SELF IG PEPTIDES THAT HELP ANTI-DNA ANTIBODY-PRODUCTION - IMPORTANCE OF CHARGED RESIDUES

Young NZB/NZW Fl (BWF1) mice develop T cell repertoires that are spont aneously stimulated by peptides derived from the V-H regions of BWF1 J 558-encoded autoantibodies (autoAb) to DNA, but not to V-H region pept ides of a J558-encoded antibody to an exogenous antigen. Immunization of young BWF1 mice with selected Ig-derived peptides accelerates anti- DNA production and nephritis, and immune tolerance induction to a comb ination of these determinants delays anti-DNA production and disease o nset. To further characterize this immunoregulatory circuitry, we aske d whether this phenomenon of spontaneous T cell activation by V-H regi on peptides is restricted to anti-DNA Ab of the V-H J558 family, and w hat are the charge and structural attributes of these T cell determina nts? We studied spontaneous T cell proliferative responses to peptides derived from an autoAb to DNA constructed from V-H 7183 and found tha t it contains several T cell determinants. Both charge and size of cer tain amino acids (AA) within each peptide seemed to be important. Pept ides containing arginine (R) or glutamic scid (E) were more likely to be T cell determinants than peptides without those AA; replacement of charged AA with uncharged PLA abolished T cell recognition of a peptid e. We previously reported that some Abs to DNA are enriched in R in th eir V-H; pathogenic BWF1 IgG anti-DNA are enriched in positively and n egatively charged AA in V-H regions. Therefore, we speculate that pept ides from natural IgM autoAb may initially activate BWF1 T cells, and as somatic mutations of Ig occur, charged AA introduced into V regions increase the number of T cell determinants, thus favoring upregulatio n of pathogenic Ab subsets. Therefore, in predisposed individuals. the ability of T cells to recognize more charged T cell determinants in a utoAb may be one mechanism promoting development of disease.