Association of autoantibodies with Ku and DNA repair proteins in connective tissue diseases
1Department of Medicine, University of Ottawa, The Ottawa Health Research Institute, 2Cell Biology Research Group, Robarts Research Institute, University of Western Ontario, London, 3University of Ottawa Institute of Mental Health Research, Ottawa, Ontario, Canada, 4Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Calgary, Calgary, Alberta, 5University of Calgary, Calgary, Alberta, Canada and 6Department of Biochemistry, Microbiology and Immunology, University of Ottawa, The Ottawa Health Research Institute, Ottawa, Ontario, Canada.
Correspondence to: C. Schild-Poulter, Cell Biology Research Group, Robarts Research Institute, P.O. Box 5015, 100 Perth Drive, London, Ontario, N6A 5K8, Canada. E-mail: cschild-poulter{at}robarts.ca
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Abstract |
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Objective. To analyse the autoimmune response to DNA damage response factors in systemic autoimmune rheumatic disease (SARD) patients and to determine their association with autoantibodies to Ku antigen.
Methods. We have screened the serum of 239 patients suffering from SARD, including systemic lupus erythematosus, systemic sclerosis and rheumatoid arthritis to detect the occurrence of autoantibodies to Ku and four other DNA damage response factors that form macromolecular complexes with Ku using an immunoprecipitation assay.
Results. We identified samples positive for autoantibodies to Ku (20.5%), DNA-dependent protein kinase catalytic subunit (DNA-PKcs, 8.4%) and poly(ADP-ribose) polymerase (5.9%), and report for the first time autoantibodies directed against two additional DNA repair proteins, Werner (6.3%) and Mre11 (9.6%). Remarkably, we found a striking correlation between the production of antibodies to Ku and the other four Ku-binding factors. Sixty-five percent of anti-Ku-positive sera were found to contain at least one of the four anti-DNA repair antibodies vs only 10% of the anti-Ku-negative sera.
Conclusion. Our results suggest that the autoantibodies directed against Ku are elicited by macromolecular protein complexes containing Ku and the associated DNA damage proteins. The presence of autoantibodies directed against macromolecular complexes known to play roles in the DNA damage response provides evidence that B-cell responses to latent or persistent DNA damage may be present at the onset or during the development of autoimmunity in certain SARDs.
KEY WORDS: Autoantigen, Autoimmunity, Autoantibody association, Ku, DNA damage
Submitted 14 May 2007;
revised version accepted 16 November 2007.
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