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 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.
Kretz-Rommel
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A
W.M. Keck Autoimmune Disease Center, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
Duncan
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SR
Rubin
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RL
D019264:Adoptive Transfer; D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D015551:Autoimmunity; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D007111:Immunity, Cellular / Q000187:drug effects; D066298:In Vitro Techniques; D008180:Lupus Erythematosus, Systemic / Q000139:chemically induced* / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D019463:Mice, Inbred MRL lpr; D008814:Mice, Inbred NZB; D011342:Procainamide / Q000031:analogs & derivatives* / Q000633:toxicity; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D013950:Thymus Gland / Q000187:drug effects / Q000276:immunology
D000974:Antibodies, Antinuclear; C051948:procainamide 4-hydroxylamine; D011342:Procainamide