期刊
HAEMATOLOGICA
卷 104, 期 3, 页码 609-621出版社
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2018.194233
关键词
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类别
资金
- ERC [310857]
- Medical University of Vienna
- NIHR Oxford Biomedical Research Centre
- Leona M. and the Harry B. Helmsley Charitable Trust
- Department of Health, UK
- Wellcome Trust [093329, 102731, 090532/Z/09/Z]
- Deutsche Forschungsgemeinschaft [SCHW1730/1-1]
- Quality, Improvement, Development and Initiative Scheme
- European Research Council (ERC) [310857] Funding Source: European Research Council (ERC)
Hyper-IgE syndromes comprise a group of inborn errors of immunity. STAT3-deficient hyper-IgE syndrome is characterized by elevated serum IgE levels, recurrent infections and eczema, and characteristic skeletal anomalies. A loss-of-function biallelic mutation in IL6ST encoding the GP130 receptor subunit (p.N404Y) has very recently been identified in a singleton patient (herein referred to as P-N404Y) as a novel etiology of hyper-IgE syndrome. Here, we studied a patient with hyper-IgE syndrome caused by a novel homozygous mutation in IL6ST (p.P498L; patient herein referred to as P-P498L) leading to abrogated GP130 signaling after stimulation with IL-6 and IL-27 in peripheral blood mononuclear cells as well as IL-6 and IL-11 in fibroblasts. Extending the initial identification of selective GP130 deficiency, we aimed to dissect the effects of aberrant cytokine signaling on T-helper cell differentiation in both patients. Our results reveal the importance of IL-6 signaling for the development of CCR6-expressing memory CD4(+) T cells (including T-helper 17-enriched subsets) and non-conventional CD8(+) T cells which were reduced in both patients. Downstream functional analysis of the GP130 mutants (p.N404Y and p.P498L) have shown differences in response to IL-27, with the p.P498L mutation having a more severe effect that is reflected by reduced T-helper 1 cells in this patient (P-P498L) only. Collectively, our data suggest that characteristic features of GP130-deficient hyper-IgE syndrome phenotype are IL-6 and IL-11 dominated, and indicate selective roles of aberrant IL-6 and IL-27 signaling on the differentiation of T-cell subsets.
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