生物
人类白细胞抗原
T细胞受体
等位基因
遗传学
免疫学
主要组织相容性复合体
自身免疫
高变区
表位
抗原
基因
T细胞
免疫系统
作者
Kazuyoshi Ishigaki,Kaitlyn A. Lagattuta,Yang Luo,Eddie A. James,Jane H. Buckner,Soumya Raychaudhuri
出处
期刊:Nature Genetics
[Springer Nature]
日期:2022-03-24
卷期号:54 (4): 393-402
被引量:33
标识
DOI:10.1038/s41588-022-01032-z
摘要
Polymorphisms in the human leukocyte antigen (HLA) genes strongly influence autoimmune disease risk. HLA risk alleles may influence thymic selection to increase the frequency of T cell receptors (TCRs) reactive to autoantigens (central hypothesis). However, research in human autoimmunity has provided little evidence supporting the central hypothesis. Here we investigated the influence of HLA alleles on TCR composition at the highly diverse complementarity determining region 3 (CDR3), which confers antigen recognition. We observed unexpectedly strong HLA-CDR3 associations. The strongest association was found at HLA-DRB1 amino acid position 13, the position that mediates genetic risk for multiple autoimmune diseases. We identified multiple CDR3 amino acid features enriched by HLA risk alleles. Moreover, the CDR3 features promoted by the HLA risk alleles are more enriched in candidate pathogenic TCRs than control TCRs (for example, citrullinated epitope-specific TCRs in patients with rheumatoid arthritis). Together, these results provide genetic evidence supporting the central hypothesis.
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