The HLA-DR15 haplotype is the strongest genetic risk factor for multiple sclerosis (MS), but our understanding of how it contributes to MS is limited. Because autoreactive CD4⁺ T cells and B cells as antigen-presenting cells are involved in MS pathogenesis, we characterized the immunopeptidomes of the two HLA-DR15 allomorphs DR2a and DR2b of human primary B cells and monocytes, thymus, and MS brain tissue. Self-peptides from HLA-DR molecules, particularly from DR2a and DR2b themselves, are abundant on B cells and thymic antigen-presenting cells. Furthermore, we identified autoreactive CD4⁺ T cell clones that can cross-react with HLA-DR-derived self-peptides (HLA-DR-SPs), peptides from MS-associated foreign agents (Epstein-Barr virus and Akkermansia muciniphila), and autoantigens presented by DR2a and DR2b. Thus, both HLA-DR15 allomorphs jointly shape an autoreactive T cell repertoire by serving as antigen-presenting structures and epitope sources and by presenting the same foreign peptides and autoantigens to autoreactive CD4⁺ T cells in MS.

HLA-DR15单倍型是多发性硬化症（MS）的最强遗传危险因素，但是我们对它如何促进MS的理解是有限的。由于自身反应性CD4 ⁺ T细胞和B细胞作为抗原呈递细胞参与了MS发病机理，因此我们表征了人类原代B细胞和单核细胞，胸腺和MS脑组织的两种HLA-DR15同种异形体DR2a和DR2b的免疫肽。来自HLA-DR分子的自身肽，特别是来自DR2a和DR2b自身的肽在B细胞和胸腺抗原呈递细胞上丰富。此外，我们鉴定了可以与HLA-DR衍生自肽（HLA-DR-SPs），MS相关外源肽（Epstein-Barr病毒和粘液阿克曼氏菌）交叉反应的自身反应性CD4 ⁺ T细胞克隆），以及DR2a和DR2b呈现的自身抗原。因此，两种HLA-DR15同种异体通过充当抗原呈递结构和表位来源，并向MS中的自身反应性CD4 ⁺ T细胞呈递相同的外源肽和自身抗原，共同塑造了自身反应性T细胞库。