The immunology of rheumatoid arthritis

• Published in: Nature immunology Vol. 22; no. 1; pp. 10 - 18
• Main Authors: Weyand, Cornelia M., Goronzy, Jörg J.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2021; Nature Publishing Group
• Subjects: 631/250/38; 692/420/256; Animals; Arthritis, Rheumatoid - etiology; Arthritis, Rheumatoid - immunology; Asymptomatic; Autoantibodies; Autoimmune diseases; Autoimmunity; Biomedical and Life Sciences; Biomedicine; Care and treatment; Cell cycle; Cell differentiation; Deoxyribonucleic acid; Development and progression; DNA; DNA Repair; Effector cells; Humans; Immune response; Immune system; Immunological tolerance; Immunology; Immunopathogenesis; Infectious Diseases; Inflammation - immunology; Lymphocytes T; Macrophages; Mitochondrial DNA; Observations; Post-translation; Review Article; Rheumatoid arthritis; Self Tolerance; Shunts; Stromal cells; Synovitis; Synovitis - immunology; T-Lymphocytes - immunology; Telomeres; United States
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/s41590-020-00816-x

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. Weyand and Goronzy discuss how the progressive loss of immune cell tolerance underlies the immunopathology associated with rheumatoid arthritis.