A PEPTIDE DERIVED FROM AN AUTOANTIBODY CAN STIMULATE T-CELLS IN THE (NZB X NZW)F-1 MOUSE MODEL OF SYSTEMIC LUPUS-ERYTHEMATOSUS

Objective. To assess the ability of peptides derived from anti-DNA to stimulate syngeneic T lymphocytes and influence lupus in (NZB x NZW)F1 (NZB/W) mice. Methods. We synthesized (by Geysen pin method) overlapping 12-mer peptides recapitulating the amino acid sequence of the V(H) region of a nephritogenic monoclonal IgG2a anti-DNA antibody (A6.1) from an NZB/W mouse. Splenic T cells were cultured with the peptides; multiple experiments assayed 12-mer and 16-mer peptides which contained a triple-base motif (KFKGK). We immunized 20-week-old NZB/W mice with the 12-mer and evaluated them for evidence of nephritis and for quantities of antibodies in plasma and glomeruli. Results. Three clusters of peptides caused proliferation of spleen cells from young, nonimmunized mice. Both the 12-mer FYNQKFKGKATL and the 16-mer GDTFYNQKFKGKATLT peptides stimulated purified T cells. The KXKXK motif occurs in 15% of murine Ig VH (NBRF protein database), compared with 100% (6 of 6) of NZB/W anti-DNA monoclonal antibody. Immunization with the 12-mer peptide increased plasma levels of IgG, anti-DNA, and immune complexes, and levels of anti-DNA in glomeruli; nephritis was accelerated. Conclusion. NZB/W anti-DNA contain peptide sequences in their VH regions that stimulate self-T cells. At least one motif is frequent in NZB/W anti-DNA. If some activated T cells provide help, this mechanism may contribute to sustained up-regulation of autoantibodies in murine lupus.