Immunopathology Lab, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632 014, Tamil Nadu, India.
Immunopathology Lab, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632 014, Tamil Nadu, India.
Life Sci. 2024 Nov 15;357:123075. doi: 10.1016/j.lfs.2024.123075. Epub 2024 Sep 26.
Rheumatoid arthritis (RA), a multigene disorder with a heritability rate of 60 %, is characterized by persistent pain, synovial hyperplasia, and cartilage and bone destruction, ultimately causing irreversible joint deformity. The etiology and pathogenesis of rheumatoid arthritis (RA) are primarily influenced by specific genetic variants, particularly HLA alleles such as HLA-DRB101 and DRB104. However, other HLA alleles such as HLA-DRB110 and DPB1 have also been found to contribute to increased susceptibility to RA. However, non-HLA genes also confer a comparatively high risk of RA disease manifestation. The most relevant single nucleotide polymorphisms (SNPs) associated with non-HLA genes are PTPN22, TRAF1, CXCL-12, TBX-5, STAT4, FCGR, PADI4, and MTHFR. In conjunction with genetic susceptibility, epigenetic alterations orchestrate paramount involvement in regulating RA pathogenesis. Increasing evidence implicates DNA methylation and histone protein modifications, including acetylation and methylation, as the primary epigenetic mechanisms that drive the pathogenesis and clinical progression of the disease. In addition to genetic and epigenetic changes, autoimmune inflammation also determines the pathological progression of the synovial membrane in joints with RA. Glycosylation changes, such as sialylation and fucosylation, in immune cells have been shown to be relevant to disease progression. Genetic heterogeneity, epigenetic factors, and changes in glycosylation do not fully explain the features of RA. Therefore, investigating the interplay between genetics, epigenetics, and autoimmunity is crucial. This review highlights the significance and interaction of these elements in RA pathophysiology, suggesting their diagnostic potential and opening new avenues for novel therapeutic approaches.
类风湿关节炎（RA）是一种多基因疾病，遗传率为 60%，其特征为持续性疼痛、滑膜增生、软骨和骨破坏，最终导致不可逆转的关节畸形。类风湿关节炎（RA）的病因和发病机制主要受特定遗传变异的影响，特别是 HLA 等位基因，如 HLA-DRB101 和 DRB104。然而，其他 HLA 等位基因，如 HLA-DRB110 和 DPB1，也被发现与 RA 的易感性增加有关。然而，非 HLA 基因也赋予了相对较高的 RA 疾病表现风险。与非 HLA 基因相关的最相关的单核苷酸多态性（SNPs）是 PTPN22、TRAF1、CXCL-12、TBX-5、STAT4、FCGR、PADI4 和 MTHFR。与遗传易感性一起，表观遗传改变在调节 RA 发病机制中起着至关重要的作用。越来越多的证据表明，DNA 甲基化和组蛋白蛋白修饰，包括乙酰化和甲基化，是驱动疾病发病机制和临床进展的主要表观遗传机制。除了遗传和表观遗传变化外，自身免疫炎症也决定了 RA 关节滑膜的病理进展。免疫细胞中的糖基化变化，如唾液酸化和岩藻糖化，与疾病进展有关。遗传异质性、表观遗传因素和糖基化变化不能完全解释 RA 的特征。因此，研究遗传、表观遗传和自身免疫之间的相互作用至关重要。这篇综述强调了这些因素在 RA 病理生理学中的重要性和相互作用，提示了它们在诊断中的潜力，并为新的治疗方法开辟了新的途径。
