The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20082251
The Journal of Experimental Medicine, Vol. 206, No. 6, 1435-1449
The Rockefeller University Press, 0022-1007 $30.00
© Shao et al.
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ARTICLE

 Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis

Lan Shao, Hiroshi Fujii, Inés Colmegna, Hisashi Oishi, Jörg J. Goronzy, and Cornelia M. Weyand

The Kathleen B. and Mason I. Lowance Center for Human Immunology and Rheumatology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322

CORRESPONDENCE Cornelia M. Weyand: cweyand{at}emory.edu

In rheumatoid arthritis (RA), dysfunctional T cells sustain chronic inflammatory immune responses in the synovium. Even unprimed T cells are under excessive replication pressure, suggesting an intrinsic defect in T cell regeneration. In naive CD4 CD45RA+ T cells from RA patients, DNA damage load and apoptosis rates were markedly higher than in controls; repair of radiation-induced DNA breaks was blunted and delayed. DNA damage was highest in newly diagnosed untreated patients. RA T cells failed to produce sufficient transcripts and protein of the DNA repair kinase ataxia telangiectasia (AT) mutated (ATM). NBS1, RAD50, MRE11, and p53 were also repressed. ATM knockdown mimicked the biological effects characteristic for RA T cells. Conversely, ATM overexpression reconstituted DNA repair capabilities, response patterns to genotoxic stress, and production of MRE11 complex components and rescued RA T cells from apoptotic death. In conclusion, ATM deficiency in RA disrupts DNA repair and renders T cells sensitive to apoptosis. Apoptotic attrition of naive T cells imposes lymphopenia-induced proliferation, leading to premature immunosenescence and an autoimmune-biased T cell repertoire. Restoration of DNA repair mechanisms emerges as an important therapeutic target in RA.

Abbreviations used: AT, ataxia telangiectasia; ATM, AT mutated; ATR, AT and RAD3 related; DSB, double-strand break; IRIF, irradiation-induced foci; PI, propidium iodide; qPCR, quantitative PCR; RA, rheumatoid arthritis; siRNA, small interfering RNA; SLE, systemic lupus erythematosis; TM, tail moment.

© 2009 Shao et al.
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