Autoantibodies against DNA double-strand break repair proteins

Autoantibodies against cellular components are commonly present in sera fro m patients with systemic rheumatic diseases and may play an important role in pathogenesis. The Ku protein was recognized 20 years ago as a major targ et of autoantibodies in a subset of Japanese patients with scleroderma-poly myositis overlap syndrome, and anti-Ku antibodies have since been shown to occur in 10-20% of patients with these and other systemic rheumatic disease s, including systemic lupus erythematosus. Ku functions physiologically in the repair of DNA double-strand breaks, where it carries out the initial re cognition of damaged DNA ends. The three dimensional structure of the Ku-DN A complex has recently been solved, and helps illuminate the relationship b etween the autoimmune epitopes and other features of the protein. In additi on to Ku, three other polypeptides in the same DNA repair pathway have more recently been identified as autoantigens: the DNA-dependent protein kinase catalytic subunit, DNA ligase IV, and XRCC4. Two hypotheses have been invo ked to explain the ability of these proteins to elicit an autoimmune respon se in susceptible individuals. One is that DNA damage induces formation of nucleoprotein complexes that present novel composite or conformational epit opes. The other is that cleavage of these proteins by caspases or Granzyme B leads to presentation of immunocryptic peptides capable of stimulating au toreactive T lymphocytes. In the case of DNA double-strand break repair pro teins, there is evidence that both of these mechanisms may be at work. Beca use of their role in the maintenance of genome stability, DNA double-strand break repair proteins have been the subject of intense study, and a wealth of new structural, biochemical and functional information makes them excel lent models for investigation of the humoral autoimmune response.