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The immunology of rheumatoid arthritis

Nature Immunology volume 22, pages 10–18 (2021)Cite this article

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Abstract

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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Fig. 1: Evolution of rheumatoid arthritis over an individual’s lifetime.
Fig. 2: DNA repair deficits in rheumatoid arthritis.
Fig. 3: Metabolic reprogramming and proinflammatory effector functions in RA T cells.

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Acknowledgements

This work was supported by the National Institutes of Health (R01 AR042527, R01 HL117913, R01 AI108906, R01 HL142068 and P01 HL129941 to C.M.W.; and R01 AI108891, R01 AG045779, U19 AI057266, R01 AI129191 and IO1 BX001669 to J.J.G.) and the Encrantz Family Discovery Fund.

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  1. Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

    Cornelia M. Weyand & Jörg J. Goronzy

  2. Department of Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA

    Cornelia M. Weyand & Jörg J. Goronzy

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Correspondence to Cornelia M. Weyand.

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Weyand, C.M., Goronzy, J.J. The immunology of rheumatoid arthritis. Nat Immunol 22, 10–18 (2021). https://doi.org/10.1038/s41590-020-00816-x

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