Department of Neurology, University of Muenster, 48149 Muenster, Germany.
Institute of Biostatistics and Clinical Research, University of Muenster, 48149 Muenster, Germany.
Proc Natl Acad Sci U S A. 2018 Feb 27;115(9):2168-2173. doi: 10.1073/pnas.1716146115. Epub 2018 Feb 12.
HLA associations, T cell receptor (TCR) repertoire bias, and sex bias have independently been shown for many diseases. While some immunological differences between the sexes have been described, they do not fully explain bias in men toward many infections/cancers, and toward women in autoimmunity. Next-generation TCR variable beta chain (TCRBV) immunosequencing of 824 individuals was evaluated in a multiparametric analysis including HLA-A -B/MHC class I background, TCRBV usage, sex, age, ethnicity, and TCRBV selection/expansion dynamics. We found that HLA-associated shaping of TCRBV usage differed between the sexes. Furthermore, certain TCRBVs were selected and expanded in unison. Correlations between these TCRBV relationships and biochemical similarities in HLA-binding positions were different in CD8 T cells of patients with autoimmune diseases (multiple sclerosis and rheumatoid arthritis) compared with healthy controls. Within patients, men showed higher TCRBV relationship Spearman's rhos in relation to HLA-binding position similarities compared with women. In line with this, CD8 T cells of men with autoimmune diseases also showed higher degrees of TCRBV perturbation compared with women. Concerted selection and expansion of CD8 T cells in patients with autoimmune diseases, but especially in men, appears to be less dependent on high HLA-binding similarity than in CD4 T cells. These findings are consistent with studies attributing autoimmunity to processes of epitope spreading and expansion of low-avidity T cell clones and may have further implications for the interpretation of pathogenic mechanisms of infectious and autoimmune diseases with known HLA associations. Reanalysis of some HLA association studies, separating the data by sex, could be informative.
HLA 相关性、T 细胞受体 (TCR) 谱偏向和性别偏向已被独立证明与许多疾病有关。虽然已经描述了两性之间的一些免疫学差异，但它们并不能完全解释为什么许多感染/癌症男性发病率较高，而自身免疫性疾病女性发病率较高。对 824 个人的下一代 TCR 可变β链 (TCRBV) 免疫测序进行了多参数分析，包括 HLA-A-B/MHC Ⅰ类背景、TCRBV 使用、性别、年龄、种族和 TCRBV 选择/扩增动力学。我们发现 HLA 相关的 TCRBV 使用模式在两性之间存在差异。此外，某些 TCRBV 被同步选择和扩增。在患有自身免疫性疾病（多发性硬化症和类风湿关节炎）的患者的 CD8 T 细胞与健康对照组相比，这些 TCRBV 关系与 HLA 结合位置生化相似性之间的相关性不同。在患者中，与女性相比，男性的 TCRBV 关系 Spearman rho 与 HLA 结合位置相似性相关更高。与此一致的是，患有自身免疫性疾病的男性的 CD8 T 细胞也表现出比女性更高程度的 TCRBV 扰动。自身免疫性疾病患者的 CD8 T 细胞的协同选择和扩增，尤其是男性，似乎比 CD4 T 细胞更不依赖于高 HLA 结合相似性。这些发现与将自身免疫归因于表位扩展和低亲和力 T 细胞克隆扩增过程的研究一致，并且可能对具有已知 HLA 相关性的感染性和自身免疫性疾病的发病机制的解释有进一步的影响。按性别对一些 HLA 关联研究进行重新分析可能会提供有价值的信息。
