TY - JOUR AB - Bile acids (BAs) are produced by liver hepatocytes and were recently shown to exert functions additional to their well-known role in lipid digestion. As yet it is not known whether the mucosal-associated invariant T (MAIT) cells, which represent 10-15% of the hepatic T cell population, are affected by BAs. The focus of the present investigation was on the association of BA serum concentration with MAIT cell function and inflammatory parameters as well as on the relationship of these parameters to body weight. Blood samples from 41 normal weight and 41 overweight children of the Lifestyle Immune System Allergy (LISA) study were analyzed with respect to MAIT cell surface and activation markers [CD107a, CD137, CD69, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha] after Escherichia coli stimulation, mRNA expression of promyelocytic leukemia zinc finger protein (PLZF) and major histocompatibility complex class I-related gene protein (MR1), the inflammatory markers C-reactive protein (CRP), interleukin (IL)-8 and macrophage inflammatory protein (MIP)-1 alpha as well as the concentrations of 13 conjugated and unconjugated BAs. Higher body weight was associated with reduced MAIT cell activation and expression of natural killer cell marker (NKp80) and chemokine receptor (CXCR3). BA concentrations were positively associated with the inflammatory parameters CRP, IL-8 and MIP-1 alpha, but were negatively associated with the number of activated MAIT cells and the MAIT cell transcription factor PLZF. These relationships were exclusively found with conjugated BAs. BA-mediated inhibition of MAIT cell activation was confirmed in vitro. Thus, conjugated BAs have the capacity to modulate the balance between pro- and anti-inflammatory immune responses. AU - Mendler, A.* AU - Pierzchalski, A.* AU - Bauer, M.* AU - Röder, S.* AU - Sattler, A.* AU - Standl, M. AU - Borte, M.* AU - von Bergen, M.* AU - Rolle-Kampczyk, U.E.* AU - Herberth, G.* C1 - 58465 C2 - 48389 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 199-213 TI - MAIT cell activation in adolescents is impacted by bile acid concentrations and body weight. JO - Clin. Exp. Immunol. VL - 200 IS - 2 PB - Wiley PY - 2020 SN - 0009-9104 ER - TY - JOUR AB - Levels of cytokines are used for in-depth characterization of patients with asthma; however, the variability over time might be a critical confounder. To analyze the course of serum cytokines in children, adolescents and adults with asthma and in healthy controls and to propose statistical methods to control for seasonal effects. Of 532 screened subjects, 514 (91 center dot 5%) were included in the All Age Asthma Cohort (ALLIANCE). The cohort included 279 children with either recurrent wheezing bronchitis (more than two episodes) or doctor-diagnosed asthma, 75 healthy controls, 150 adult asthmatics and 31 adult healthy controls. Blood samples were collected and 25 mu l serum was used for analysis with the Bio-Plex Pr human cytokine 27-Plex assay. Mean age, body mass index and gender in the three groups of wheezers, asthmatic children and adult asthmatics were comparable to healthy controls. Wheezers (34 center dot 5%), asthmatic children (78 center dot 7%) and adult asthmatics (62 center dot 8%) were significantly more often sensitized compared to controls (4 center dot 5, 22 and 22 center dot 6%, respectively). Considering the entire cohort, interleukin (IL)-1ra, IL-4, IL-9, IL-17, macrophage inflammatory protein (MIP)-1-alpha and tumor necrosis factor (TNF)-alpha showed seasonal variability, whereas IL-1 beta, IL-7, IL-8, IL-13, eotaxin, granulocyte colony-stimulating factor (G-CSF), interferon gamma-induced protein (IP)-10, MIP-1 beta and platelet-derived growth factor (PDGF)-BB did not. Significant differences between wheezers/asthmatics and healthy controls were observed for IL-17 and PDGF-BB, which remained stable after adjustment for the seasonality of IL-17. Seasonality has a significant impact on serum cytokine levels in patients with asthma. Because endotyping has achieved clinical importance to guide individualized patient-tailored therapy, it is important to account for seasonal effects. AU - Weckmann, M.* AU - Thiele, D.* AU - Liboschik, L.* AU - Bahmer, T.* AU - Pech, M.* AU - Dittrich, A.M.* AU - Fuchs, O.* AU - Happle, C.* AU - Schaub, B.* AU - Ricklefs, I.* AU - Rabe, K.F.* AU - ALLIANCE Study Group (von Mutius, E.) AU - Hansen, G.* AU - König, I.R.* AU - Kopp, M.V.* C1 - 61158 C2 - 49645 CY - 111 River St, Hoboken 07030-5774, Nj Usa TI - Cytokine levels in children and adults with wheezing and asthma show specific patterns of variability over time. JO - Clin. Exp. Immunol. PB - Wiley PY - 2020 SN - 0009-9104 ER - TY - JOUR AB - This review takes the reader through 45 years of islet autoantibody research, from the discovery of islet-cell antibodies in 1974 to today’s population-based screening for presymptomatic early-stage type 1 diabetes. The review emphasizes the current practical value of, and factors to be considered in, the measurement of islet autoantibodies. AU - Bonifacio, E. AU - Achenbach, P. C1 - 56730 C2 - 47236 SP - 294-305 TI - Birth and coming of age of islet autoantibodies. JO - Clin. Exp. Immunol. VL - 198 IS - 3 PY - 2019 SN - 0009-9104 ER - TY - JOUR AB - Enteroviruses (EV) have been historically associated to type 1 diabetes. Definitive proof for their implication in disease development is lacking, but growing evidence suggests that they could be involved in beta cell destruction either directly by killing beta cells or indirectly by creating an exacerbated inflammatory response in the islets, capable of attracting autoreactive T cells to the 'scene of the crime'. Epidemiological and serological studies have been associated with the appearance of islet autoimmunity and EV RNA has been detected in prospective studies. In addition, the EV capsid protein has been detected in the islets of recent-onset type 1 diabetic donors, suggesting the existence of a low-grade EV infection that could become persistent. Increasing evidence in the field shows that a 'viral signature' exists in type 1 diabetes and involves interferon responses that could be sustained during prolonged periods. These include the up-regulation of markers such as protein kinase R (PKR), melanoma differentiation-associated protein 5 (MDA5), retinoic acid inducible gene I (RIG-I), myxovirus resistance protein (MxA) and human leukocyte antigen-I (HLA-I) and the release of chemokines able to attract immune cells to the islets leading to insulitis. In this scenario, the hyperexpression of HLA-I molecules would promote antigen presentation to autoreactive T cells, favoring beta cell recognition and, ultimately, destruction. In this review, an overview is provided of the standing evidence that implicates EVs in beta cell 'murder', the time-line of events is investigated from EV entry in the cell to beta cell death and possible accomplices are highlighted that might be involved in beta cell demise. AU - Rodriguez-Calvo, T. C1 - 54500 C2 - 45638 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 15-24 TI - Enterovirus infection and type 1 diabetes: Unraveling the crime scene. JO - Clin. Exp. Immunol. VL - 195 IS - 1 PB - Wiley PY - 2018 SN - 0009-9104 ER - TY - JOUR AB - Preterm delivery is the leading cause of perinatal morbidity and mortality. Among the most important complications in preterm infants are peri- or postnatal infections. Myeloid-derived suppressor cells (MDSC) are myeloid cells with suppressive activity on other immune cells. Emerging evidence suggests that granulocytic MDSC (GR-MDSC) play a pivotal role in mediating maternal-fetal tolerance. The role of MDSC for postnatal immune-regulation in neonates is incompletely understood. Until the present time, nothing was known about expression of MDSC in preterm infants. In the present pilot study, we quantified GR-MDSC counts in cord blood and peripheral blood of preterm infants born between 23 + 0 and 36 + 6 weeks of gestation (WOG) during the first 3 months of life and analysed the effect of perinatal infections. We show that GR-MDSC are increased in cord blood independent of gestational age and remain elevated in peripheral blood of preterm infants during the neonatal period. After day 28 they drop to nearly adult levels. In case of perinatal or postnatal infection, GR-MDSC accumulate further and correlate with inflammatory markers C-reactive protein (CRP) and white blood cell counts (WBC). Our results point towards a role of GR-MDSC for immune-regulation in preterm infants and render them as a potential target for cell-based therapy of infections in these patients. AU - Schwarz, J.* AU - Scheckenbach, V.* AU - Kugel, H.* AU - Spring, B.* AU - Pagel, J.* AU - Härtel, C.* AU - Pauluschke-Fröhlich, J.* AU - Peter, A. AU - Poets, C.F.* AU - Gille, C.* AU - Köstlin, N.* C1 - 52821 C2 - 44185 TI - Granulocytic myeloid-derived suppressor cells (GR-MDSC) accumulate in cord blood of preterm infants and remain elevated during the neonatal period. JO - Clin. Exp. Immunol. PY - 2017 SN - 0009-9104 ER - TY - JOUR AB - Autoimmune diabetes is characterized by autoantigen-specific T cell-mediated destruction of pancreatic islet beta cells and CD8(+) T cells are key players during this process. We assessed whether the bitransgenic RIP-CD80 x RIP-LCMV-GP (RIP-CD80GP) mice may be a versatile antigen specific model of inducible CD8(+) T cell mediated autoimmune diabetes. Antigen-encoding DNA, peptide loaded dendritic cells, and antigen plus incomplete Freund's adjuvant were used for vaccination. Of 14 pancreatic proteins tested by DNA vaccination, murine pre-proinsulin 2 (100% of mice; median time after vaccination, 60 days), and Igrp (77%, 58 days) could induce diabetes. DNA vaccination with zinc transporter 8, Ia-2, Ia-2β, Gad67, Chromogranin A, IAPP, and Nkx2.2 induced diabetes development in 25-33% of mice, and with Gad65, Sgne1, Pdx1, Cel, glucagon, and control HBsAg in <20% of mice. Diabetes induction efficiency could be increased by DNA vaccination with a vector encoding a ubiquitin-antigen fusion construct. Diabetic mice had florid T cell islet infiltration. CD8(+) T cell targets of Igrp were identified with a peptide library based ELISpot assay, and diabetes could also be induced by vaccination with MHC class I restricted Igrp peptides loaded on mature dendritic cells. Vaccination with antigen plus incomplete Freund's adjuvant, which can prevent diabetes in other models, led to rapid diabetes development in the RIP-CD80GP mouse. We conclude that RIP-CD80GP mice are a versatile model of antigen specific autoimmune diabetes and may complement existing mouse models of autoimmune diabetes for evaluating CD8(+) T cell-targeted prevention strategies. AU - Fuchs, Y.F.* AU - Adler, K.* AU - Lindner, A.* AU - Karasinsky, A.* AU - Wilhelm, C.* AU - Weigelt, M.* AU - Balke, H. AU - Förtsch, K. AU - Mortler-Hildebrandt, L.F. AU - Harlan, D.M.* AU - Pechhold, K.* AU - Ziegler, A.-G. AU - Bonifacio, E.* C1 - 29168 C2 - 31722 CY - Hoboken SP - 199-206 TI - Igrp and insulin vaccination induce CD8+ T cell mediated autoimmune diabetes in the RIP-CD80GP mouse. JO - Clin. Exp. Immunol. VL - 176 IS - 2 PB - Wiley-Blackwell PY - 2014 SN - 0009-9104 ER - TY - JOUR AB - Overall asthmatic symptoms can be controlled with diverse therapeutic agents. However, certain symptomatic individuals remain at risk for serious morbidity and mortality, which prompts the identification of novel therapeutic targets and treatment strategies. Thus, using an adjuvant-free T helper type 2 (Th2) murine model, we have deciphered the role of interleukin (IL)-1 signalling during allergic airway inflammation (AAI). Because functional IL-1 beta depends on inflammasome activation we first studied asthmatic manifestations in specific inflammasome-deficient [NACHT, LRR and PYD domains-containing protein 3 (NLRP3(-/-)) and apoptosis-associated specklike protein containing a caspase recruitment domain (ASC(-/-))] and IL-1 receptor type 1(-/-) (IL-1R1(-/-)) mice on the BALB/c background. To verify the onset of disease we assessed cellular infiltration in the bronchial regions, lung pathology, airway hyperresponsiveness and ovalbumin (OVA)-specific immune responses. In the absence of NLRP3 inflammasome-mediated IL-1 beta release all symptoms of AAI were reduced, except OVA-specific immunoglobulin levels. To address whether manipulating IL-1 signalling reduced asthmatic development, we administered the IL-1R antagonist anakinra (Kineret (R)) during critical immunological time-points: sensitization or challenge. Amelioration of asthmatic symptoms was only observed when anakinra was administered during OVA challenge. Our findings indicate that blocking IL-1 signalling could be a potential complementary therapy for allergic airway inflammation. AU - Ritter, M.* AU - Straubinger, K.* AU - Schmidt, S.* AU - Busch, D.H. AU - Hagner, S.* AU - Garn, H.* AU - da Costa, C.P.* AU - Layland, L.E.* C1 - 34375 C2 - 35260 CY - Hoboken SP - 212-223 TI - Functional relevance of NLRP3 inflammasome-mediated interleukin (IL)-1 beta during acute allergic airway inflammation. JO - Clin. Exp. Immunol. VL - 178 IS - 2 PB - Wiley-Blackwell PY - 2014 SN - 0009-9104 ER - TY - JOUR AB - The impact of gestation and fetal-maternal interactions on pre-existent autoimmune beta cell destruction is widely unknown. The aim of this study was to investigate the influence of gestation per se and fetal mismatching on the onset of autoimmune diabetes in female non-obese diabetic (NOD) mice. We examined cumulative diabetes frequencies of NOD dams mated to syngeneic NOD, haploidentical CByB6F1/J and fully mismatched C57BL/6J male mice. Pregnancy from NOD males neither increased nor accelerated the diabetes onset of NOD dams (71% by age 28 weeks) compared to unmated female NOD mice (81% by age 28 weeks; P = 0·38). In contrast, delayed diabetes onset was observed when NOD dams were mated at 10 weeks of age with major histocompatibility complex (MHC) haploidentical CByB6F1/J male mice (38% at age 28 weeks; P = 0·01). Mating with fully MHC mismatched C57BL/6J male mice (72% diabetes by age 28 weeks; P = 0·22) or mating with the haploidentical males at the later time-point of age 13 weeks (64% versus 91% in unmated litter-matched controls; P = 0·13) did not delay diabetes significantly in NOD females. Because infusion of haploidentical male mouse splenocytes was found previously to prevent diabetes in NOD mice we looked for, but found no evidence of, persistent chimeric lymphocytes from haploidentical paternal origin within the dams' splenocytes. Gestation per se appears to have no aggravating or ameliorating effects on pre-existent autoimmune beta cell destruction, but pregnancy from MHC partially mismatched males delays diabetes onset in female NOD mice. AU - Adler, K. AU - Krause, S.* AU - Fuchs, Y.F.* AU - Foertsch, K.* AU - Ziegler, A.-G. AU - Bonifacio, E.* C1 - 7924 C2 - 29922 SP - 274-278 TI - The effect of gestation and fetal mismatching on the development of autoimmune diabetes in non-obese diabetic mice. JO - Clin. Exp. Immunol. VL - 168 IS - 3 PB - Wiley-Blackwell PY - 2012 SN - 0009-9104 ER - TY - JOUR AB - Ifosfamide is a DNA-alkylating agent used frequently in chemotherapy of human malignancies. Ifosfamide and its major decomposition products deplete intracellular glutathione (GSH). Glutathione is the major intracellular thiol reductant that protects cells against oxidative injury. Ifosfamide depletion of intracellular GSH in human dendritic cells (DC), T cells and natural killer (NK) cells impairs their functional activity which can be restored by reconstituting GSH. Here we assessed the effect of ifosfamide on DC-mediated stimulation of NK cell proliferation via T cells and on direct DC stimulation of NK cell cytotoxicity and interferon (IFN)-gamma production. Indirect DC stimulation of NK cell proliferation via T cells and T cell-derived interleukin (IL)-2 were reduced by ifosfamide treatment of DC and reconstitution of GSH in DC restored both responses. When DC and NK cells were treated with ifosfamide, DC could overcome the negative effect of ifosfamide on NK cytotoxic function whereas NK cell IFN-gamma production was less efficiently restored. The ability of IL-2 activated NK cells to kill autologous immature DC or to induce DC maturation was reduced moderately by treatment of both cell types with ifosfamide. Overall, our results suggest that DC may stimulate anti-tumour effector cells in patients even if they had received treatment with chemotherapeutic agents such as ifosfamide. AU - Kuppner, M.C.* AU - Bleifuß, E. AU - Nößner, E. AU - Mocikat, R. AU - Hesler, C.V.* AU - Mayerhofer, C.* AU - Issels, R.D. C1 - 1908 C2 - 25398 SP - 429-438 TI - Differential effects of ifosfamide on dendritic cell-mediated stimulation of T cell interleukin-2 production, natural killer cell cytotoxicity and interferon-gamma production. JO - Clin. Exp. Immunol. VL - 153 IS - 3 PB - Blackwell PY - 2008 SN - 0009-9104 ER - TY - JOUR AB - Many studies concerning the role of T cells and cytokines in allergy have been performed, but little is known about the role of natural killer (NK) cells. Accordingly, the expression of co-stimulatory, inhibitory and apoptosis receptors, cytokine profiles and their effect on immunoglobulin isotypes were investigated in polyallergic atopic dermatitis (AD) patients with hyper immunoglobulin E (IgE) and healthy individuals. AD patients showed significantly decreased peripheral blood NK cells compared to healthy individuals. Freshly isolated NK cells of polyallergic patients spontaneously released higher amounts of interleukin (IL)-4, IL-5, IL-13 and interferon (IFN)-g compared to healthy individuals. NK cells were differentiated to NK1 cells by IL-12 and neutralizing anti-IL-4 monoclonal antibodies (mAb), and to NK2 cells by IL- 4 and neutralizing anti-IL-12 mAb. Following IL-12 stimulation, NK cells produced increased levels of IFN-g and decreased IL-4. In contrast, stimulation of NK cells with IL-4 inhibited IFN-g , but increased IL-13, production. The effect of NK cell subsets on IgE regulation was examined in co-cultures of in vitro differentiated NK cells with peripheral blood mononuclear cells (PBMC) or B cells. NK1 cells significantly inhibited IL-4- and soluble CD40-ligandstimulated IgE production; however, NK2 cells did not have any effect. The inhibitory effect of NK1 cells on IgE production was blocked by neutralization of IFN-g . Except for CD40, NK cell subsets showed different expression of killer-inhibitory receptors and co-stimulatory molecules between the polyallergic and healthy subjects. These results indicate that human NK cells show differences in numbers, su AU - Aktas, E.* AU - Akdis, M.* AU - Bilgic, S.* AU - Disch, R.* AU - Falk, C.S. AU - Blaser, K.* AU - Akdis, C.* AU - Deniz, G.* C1 - 4549 C2 - 22601 SP - 301-309 TI - Different natural killer (NK) receptor expression and immunoglobulin E (IgE) regulation by NK1 and NK2 cells. JO - Clin. Exp. Immunol. VL - 140 PY - 2005 SN - 0009-9104 ER - TY - JOUR AB - The inflammatory process in chronic obstructive pulmonary disease (COPD) is active mainly in the airways, but little is known about the properties of the inflammatory cells in this compartment. We have studied leucocytes in induced sputum of COPD patients compared to controls in order to uncover what types of macrophages might be involved in the disease. Sputum induction was performed by inhalation of nebulized sodium chloride solution. Leucocytes were isolated and stained with specific monoclonal antibodies for analysis in flow cytometry. Flow cytometry analysis revealed that a major portion of CD14+ macrophages in COPD has lower forward scatter, i.e. they are small macrophages. While in control donors these small macrophages accounted for 6·9% of all macrophages, the percentage of these cells in COPD was 45·7%. CD14 and HLA-DR expression was high on these small sputum macrophages while the large sputum macrophages expressed only low levels of these surface molecules, both in control donors and COPD patients. Small sputum macrophages of both control donors and COPD patients showed higher levels of constitutive tumour necrosis factor (TNF) compared to the large macrophages. TNF was inducible by lipopolysaccharide (LPS) preferentially in the small sputum macrophages in the control donors but there was no further induction in COPD patients. These data show that the small sputum macrophages are a major macrophage population in COPD and that these cells exhibit features of highly active inflammatory cells and may therefore be instrumental in airway inflammation in COPD. AU - Frankenberger, M. AU - Menzel, M. AU - Betz, R. AU - Kaßner, G. AU - Weber, N. AU - Kohlhäufl, M. AU - Häußinger, K. AU - Ziegler-Heitbrock, L. C1 - 2917 C2 - 22130 SP - 507-516 TI - Characterization of a population of small macrophages in induced sputum of patients with chronic obstructive pulmonary disease and healthy volunteers. JO - Clin. Exp. Immunol. VL - 138 IS - 3 PY - 2004 SN - 0009-9104 ER - TY - JOUR AB - The incidenlal finding of monocional immunoglobuiin components (MC) in some infections prompted us lo study this phenomenon more systematically. Using isoelectric focusing withimmunoblotting {detection limit for MC O'l mg/ml), the following infections were studied for thepresence of MC: visceral leishmaniasis, cytomcgalovirus (CMV) infection, echinococcosis andinfectious mononucleosis. MC were found in 16 of 20 leishmania patients and in eight of 18 CMV patients, but in only one of 20 echinococcosis patients and in none of 30 infectious mononucleosispatients. The MC were mostly transient, where tested. A minority of the MC found in theleishmaniasis patients was shown to bind to leishmania antigens. The specificity ofthe majority ofthe MC remains unknown. Further study is required to explain the high incidence of MC in CMV infection and visceral leishmaniasis. AU - Haas, H. AU - Anders, S. AU - Bornkamm, G.W. AU - Mannweiler, E. AU - Schmitz, H. AU - Radl, J. AU - Schlaak, M. C1 - 19270 C2 - 12344 SP - 435-440 TI - Do Infections Induce Monoclonal Immunoglobulin Components?. JO - Clin. Exp. Immunol. VL - 81 PY - 1990 SN - 0009-9104 ER - TY - JOUR AB - Rabbit red blood cells have previously been shown to rosette with a subpopulation of thymocytes and with mitogen activated peripheral lymphocytes but not with unstimulated lymphocytes. Using monoclonal antibodies and double marker assays we studied the phenotype of these cells. In thymus, over 90% of rosetting cells express antigens of immature thymocytes (HTA1, OKT6). A proportion of the rosetting cells shows in addition antigens of mature thymocytes (OKT3, UCHT1). These cells probably correspond to a stage of intrathymic maturation between common and mature thymocytes. Virtually all rosetting cells are T cells and express an antigen related to T cell activation (TAC) when lymphocytes are activated by mitogens like PHA or Con A. Few rosetting cells are Ia positive. Two other antigens (OKT9, OKT10) known to be associated with proliferating and immature cells, are found in variable proportions on rosetting cells. After stimulation with allogeneic lymphocytes, fewer rosettes are detected than after stimulation by mitogens. Cells activated by a soluble antigen (PPD) and forming rosettes with rabbit red blood cells have a helper phenotype (Leu3a positive). Screening of leukaemia cell samples revealed that only cells from patients with T-ALL form rosettes with rabbit red blood cells. Rosette formation is almost totally inhibited by a polyclonal anti-thymocyte serum and two monoclonal antibodies (OKT11A, Lyt3) which have been shown to block rosettes with sheep erythrocytes. AU - Munker, R. AU - Stünkel, K.G.E. AU - Thiel, E.V. AU - Thierfelder, S.S. C1 - 41409 C2 - 38416 SP - 479-486 TI - Analysis with monoclonal antibodies of human lymphoid cells forming rosettes with rabbit red blood cells. JO - Clin. Exp. Immunol. VL - 51 IS - 3 PY - 1983 SN - 0009-9104 ER -