Persistence of autoreactive T cell drive is required to elicit anti-chromatin antibodies in a murine model of drug-induced lupus

Long-term treatment,vith procainamide and numerous other medications is occ asionally associated with the development of drug-induced lupus, We recentl y established a murine model for this syndrome by disrupting central T cell tolerance. Two intrathymic injections of procainamide-hydroxylamine (PAHA) , a reactive metabolite of procainamide, into (C57BL/6 x DBA/2)F-1 mice res ulted in the appearance of chromatin-reactive T cells and anti-chromatin au toantibodies. The current study explores in this model the role of autoreac tive T cells in autoantibody production and examines why autoantibodies aft er a single intrathymic drug injection were much more limited in isotype an d specificity. Injection of as few as 5000 chromatin-reactive T cells into naive, syngeneic mice induced a rapid IgM anti-denatured DNA response, whil e injection of at least 100-fold greater number of activated T cells was re quired for induction of IgG anti-chromatin Abs, suggesting that small numbe rs of autoreactive T cells can be homeostatically controlled. Mice subjecte d to a single intrathymic PAHA injection after receiving splenic B cells fr om an intrathymic PAHA-injected syngeneic donor also developed anti-chromat in hbs, but adoptive transfer of similarly primed T cells or of B cells wit hout intrathymic PAHA injection of the recipient failed to produce an anti- chromatin response. However, anti-chromatin Abs developed after a single in trathymic PAHA injection in Fas-deficient C57BL/6-lpr/lpr mice, suggesting that activation induced cell death limited autoimmunity in normal mice. Tak en together, these results imply that chromatin-reactive T cells produced b y intrathymic PAHA created a B cell population primed to somatically mutate and Ig class switch when subjected to a heavy load or second wave of autor eactive T cells.