Mechanism of self-tolerance and events leading to autoimmune disease and autoantibody response.
This review summarizes recent studies on the mechanisms of self-tolerance and autoimmune disease pathogenesis based primarily on the murine ovarian autoimmune disease models. The ovarian autoimmune disease was induced experimentally by three approaches: (1) transfer of normal T cells into syngeneic athymic nu/nu mice, (2) neonatal thymectomy, or (3) immunization with a well-defined peptide from the ovarian antigen, ZP3. Self-reactive T cells with capacity to elicit autoimmune oophoritis and autoimmune gastritis are not deleted in the neonatal or adult thymus. In the adult spleen, T cells are not pathogenic until regulatory T cells have been depleted. Thus the balance of activity between pathogenic T cells and regulatory T cells appears to determine the tolerance status of the host to self-antigens responsible for these autoimmune diseases. Murine autoimmune disease of the ovaries was found to occur through two independent pathways. The first is by depletion of regulatory T cells, as created by thymectomy within 4 days after birth. Alternatively, pathogenic T cells can be activated through molecular mimicry at the level of T cell peptide. This appears to depend on the sharing between non-ovarian and ovarian peptides of critical amino acid residues required for activation of pathogenic T cells. Finally, when T cells that recognize the ZP3 peptide are activated, endogenous ovarian antigens can spontaneously stimulate B cells to produce antibodies that react with ZP3 domains outside the immunizing T cell peptide.
Department of Pathology, University of Virginia, Charlottesville 22908.
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D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D005260:Female; D007108:Immune Tolerance; D051379:Mice; D009869:Oophoritis / Q000276:immunology; D010049:Ovarian Diseases / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013272:Stomach Diseases / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D001323:Autoantibodies; D011948:Receptors, Antigen, T-Cell