RAPID INDUCTION OF AUTOANTIBODIES BY ENDOGENOUS OVARIAN ANTIGENS AND ACTIVATED T-CELLS - IMPLICATION IN AUTOIMMUNE-DISEASE PATHOGENESIS ANDB-CELL TOLERANCE

Animals immunized with nuclear antigenic peptides produce autoantibodi es to distant antigenic sites and neighboring Ags within a multimolecu lar complex. This has led to the hypothesis that induction of autoanti bodies in systemic autoimmune diseases might be triggered by a T cell epitope. We have investigated the T to B epitope spreading phenomenon based on the murine autoimmune oophoritis model. Mice immunized with a ZP3 T cell peptide spontaneously produced amplified autoantibodies (a mAb) against linear ZP3 B cell epitopes outside the peptide immunogen. Each ZP3 B cell peptide, chimerized to a foreign promiscuous T cell e pitope, elicited Ab to the peptide within the native ZP3 molecule. Mic e with amAb often had no oophoritis; but more importantly, bilateral o variectomy 1 day before ZP3 T epitope injection inhibited the inductio n of the amAb response, whereas ovariectomy 2 to 4 days after immuniza tion was not inhibitory. Because endogenous ovarian Ag depletion befor e detectable ZP3 T cell response (day 5) and oophoritis (day 7) failed to prevent the amAb response, the autoantibodies are likely stimulate d by endogenous ZP3 Ags present outside the normal ovaries. AmAb, of o nly the IgG class, appeared on day 7; this was 2 to 3 days after detec table T cell response, and 5 to 6 days before Ab response to the T cel l peptide immunogen. The rapid, class-switched amAb response indicates that B cells in female mice are not tolerant to self ovarian Ag and t hey may normally be primed by ZP3. As evidence for their pathogenic po tentials, amAb were produced in response to oophoritogenic, nonovarian T cell peptides that mimic ZP3; moreover, an excellent correlation ex isted between amAb titers and fertility reduction.