Early cellular events in systemic autoimmunity driven by chromatin-reactive T cells.
In vivo exposure of the thymus of normal mice to procainamide-hydroxylamine, a lupus-inducing drug, causes development of chromatin-reactive T cells. Autoantibodies subsequently appear, but their origin and significance are unknown. The current studies were undertaken to determine the specificities of B cells that respond to chromatin-reactive T cells at the initiation of this autoimmune process. Three days after adoptive transfer of 6 x 10(6) chromatin-reactive T cells, B cells with the capacity to secrete IgM anti-chromatin antibodies were detected in 1/10(6) splenocytes, and these became 10- to 50-fold more numerous if either the donor T cells or the recipient had defective Fas due to the lpr allele. Five days later these mice developed IgG anti-chromatin-secreting B cells at a precursor frequency of 3-6 x 10(-5). B cells with dDNA-binding activity isolated from mice primed in vivo to a complex of methylated pigeon cytochrome c and dDNA could stimulate naive, cytochrome c-reactive T cells in vitro, demonstrating that B cells can internalize dDNA-bound proteins through their dDNA immunoblobulin receptor and can functionally present a T cell epitope. However, no capacity of chromatin for binding anti-dDNA antibodies was detected, and IgM dDNA-specific B cells did not expand when challenged with chromatin-reactive T cells in vivo. The rapid and robust expansion of anti-chromatin-secreting B cells indicates that the normal immune repertoire includes nontolerant autoreactive B cells that respond to strong T cell drive and are readily manifested if Fas-mediated activation-induced cell death is inhibited.
Kretz-Rommel
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Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, 92121, USA.
Rubin
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D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D002455:Cell Division; D002843:Chromatin / Q000276:immunology*; D004195:Disease Models, Animal; D008177:Lupus Vulgaris / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology*
D002843:Chromatin