D-PENICILLAMINE-INDUCED AND QUINIDINE-INDUCED ANTINUCLEAR ANTIBODIES IN A.SW (H-2(S)) MICE - SIMILARITIES WITH AUTOANTIBODIES IN SPONTANEOUS AND HEAVY METAL-INDUCED AUTOIMMUNITY

Ten percent of human lupus syndromes occur in patients as a result of treatment with certain medications. H-2(s) mice can produce autoantibodies following treatment with various drugs or heavy metals and they are a potential animal model of drug-induced lupus. We have examined nine anti-chromatin monoclonal antibodies (mAb) from A.SW mice that had been treated with either D-penicillamine or quinidine, two lupus-inducing drugs in humans. These mAb are specific either for DNA or histone-DNA complexes corresponding to nucleosomes or subnucleosome particles. Only one mAb reacts with an unknown chromatin antigen. The V region sequences of six of these mAb were studied and are notable by several features. As previously observed in spontaneous autoantibodies to DNA or histone-DNA complexes, arginine or asparagine residues are found at critical locations throughout the V regions. Many of these residues, potentially important for binding to DNA or DNA-histone complexes, result either from somatic mutations or atypical V-H-D-J(H) rearrangements. Another significant characteristic is that the V-H genes of several D-penicillamine- or quinidine-induced mAb are most similar to those of anti-nucleolar mAb obtained from mercury-injected A.SW mice. The implications of these findings for the pathogenesis of spontaneous or induced autoimmunity are discussed.