T cell peptide of a self-protein elicits autoantibody to the protein antigen. Implications for specificity and pathogenetic role of antibody in autoimmunity.

A 13-mer peptide of the ZP3 glycoprotein from mouse zona pellucida has a T cell epitope that induces autoimmune oophoritis and a B cell epitope that reacts with antibody to murine ZP3. When the B cell epitope was partially truncated, the ZP3 peptides no longer induced antibody to the B cell epitope, but unexpectedly they elicited antibody to the zona pellucida. These autoantibodies were of IgG class, detected in sera and bound to the ovarian zona pellucida. That an exclusive T cell peptide of murine ZP3, without coinjection of the whole ZP3 protein, elicited autoantibodies against ZP3 outside the T cell peptide was confirmed as follows. First, the ZP3 T cell peptide did not contain additional B cell epitopes that cross-reacted with native ZP3. Second, endogenous ovarian Ag were required because autoantibodies were not detected in ovariectomized mice immunized with ZP3 peptides lacking the B epitope. This autoantibody amplification phenomenon demonstrates conclusively that 1) self-reactive B cells for ovarian autoantigens respond to endogenous ovarian Ag in vivo after activation of ZP3-specific Th cells and 2) serum antibody in an autoimmune disease need not mirror the immunogen that initiates the disease process. Nonetheless, the autoantibodies bound to the zona pellucida in vivo and are potentially important in disease pathogenesis.