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.

Autoantibodies to the native p80 subunit of Ku are more common than are anti-p70 antibodies. When anti-p70 antibodies were detected, they generally were found together with anti-p80. A novel type of autoantibody capable of stabilizing the p70/p80 heterodimer was identified in human sera for the first time. These "stabilizing" autoantibodies are found in sera containing both anti-p70 and anti-p80 antibodies, and also are produced by mice immunized with human Ku antigen. Autoimmunity to Ku may be initiated with an immune response to p80, followed by spreading to p70. We hypothesize that stabilizing antibodies could facilitate the spreading of autoimmunity from one subunit of Ku to another by altering the processing of p70 or p80 by antigen-presenting cells.

We report a woman with systemic lupus erythematosus (SLE) with diffuse proliferative glomerulonephritis and anti-dsDNA antibodies whose serum contained autoantibodies specific for the phosphorylated form of RNA polymerase II (RNAP IIO), Su and ribosomal P antigen, as well as anti-topoisomerase I antibodies, a marker for scleroderma (SSc). Over 6 years, the patient exhibited clinical manifestations consistent with SLE without clinical evidence of scleroderma. The reactivity of her serum autoantibodies with the phosphoproteins ribosomal P, topoisomerase I, and RNAP IIO is consistent with recognition of autoepitopes comprised in part of phosphate groups. This may explain the unexpected coexistence of marker autoantibodies for SLE and scleroderma, possibly with implications for the mechanisms of autoantibody generation.

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