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Research Article Free access | 10.1172/JCI119356
W.M. Keck Autoimmune Disease Center, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
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W.M. Keck Autoimmune Disease Center, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
Find articles by Duncan, S. in: JCI | PubMed | Google Scholar
W.M. Keck Autoimmune Disease Center, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
Find articles by Rubin, R. in: JCI | PubMed | Google Scholar
Published April 15, 1997 - More info
A side effect of therapy with procainamide and numerous other medications is a lupus-like syndrome characterized by autoantibodies directed against denatured DNA and the (H2A-H2B)-DNA subunit of chromatin. We tested the possibility that an effect of lupus-inducing drugs on central T cell tolerance underlies these phenomena. Two intrathymic injections of procainamide-hydroxylamine (PAHA), a reactive metabolite of procainamide, resulted in prompt production of IgM antidenatured DNA antibodies in C57BL/6xDBA/2 F1 mice. Subsequently, IgG antichromatin antibodies began to appear in the serum 3 wk after the second injection and were sustained for several months. Specificity, inhibition and blocking studies demonstrated that the PAHA-induced antibodies showed remarkable specificity to the (H2A-H2B)-DNA complex. No evidence for polyclonal B cell activation could be detected based on enumeration of Ig-secreting B cells and serum Ig levels, suggesting that a clonally restricted autoimmune response was induced by intrathymic PAHA. The IgG isotype of the antichromatin antibodies indicated involvement of T cell help, and proliferative responses of splenocytes to oligonucleosomes increased up to 100-fold. As little as 5 microM PAHA led to a 10-fold T cell proliferative response to chromatin in short term organ culture of neonatal thymi. We suggest that PAHA interferes with self-tolerance mechanisms accompanying T cell maturation in the thymus, resulting in the emergence of chromatin-reactive T cells followed by humoral autoimmunity.