Rheumatoid arthritis (RA), multiple sclerosis (MS), type 1 diabetes (T1D), and celiac disease (CD), are strongly associated with susceptible HLA class II haplotypes. The peptide-binding pockets of these molecules are polymorphic, thus each HLA class II protein presents a distinct set of peptides to CD4⁺ T cells. Peptide diversity is increased through post-translational modifications, generating non-templated sequences that enhance HLA binding and/or T cell recognition. The high-risk HLA-DR alleles that confer susceptibility to RA are notable for their ability to accommodate citrulline, promoting responses to citrullinated self-antigens. Likewise, HLA-DQ alleles associated with T1D and CD favor the binding of deamidated peptides. In this review, we discuss structural features that promote modified self-epitope presentation, provide evidence supporting the relevance of T cell recognition of such antigens in disease processes, and make a case that interrupting the pathways that generate such epitopes and reprogramming neoepitope-specific T cells are key strategies for effective therapeutic intervention.

类风湿性关节炎 (RA)、多发性硬化症 (MS)、1 型糖尿病 (T1D) 和乳糜泻 (CD) 与易感 HLA II 类单倍型密切相关。这些分子的肽结合袋是多态性的，因此每个 HLA II 类蛋白向 CD4 ^{+呈现一组不同的肽}T细胞。通过翻译后修饰增加肽多样性，生成增强 HLA 结合和/或 T 细胞识别的非模板序列。赋予 RA 易感性的高风险 HLA-DR 等位基因以其适应瓜氨酸的能力而闻名，从而促进对瓜氨酸自身抗原的反应。同样，与 T1D 和 CD 相关的 HLA-DQ 等位基因有利于脱酰胺肽的结合。在这篇综述中，我们讨论了促进修饰自身表位呈递的结构特征，提供了支持 T 细胞识别此类抗原在疾病过程中相关性的证据，并提出了中断生成此类表位的途径并重新编程新表位特异性 T 的案例。细胞是有效治疗干预的关键策略。