A well known side effect of procainamide therapy is the production of antinuclear antibodies and, less frequently, systemic symptoms resembling lupus erythematosus. Autoantibodies elicited by procainamide are restricted to histones and dDNA, but these are heterogeneous within the patient population, and evidence for a generalized immune dysregulation due to procainamide therapy was obtained. Our working model for procainamide-induced autoimmunity is that reactive, transient metabolites of procainamide are generated in localized immunological compartments, triggering autoantigen release and producing cytotoxic or dysfunctional effects on selective subsets of lymphocytes. Preliminary studies demonstrated that phagocytic cells can metabolize procainamide to a cytotoxic product, and we propose to identify the enzymatic pathway responsible for procainamide oxidation. The sensitivity of lymphocyte subsets to procainamide metabolites will be studied by using a bioassay and measurements of lymphocyte functions such as proliferation, specific antibody synthesis and IL-2 production. Leukocytes from patients with a medical history of drug-induced lupus will be compared with asymptomatic procainamide-treated patients and with a normal population for sensitivity to the toxic effect of procainamide and with a normal population for sensitivity to the toxic effect of procainamide metabolites and for capacity to produce these metabolites after initiation of phagocytosis. The hypothesis will be tested that extracellular nucleohistone, generated secondary to release from a DNA repair process or as a result of cell death, becomes immunogenic due to excessive antigen load and is presented to the immune system in a unique form. Finally, a murine model for procainamide-induced autoimmunity will be developed based on administration of procainamide metabolite to normal mice with the genetic capacity to produce anti-histone antibodies. These studies will establish in vitro mechanisms for elicitation of autoantibodies by drugs such as procainamide, and the murine model will provide an in vivo system for testing these mechanisms and defining the sequence of events leading up to this form of autoimmunity.