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Rejuvenating the immune system in rheumatoid arthritis

Nature Reviews Rheumatology volume 5, pages 583–588 (2009)Cite this article

Abstract

In rheumatoid arthritis (RA), the aging process of the immune system is accelerated. Formerly, this phenomenon was suspected to be a consequence of chronic inflammatory activity. However, newer data strongly suggest that deficiencies in maintaining telomeres and overall DNA stability cause excessive apoptosis of RA T cells, imposing proliferative pressure and premature aging on the system. Already during the early stages of their life cycle, and long before they participate in the inflammatory process, RA T cells are lost owing to increased apoptotic susceptibility. A search for underlying mechanisms has led to the discovery of defective pathways of repairing broken DNA and elongating and protecting telomeric sequences at the chromosomal ends. Two enzymatic machineries devoted to DNA repair and maintenance have been implicated. RA T cells fail to induce sufficient amounts of the telomeric repair enzyme telomerase, leaving telomeric ends uncapped and thus susceptible to damage. Of equal importance, RA T cells produce low levels of the DNA repair enzyme ataxia telangiectasia mutated and the complex of nucleoproteins that sense and fix DNA double-strand breaks. The inability to repair damaged DNA renders naive T cells vulnerable to apoptosis, exhausts T-cell regeneration and reshapes the T cell repertoire. Therapeutic attempts to reset the immune systems of patients with RA and prevent premature immunosenescence should include restoration of DNA repair capability.

Key Points

  • In rheumatoid arthritis (RA) naive T cells have shortened telomeres and contracted diversity, and memory T cells reach their differentiation potential, lose CD28 and acquire alternative regulator receptors

  • In RA, T cells' telomeric maintenance is dysfunctional, owing to insufficient production of the repair enzyme telomerase

  • RA T cells have a high load of DNA double-strand breaks, jeopardizing DNA integrity and cell survival

  • The failure to repair damaged DNA is caused by deficiency of the ataxia telangiectasia mutated (ATM)–MRE11–RAD50–NBS1 DNA repair machinery; mutations in ATM cause the immunodeficiency syndrome ataxia telangiectasia

  • The inability to maintain telomeric integrity and to repair broken DNA leads to excessive apoptotic death of RA T cells, and places the immune system under chronic proliferative stress

  • Recognizing that molecular deficiencies in nuclear stability can exhaust immune regeneration and lead to premature immune aging could change the pathogenetic concept of RA and advance the pursuit of novel therapies

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Figure 1: Defective telomeric repair and impaired clonal expansion in RA T cells.
Figure 2: Insufficient telomeric protection in RA T cells.
Figure 3: RA T cells accumulate unrepaired DNA double-strand breaks, the most lethal DNA lesion.
Figure 4: DNA instability in naive RA T cells.
Figure 5: DNA instability and autoreactivity in RA.

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Acknowledgements

The authors wish to thank Linda Arneson and Tamela Yeargin for their editorial support. This work was funded in part by grants from the NIH (AR 42527, AR 41974, AI 44142, AI 57266, AG 15043) and the “Within Our Reach” campaign of the American College of Rheumatology Research and Education Foundation.

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Authors and Affiliations

  1. Kathleen B. and Mason I. Lowance Center for Human Immunology and Rheumatology, Emory University, Atlanta, GA, USA

    Cornelia M. Weyand, Lan Shao & Jörg J. Goronzy

  2. Department of Hematology and Rheumatology, Tohoku University School of Medicine, Sendai, Japan

    Hiroshi Fujii

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Correspondence to Cornelia M. Weyand.

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Weyand, C., Fujii, H., Shao, L. et al. Rejuvenating the immune system in rheumatoid arthritis. Nat Rev Rheumatol 5, 583–588 (2009). https://doi.org/10.1038/nrrheum.2009.180

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