Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis

J Exp Med. 2009 Jun 8;206(6):1435-49. doi: 10.1084/jem.20082251. Epub 2009 May 18.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Apoptosis / physiology
  • Arthritis, Rheumatoid* / enzymology
  • Arthritis, Rheumatoid* / genetics
  • Ataxia Telangiectasia Mutated Proteins
  • CD4 Antigens / genetics
  • CD4 Antigens / immunology
  • Cell Cycle Proteins / genetics
  • Comet Assay
  • DNA Damage
  • DNA Repair*
  • DNA-Binding Proteins / deficiency*
  • 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 / deficiency*
  • Protein Serine-Threonine Kinases / genetics
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / radiation effects
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / deficiency*
  • Tumor Suppressor Proteins / genetics

Substances

  • CD4 Antigens
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • MRE11 protein, human
  • Recombinant Fusion Proteins
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein Serine-Threonine Kinases
  • MRE11 Homologue Protein
  • Leukocyte Common Antigens
  • PTPRC protein, human