Year: 2009
Type: article
Abstract: 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.
DOI: 10.1084/jem.20082251
Institution: Emory University
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Funders: National Institutes of Health, National Institute on Aging, National Heart, Lung, and Blood Institute, National Eye Institute, National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Advancing Translational Sciences
Awards: CD8 T Cells in Rheumatoid Arthritis, G1911962955, G2260927788, G2540523102, G353744, G366100091, Oligoclonal T Cell Expansion and Rheumatoid Arthritis, G429955531, G6170789353, G64106078, G661928818, Ocular Disease in Giant Cell Arteritis, G8039560308, G9000128015, The NOTCH Signaling Pathway in Large Vessel Vasculitis, Vaccine and Infection Induced Immunity in the Young and Aged, G953332266, G971417677
OpenAlex ID: W2113206255