Initiation of autoimmunity by a reactive metabolite of a lupus-inducing drug in the thymus

Drug-induced lupus is a side effect of deliberate ingestion of various medi cations, but its etiology, underlying mechanisms, and pathogenesis are puzz ling. In vivo metabolic transformation of lupus-inducing drugs to reactive products explains how a heterogeneous set of drugs can mediate the same dis ease syndrome. Evidence has accumulated that drugs are transformed by extra cellular oxidation from reactive oxygen species and myeloperoxidase produce d when neutrophils are activated, maximizing the in situ accumulation of re active drug metabolites within lymphoid compartments. The metabolite of pro cainamide, procainamide hydroxylamine, displays diverse biologic properties , but no apparent autoimmune effect has been observed. However, when procai namide hydroxylamine was introduced into the thymus of young adult normal m ice, a delayed but robust autoimmune response developed. Disruption of cent ral T-cell tolerance by intrathymic procainamide hydroxylamine resulted in the production of chromatin-reactive T cells that apparently drove the auto antibody response in the periphery. Drug-induced autoantibodies in this mou se model were remarkably similar to those in patients with procainamide-ind uced lupus. Therefore, this system has considerable promise to provide insi ght into the initiating events in drug-induced lupus and may provide a para digm for how other xenobiotics might induce systemic autoimmunity.