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 u nknown. 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) ch romatin-reactive T cells, B cells with the capacity to secrete IgM anti-chr omatin 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 in ternalize dDNA-bound proteins through their dDNA immunoblobulin receptor an d can functionally present a T cell epitope, However, no capacity of chroma tin for binding anti-dDNA antibodies was detected, and IgM dDNA-specific B cells did not expand when challenged with chromatin-reactive T cells in viv o, The rapid and robust expansion of anti-chromatin-secreting B cells indic ates 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. (C) 2001 Academic Pre ss.