TY  - JOUR
AB  - Balancing natural selection is a process by which genetic variants arise in populations that are beneficial to heterozygous carriers, but pathogenic when homozygous. We systematically investigated the prevalence, structural, and functional consequences of pathogenic IL10RA variants that are associated with monogenic inflammatory bowel disease. We identify 36 non-synonymous and non-sense variants in the IL10RA gene. Since the majority of these IL10RA variants have not been functionally characterized, we performed a systematic screening of their impact on STAT3 phosphorylation upon IL-10 stimulation. Based on the geographic accumulation of confirmed pathogenic IL10RA variants in East Asia and in Northeast China, the distribution of infectious disorders worldwide, and the functional evidence of IL-10 signaling in the pathogenesis, we identify Schistosoma japonicum infection as plausible selection pressure driving variation in IL10RA. Consistent with this is a partially augmented IL-10 response in peripheral blood mononuclear cells from heterozygous variant carriers. A parasite-driven heterozygote advantage through reduced IL-10 signaling has implications for health care utilization in regions with high allele frequencies and potentially indicates pathogen eradication strategies that target IL-10 signaling.
AU  - Aschenbrenner, D.*
AU  - Ye, Z.*
AU  - Zhou, Y.*
AU  - Hu, W.*
AU  - Brooks, I.*
AU  - Williams, I.*
AU  - Capitani, M.*
AU  - Gartner, L.*
AU  - Kotlarz, D.M.
AU  - Snapper, S.B.*
AU  - Klein, C.*
AU  - Muise, A.M.*
AU  - Marsden, B.D.*
AU  - Huang, Y.*
AU  - Uhlig, H.H.*
C1  - 66676
C2  - 53266
TI  - Pathogenic interleukin-10 receptor alpha variants in humans - balancing natural selection and clinical implications.
JO  - J. Clin. Immunol.
PY  - 2022
SN  - 0271-9142
ER  - 

TY  - JOUR
AB  - Hyper-IgE syndromes (HIES) are a group of inborn errors of immunity (IEI) caused by monogenic defects such as in the gene STAT3 (STAT3-HIES). Patients suffering from HIES show an increased susceptibility to Staphylococcus aureus (S. aureus) including skin abscesses and pulmonary infections. To assess if the underlying immune defect of STAT3-HIES patients influences the resistance patterns, pathogenicity factors or strain types of S. aureus. We characterized eleven S. aureus strains isolated from STAT3-HIES patients (n = 4) by whole genome sequencing (WGS) to determine presence of resistance and virulence genes. Additionally, we used multi-locus sequence typing (MLST) and protein A (spa) typing to classify these isolates. Bacterial isolates collected from this cohort of STAT3-HIES patients were identified as common spa types in Germany. Only one of the isolates was classified as methicillin-resistant S. aureus (MRSA). For one STAT3 patient WGS illustrated that infection and colonization occurred with different S. aureus isolates rather than one particular clone. The identified S. aureus carriage profile on a molecular level suggests that S. aureus strain type in STAT3-HIES patients is determined by local epidemiology rather than the underlying immune defect highlighting the importance of microbiological assessment prior to antibiotic treatment.
AU  - Schwierzeck, V.
AU  - Effner, R.
AU  - Abel, F.*
AU  - Reiger, M.
AU  - Notheis, G.*
AU  - Held, J.*
AU  - Simon, V.*
AU  - Dintner, S.*
AU  - Hoffmann, R.*
AU  - Hagl, B.
AU  - Huebner, J.*
AU  - Mellmann, A.*
AU  - Renner, E.D.
C1  - 65396
C2  - 52296
SP  - 1301-1309
TI  - Molecular assessment of Staphylococcus Aureus strains in STAT3 Hyper-IgE syndrome patients.
JO  - J. Clin. Immunol.
VL  - 42
IS  - 6
PY  - 2022
SN  - 0271-9142
ER  - 

TY  - JOUR
AB  - Purpose: MALT1 deficiency is a combined immune deficiency characterized by recurrent infections, eczema, chronic diarrhea, and failure to thrive. Clinical and immunological characterizations of the disease have not been previously reported in large cohorts. We sought to determine the clinical, immunological, genetic features, and the natural history of MALT-1 deficiency. Methods: The clinical findings and treatment outcomes were evaluated in nine new MALT1-deficient patients. Peripheral lymphocyte subset analyses, cytokine secretion, and proliferation assays were performed. We also analyzed ten previously reported patients to comprehensively evaluate genotype/phenotype correlation. Results: The mean age of patients and disease onset were 33 ± 17 and 1.6 ± 0.7 months, respectively. The main clinical findings of the disease were recurrent infections (100%), skin involvement (100%), failure to thrive (100%), oral lesions (67%), chronic diarrhea (56%), and autoimmunity (44%). Eosinophilia and high IgE were observed in six (67%) and two (22%) patients, respectively. The majority of patients had normal T and NK cells, while eight (89%) exhibited reduced B cells. Immunoglobulin replacement and antibiotics prophylaxis were mostly ineffective in reducing the frequency of infections and other complications. One patient received hematopoietic stem cell transplantation (HSCT) and five patients died as a complication of life-threatening infections. Analyzing this cohort with reported patients revealed overall survival in 58% (11/19), which was higher in patients who underwent HSCT (P = 0.03). Conclusion: This cohort provides the largest analysis for clinical and immunological features of MALT1 deficiency. HSCT should be offered as a curative therapeutic option for all patients at the early stage of life.
AU  - Sefer, A.P.*
AU  - Abolhassani, H.*
AU  - Ober, F.
AU  - Kayaoglu, B.*
AU  - Bilgic Eltan, S.*
AU  - Kara, A.*
AU  - Erman, B.*
AU  - Surucu Yilmaz, N.*
AU  - Aydogmus, C.*
AU  - Aydemir, S.*
AU  - Charbonnier, L.M.*
AU  - Kolukisa, B.*
AU  - Azizi, G.*
AU  - Delavari, S.*
AU  - Momen, T.*
AU  - Aliyeva, S.*
AU  - Kendir Demirkol, Y.*
AU  - Tekin, S.*
AU  - Kiykim, A.*
AU  - Baser, O.F.*
AU  - Cokugras, H.*
AU  - Gursel, M.*
AU  - Karakoc-Aydiner, E.*
AU  - Ozen, A.*
AU  - Krappmann, D.
AU  - Chatila, T.A.*
AU  - Rezaei, N.*
AU  - Baris, S.*
C1  - 64198
C2  - 52103
CY  - 233 Spring St, New York, Ny 10013 Usa
SP  - 634-652
TI  - Expanding the clinical and immunological phenotypes and natural history of MALT1 deficiency.
JO  - J. Clin. Immunol.
VL  - 42
IS  - 3
PB  - Springer/plenum Publishers
PY  - 2022
SN  - 0271-9142
ER  - 

TY  - JOUR
AB  - Purpose: Biallelic pathogenic NBAS variants manifest as a multisystem disorder with heterogeneous clinical phenotypes such as recurrent acute liver failure, growth retardation, and susceptibility to infections. This study explores how NBAS-associated disease affects cells of the innate and adaptive immune system. Methods: Clinical and laboratory parameters were combined with functional multi-parametric immunophenotyping methods in fifteen NBAS-deficient patients to discover possible alterations in their immune system. Results: Our study revealed reduced absolute numbers of mature CD56dim natural killer (NK) cells. Notably, the residual NK cell population in NBAS-deficient patients exerted a lower potential for activation and degranulation in response to K562 target cells, suggesting an NK cell–intrinsic role for NBAS in the release of cytotoxic granules. NBAS-deficient NK cell activation and degranulation was normalized upon pre-activation by IL-2 in vitro, suggesting that functional impairment was reversible. In addition, we observed a reduced number of naïve B cells in the peripheral blood associated with hypogammaglobulinemia. Conclusion: In summary, we demonstrate that pathogenic biallelic variants in NBAS are associated with dysfunctional NK cells as well as impaired adaptive humoral immunity.
AU  - Lenz, D.*
AU  - Pahl, J.*
AU  - Hauck, F.*
AU  - Alameer, S.*
AU  - Balasubramanian, M.*
AU  - Baric, I.*
AU  - Boy, N.*
AU  - Church, J.A.*
AU  - Crushell, E.*
AU  - Dick, A.*
AU  - Distelmaier, F.*
AU  - Gujar, J.*
AU  - Indolfi, G.*
AU  - Lurz, E.*
AU  - Peters, B.*
AU  - Schwerd, T.*
AU  - Serranti, D.*
AU  - Kölker, S.*
AU  - Klein, C.*
AU  - Hoffmann, G.F.*
AU  - Prokisch, H.
AU  - Greil, J.*
AU  - Cerwenka, A.*
AU  - Giese, T.*
AU  - Staufner, C.*
C1  - 62807
C2  - 51074
CY  - 233 Spring St, New York, Ny 10013 Usa
TI  - NBAS variants are associated with quantitative and qualitative NK and B cell deficiency.
JO  - J. Clin. Immunol.
PB  - Springer/plenum Publishers
PY  - 2021
SN  - 0271-9142
ER  - 

TY  - JOUR
AB  - Hereditary defects in several genes have been shown to disturb the normal immune response to EBV and to give rise to severe EBV-induced lymphoproliferation in the recent years. Nevertheless, in many patients, the molecular basis of fatal EBV infection still remains unclear. The Fanconi anemia-associated protein 24 (FAAP24) plays a dual role in DNA repair. By association with FANCM as component of the FA core complex, it recruits the FA core complex to damaged DNA. Additionally, FAAP24 has been shown to evoke ATR-mediated checkpoint responses independently of the FA core complex. By whole exome sequencing, we identified a homozygous missense mutation in the FAAP24 gene (cC635T, pT212M) in two siblings of a consanguineous Turkish family who died from an EBV-associated lymphoproliferative disease after infection with a variant EBV strain, expressing a previously unknown EBNA2 allele.In order to analyze the functionality of the variant FAAP24 allele, we used herpes virus saimiri-transformed patient T cells to test endogenous cellular FAAP24 functions that are known to be important in DNA damage control. We saw an impaired FANCD2 monoubiquitination as well as delayed checkpoint responses, especially affecting CHK1 phosphorylation in patient samples in comparison to healthy controls. The phenotype of this FAAP24 mutation might have been further accelerated by an EBV strain that harbors an EBNA2 allele with enhanced activities compared to the prototype laboratory strain B95.8. This is the first report of an FAAP24 loss of function mutation found in human patients with EBV-associated lymphoproliferation.
AU  - Daschkey, S.*
AU  - Bienemann, K.*
AU  - Schuster, V.*
AU  - Kreth, H.W.*
AU  - Linka, R.M.*
AU  - Hönscheid, A.*
AU  - Fritz, G.*
AU  - Johannes, C.*
AU  - Fleckenstein, B.*
AU  - Kempkes, B.
AU  - Gombert, M.*
AU  - Ginzel, S.*
AU  - Borkhardt, A.*
C1  - 49193
C2  - 41697
CY  - New York
SP  - 684-692
TI  - Fatal lymphoproliferative disease in two siblings lacking functional FAAP24.
JO  - J. Clin. Immunol.
VL  - 36
IS  - 7
PB  - Springer/plenum Publishers
PY  - 2016
SN  - 0271-9142
ER  - 

TY  - JOUR
AB  - Infections with fungi can cause systemic life-threatening diseases in immunocompromised individuals like cancer or AIDS patients. Recent work has uncovered essential roles for C-type lectin pattern recognition receptors, spleen tyrosine kinase (SYK) and the cytosolic NLRP3 inflammasome in innate antifungal immunity. Upon fungal infection, SYK is activated by several ITAM-containing or ITAM-coupled C-type lectin receptors on myeloid cells leading to the production of pro-inflammatory cytokines including IL-1beta to initiate antifungal responses. Mature IL-1beta production requires in addition to the synthesis of pro-IL-1beta a cleavage of the precursor protein by the inflammatory Caspase-1 which is controlled within the NLRP3 inflammasome. SCOPE: Here, we discuss how ITAM receptor signaling and NLRP3 cooperate for the induction of antifungal immunity.
AU  - Poeck, H.*
AU  - Ruland, J.
C1  - 6006
C2  - 27789
SP  - 496-501
TI  - ITAM receptor signaling and the NLRP3 inflammasome in antifungal immunity.
JO  - J. Clin. Immunol.
VL  - 30
IS  - 4
PB  - Springer
PY  - 2010
SN  - 0271-9142
ER  - 

TY  - JOUR
AU  - Hügle, B.*
AU  - Suchowersky, H.*
AU  - Hellebrand, H.*
AU  - Adler, B.
AU  - Borte, B.*
AU  - Sack, U.*
AU  - Schulte Overberg-Schmidt, U.*
AU  - Strnad, N.*
AU  - Otto, J.*
AU  - Meindl, A.*
AU  - Schuster, V.*
C1  - 4852
C2  - 23023
SP  - 515-522
TI  - Persistent hypogammaglobulinemia following mononucleosis in boys is highly suggestive of X-linked lymphoproliferative disease--report of three cases.
JO  - J. Clin. Immunol.
VL  - 24
PY  - 2005
SN  - 0271-9142
ER  -