701. Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis.
- Author
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Shao L, Fujii H, Colmegna I, Oishi H, Goronzy JJ, and Weyand CM
- Subjects
- Adult, Apoptosis physiology, Ataxia Telangiectasia Mutated Proteins, CD4 Antigens genetics, CD4 Antigens immunology, Cell Cycle Proteins genetics, Comet Assay, DNA Damage, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Female, Gene Expression Regulation, Humans, Leukocyte Common Antigens genetics, Leukocyte Common Antigens immunology, MRE11 Homologue Protein, Middle Aged, Protein Serine-Threonine Kinases genetics, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, T-Lymphocytes cytology, T-Lymphocytes radiation effects, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Proteins genetics, Arthritis, Rheumatoid enzymology, Arthritis, Rheumatoid genetics, DNA Repair, DNA-Binding Proteins deficiency, Protein Serine-Threonine Kinases deficiency, T-Lymphocytes immunology, Tumor Suppressor Proteins deficiency
- 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.
- Published
- 2009
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