类风湿性关节炎
免疫学
自身免疫
效应器
生物
免疫系统
T细胞
炎症
自身抗体
基因组不稳定性
细胞生物学
医学
DNA损伤
遗传学
抗体
DNA
作者
Cornelia M. Weyand,Jörg J. Goronzy
标识
DOI:10.1038/s41590-020-00816-x
摘要
The immunopathogenesis of rheumatoid arthritis (RA) spans decades, beginning with the production of autoantibodies against post-translationally modified proteins (checkpoint 1). After years of asymptomatic autoimmunity and progressive immune system remodeling, tissue tolerance erodes and joint inflammation ensues as tissue-invasive effector T cells emerge and protective joint-resident macrophages fail (checkpoint 2). The transition of synovial stromal cells into autoaggressive effector cells converts synovitis from acute to chronic destructive (checkpoint 3). The loss of T cell tolerance derives from defective DNA repair, causing abnormal cell cycle dynamics, telomere fragility and instability of mitochondrial DNA. Mitochondrial and lysosomal anomalies culminate in the generation of short-lived tissue-invasive effector T cells. This differentiation defect builds on a metabolic platform that shunts glucose away from energy generation toward the cell building and motility programs. The next frontier in RA is the development of curative interventions, for example, reprogramming T cell defects during the period of asymptomatic autoimmunity.
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