU - Bischof, W.* AU - Fahlbusch, B.* AU - Schendel, D.J. AU - Wichmann, H.-E. AU - Heinrich, J. C1 - 10114 C2 - 20294 SP - 634-640 TI - Different effects of endotoxin versus mite and cat allergen exposure on T-cell differentiation in infants. JO - J. Allergy Clin. Immunol. VL - 110 PB - Mosby PY - 2002 SN - 0091-6749 ER - TY - JOUR AU - Traidl-Hoffmann, C. AU - Kasche, A. AU - Jakob, T. AU - Huger, M. AU - Plötz, S.G. AU - Feussner, I.* AU - Ring, J.* AU - Behrendt, H. C1 - 22116 C2 - 20796 SP - 831-838 TI - Lipid mediators from pollen act as chemoattractants and activators of polymorphonuclear granulocytes. JO - J. Allergy Clin. Immunol. VL - 109 PY - 2002 SN - 0091-6749 ER - TY - JOUR AU - Jakob, T. AU - Ring, J.* AU - Udey, M.C.* C1 - 10115 C2 - 20798 SP - 688-696 TI - Multistep navigation of Langerhans/dentritic cells in and out of the skin. JO - J. Allergy Clin. Immunol. VL - 108 PY - 2001 SN - 0091-6749 ER - TY - JOUR AU - Schäfer, T.* AU - Heinrich, J. AU - Wjst, M. AU - Heinrich, A. AU - Ring, J.* AU - Wichmann, H.-E. C1 - 21370 C2 - 19486 SP - 1280-1284 TI - Association between severity of atopic eczema and degree of sensitization to aeroallergens in schoolchildren. JO - J. Allergy Clin. Immunol. VL - 104 PY - 1999 SN - 0091-6749 ER -