Rapid induction of autoantibodies by endogenous ovarian antigens and activated T cells: implication in autoimmune disease pathogenesis and B cell tolerance.
Animals immunized with nuclear antigenic peptides produce autoantibodies to distant antigenic sites and neighboring Ags within a multimolecular complex. This has led to the hypothesis that induction of autoantibodies 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 (amAb) against linear ZP3 B cell epitopes outside the peptide immunogen. Each ZP3 B cell peptide, chimerized to a foreign promiscuous T cell epitope, elicited Ab to the peptide within the native ZP3 molecule. Mice with amAb often had no oophoritis; but more importantly, bilateral ovariectomy 1 day before ZP3 T epitope injection inhibited the induction of the amAb response, whereas ovariectomy 2 to 4 days after immunization was not inhibitory. Because endogenous ovarian Ag depletion before detectable ZP3 T cell response (day 5) and oophoritis (day 7) failed to prevent the amAb response, the autoantibodies are likely stimulated by endogenous ZP3 Ags present outside the normal ovaries. AmAb, of only the IgG class, appeared on day 7; this was 2 to 3 days after detectable T cell response, and 5 to 6 days before A response to the T cell peptide immunogen. The rapid, class-switched amAb response indicates that B cells in female mice are not tolerant to self ovarian Ag and they may normally be primed by ZP3. As evidence for their pathogenic potentials, amAb were produced in response to oophoritogenic, nonovarian T cell peptides that mimic ZP3; moreover, an excellent correlation existed between amAb titers and fertility reduction.
Lou
Y H
YH
Department of Pathology, University of Virginia, Charlottesville 22908, USA.
McElveen
M F
MF
Garza
K M
KM
Tung
K S
KS
D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis*; D001324:Autoantigens / Q000276:immunology / Q000494:pharmacology*; D001327:Autoimmune Diseases / Q000209:etiology / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D003429:Cross Reactions; D003433:Crosses, Genetic; D018604:Epitope Mapping; D005260:Female; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009869:Oophoritis / Q000209:etiology / Q000276:immunology*; D010052:Ovariectomy; D010053:Ovary / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*; D015044:Zona Pellucida / Q000276:immunology
D001323:Autoantibodies; D001324:Autoantigens; D010446:Peptide Fragments