Self Ig peptides that help anti-DNA antibody production: importance of charged residues

Abstract

Young NZB/NZW F1 (BWF1) mice develop T cell repertoires that are spontaneously stimulated by peptides derived from the V_H regions of BWF1 J558-encoded autoantibodies (autoAb) to DNA, but not to V_H region peptides 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 combination of these determinants delays anti-DNA production and disease onset. To further characterize this immunoregulatory circuitry, we asked whether this phenomenon of spontaneous T cell activation by V_H region peptides is restricted to anti-DNA Ab of the V_H J558 family, and what are the charge and structural attributes of these T cell determinants? We studied spontaneous T cell proliferative responses to peptides derived from an autoAb to DNA constructed from V_H 7183 and found that it contains several T cell determinants. Both charge and size of certain amino acids (AA) within each peptide seemed to be important. Peptides containing arginine (R) or glutamic acid (E) were more likely to be T cell determinants than peptides without those AA; replacement of charged AA with uncharged AA abolished T cell recognition of a peptide. We previously reported that some Abs to DNA are enriched in R in their V_H; pathogenic BWF1 IgG anti-DNA are enriched in positively and negatively charged AA in V_H Therefore, we speculate that peptides 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 upregulation of pathogenic Ab subsets. Therefore, in predisposed individuals, the ability of T cells to recognize more charged T cell determinants in autoAb may be one mechanism promoting development of disease.