Autoantibodies that stabilize the molecular interaction of Ku antigen with DNA-dependent protein kinase catalytic subunit

Authors

  • M. SATOH,

    1. Departments of Medicine and Microbiology/Immunology, Thurston Arthritis Research Centre and UNC Lineberger Comprehensive Cancer Centre, University of North Carolina, Chapel Hill, NC, USA,
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  • A. K. AJMANI,

    1. Departments of Medicine and Microbiology/Immunology, Thurston Arthritis Research Centre and UNC Lineberger Comprehensive Cancer Centre, University of North Carolina, Chapel Hill, NC, USA,
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  • L. STOJANOV,

    1. Departments of Medicine and Microbiology/Immunology, Thurston Arthritis Research Centre and UNC Lineberger Comprehensive Cancer Centre, University of North Carolina, Chapel Hill, NC, USA,
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  • J. J. LANGDON,

    1. Departments of Medicine and Microbiology/Immunology, Thurston Arthritis Research Centre and UNC Lineberger Comprehensive Cancer Centre, University of North Carolina, Chapel Hill, NC, USA,
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  • T. OGASAWARA,

    1. Department of Medicine, Keio University School of Medicine, Tokyo, Japan,
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  • J. WANG,

    1. Departments of Medicine and Microbiology/Immunology, Thurston Arthritis Research Centre and UNC Lineberger Comprehensive Cancer Centre, University of North Carolina, Chapel Hill, NC, USA,
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  • M. A. DOOLEY,

    1. Departments of Medicine and Microbiology/Immunology, Thurston Arthritis Research Centre and UNC Lineberger Comprehensive Cancer Centre, University of North Carolina, Chapel Hill, NC, USA,
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  • H. B. RICHARDS,

    1. Departments of Medicine and Microbiology/Immunology, Thurston Arthritis Research Centre and UNC Lineberger Comprehensive Cancer Centre, University of North Carolina, Chapel Hill, NC, USA,
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  • J. B. WINFIELD,

    1. Departments of Medicine and Microbiology/Immunology, Thurston Arthritis Research Centre and UNC Lineberger Comprehensive Cancer Centre, University of North Carolina, Chapel Hill, NC, USA,
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  • T. H. CARTER,

    1. Department of Biological Sciences, St John’s University, Jamaica, NY, USA
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  • W. H. REEVES

    1. Departments of Medicine and Microbiology/Immunology, Thurston Arthritis Research Centre and UNC Lineberger Comprehensive Cancer Centre, University of North Carolina, Chapel Hill, NC, USA,
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Westley H. Reeves MD Division of Rheumatology and Immunology, University of North Carolina at Chapel Hill, 3330 Thurston Building, CB no. 7280, Chapel Hill, NC 27599-7280, USA.

Abstract

DNA-dependent protein kinase (DNA-PK) consists of a DNA binding subunit (Ku autoantigen), and a catalytic subunit (DNA-PKcs). In the present study, human autoantibodies that recognize novel antigenic determinants of DNA-PK were identified. One type of autoantibody stabilized the interaction of DNA-PKcs with Ku and recognized the DNA-PKcs–Ku complex, but not biochemically purified DNA-PKcs. Another type recognized purified DNA-PKcs. Autoantibodies to Ku (p70/p80 heterodimer), ‘stabilizing’ antibodies, and antibodies to DNA-PKcs comprise a linked autoantibody set, since antibodies recognizing purified DNA-PKcs were strongly associated with stabilizing antibodies, whereas stabilizing antibodies were strongly associated with anti-Ku. This hierarchical pattern of autoantibodies specific for components of DNA-PK (anti-Ku>stabilizing antibodies>anti-DNA-PKcs) may have implications for the pathogenesis of autoimmunity to DNA-PK and other chromatin particles. The data raise the possibility that altered antigen processing and/or stabilization of the DNA-PKcs–Ku complex due to autoantibody binding could play a role in spreading autoimmunity from Ku to the weakly associated antigen DNA-PKcs.

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