小柯机器人

美国哈佛医学院Soumya Raychaudhuri研究团队发现，人类白细胞抗原（HLA）自身免疫风险等位基因限制T细胞受体的高变异区域。2022年3月24日，《自然—遗传学》杂志在线发表了这项成果。

研究人员表示，HLA基因的多态性强烈地影响着自身免疫性疾病的风险。HLA风险等位基因可能影响胸腺选择来增加对自身抗原有反应的T细胞受体（TCR）的频率（中心假说）。然而，对人类自身免疫的研究几乎没有提供支持中心假说的证据。

研究人员报道了HLA等位基因对高度多样化的互补性决定区3（CDR3）的TCR组成的影响，该区赋予抗原识别。研究人员观察到出乎意料的强HLA-CDR3关联。最强的关联是在HLA-DRB1的第13个氨基酸位置发现的，这个位置是介导多种自身免疫性疾病的遗传风险。研究人员发现多个CDR3氨基酸特征被HLA风险等位基因富集。此外，HLA风险等位基因所促进的CDR3特征在候选致病性TCR中比在对照组TCR（例如类风湿性关节炎患者的瓜氨酸表位特异性TCR）中更为丰富。总之，这些结果提供了支持中心假说的遗传学证据。

附：英文原文

Title: HLA autoimmune risk alleles restrict the hypervariable region of T cell receptors

Author: Ishigaki, Kazuyoshi, Lagattuta, Kaitlyn A., Luo, Yang, James, Eddie A., Buckner, Jane H., Raychaudhuri, Soumya

Issue&Volume: 2022-03-24

Abstract: 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.

DOI: 10.1038/s41588-022-01032-z

Source: https://www.nature.com/articles/s41588-022-01032-z

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
官方网址：https://www.nature.com/ng/
投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex