Center for Translational Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA, United States.
Front Immunol. 2022 Aug 1;13:972121. doi: 10.3389/fimmu.2022.972121. eCollection 2022.
Genetic variants associated with susceptibility to autoimmune disease have provided important insight into the mechanisms responsible for the loss of immune tolerance and the subsequent development of autoantibodies, tissue damage, and onset of clinical disease. Here, we review how genetic variants shared across multiple autoimmune diseases have contributed to our understanding of global tolerance failure, focusing on variants in the human leukocyte antigen region, PTPN2 and PTPN22, and their role in antigen presentation and T and B cell homeostasis. Variants unique to a specific autoimmune disease such as those in PADI2 and PADI4 that are associated with rheumatoid arthritis are also discussed, addressing their role in disease-specific immunopathology. Current research continues to focus on determining the functional consequences of autoimmune disease-associated variants but has recently expanded to variants in the non-coding regions of the genome using novel approaches to investigate the impact of these variants on mechanisms regulating gene expression. Lastly, studying genetic risk variants in the setting of autoimmunity has clinical implications, helping predict who will develop autoimmune disease and also identifying potential therapeutic targets.
与自身免疫性疾病易感性相关的遗传变异为阐明导致免疫耐受丧失以及随后发生自身抗体、组织损伤和临床疾病的机制提供了重要线索。在这里，我们回顾了跨多种自身免疫性疾病共享的遗传变异如何有助于我们理解全球耐受失败，重点关注人类白细胞抗原区域、PTPN2 和 PTPN22 中的变异及其在抗原呈递和 T 和 B 细胞稳态中的作用。还讨论了特定于特定自身免疫性疾病的变异，如与类风湿关节炎相关的 PADI2 和 PADI4 中的变异，探讨了它们在疾病特异性免疫病理学中的作用。目前的研究继续集中于确定自身免疫性疾病相关变异的功能后果，但最近已使用新方法扩展到基因组非编码区域的变异，以研究这些变异对调节基因表达的机制的影响。最后，在自身免疫的背景下研究遗传风险变异具有临床意义，有助于预测谁将患上自身免疫性疾病，并确定潜在的治疗靶点。
