AUTOIMMUNITY CAUSED BY DISRUPTION OF CENTRAL T-CELL TOLERANCE - A MURINE MODEL OF DRUG-INDUCED LUPUS

A side effect of therapy with procainamide and numerous other medicati ons is a lupus-like syndrome characterized by autoantibodies directed against denatured DNA and the (H2A-H2B)-DNA subunit of chromatin. We t ested the possibility that an effect of lupus-inducing drugs on centra l T cell tolerance underlies these phenomena. Two intrathymic injectio ns of procainamide-hydroxylamine (PAHA), a reactive metabolite of proc ainamide, resulted in prompt production of IgM antidenatured DNA antib odies in C57BL/6xDBA/2 F1 mice. Subsequently, IgG antichromatin antibo dies began to appear in the serum 3 wk after the second injection and were sustained for several months. Specificity, inhibition and blockin g studies demonstrated that the PAHA-induced antibodies showed remarka ble specificity to the (H2A-H2B)-DNA complex. No evidence for polyclon al B cell activation could be detected based on enumeration of Ig-secr eting B cells and serum Ig levels, suggesting that a clonally restrict ed autoimmune response was induced by intrathymic PAHA. The IgG isotyp e of the antichromatin antibodies indicated involvement of T cell help , and proliferative responses of splenocytes to oligonucleosomes incre ased up to 100-fold. As little as 5 mu M PAHA led to a 10-fold T cell proliferative response to chromatin in short term organ culture of neo natal thymi. We suggest that PAHA interferes with self-tolerance mecha nisms accompanying T cell maturation in the thymus, resulting in the e mergence of chromatin-reactive T cells followed by humoral autoimmunit y.