Elucidation of Autoimmune Disease Mechanism Based on Testicular and Ovarian Autoimmune Disease Models

Abstract

This paper describes several selected models of autoimmune disease of the gonads. Based on these findings, I have reviewed current knowledge concerning the tolerance mechanisms that normally prevent gonadal autoimmunity, the potential events that can overcome such mechanism to trigger autoimmune diseases. In addition we also summarize the immunopathology of orchitis and our understanding of the mechanisms responsible for the immunopathology of the disease. Recent studies indicate that pathogenic T cells capable of eliciting autoimmune diseases in these organs develop in both the neonatal and adult thymuses and they persist in the normal peripheral immune system. However, the function of the pathogenic T cells in adult mice is normally under the control of regulatory T cells which maintain peripheral tolerance, and important phenotypic differences are being defined between these two functional CD4+ T cell subsets. When the clonal balance of these T cell subsets is tipped in favor of pathogenic T cells, autoimmune diseases of the gonads could ensue. Pathogenic T cells responsible for autoimmune oophoritis can be activated through stimulation by non-ovarian peptides that cross-react with self ovarian peptides at the level of the T cell receptor. This novel form of antigen mimicry depends in part on the sharing, between unrelated peptides, the few critical amino acids required for activation of pathogenic T cells. Antibodies can bind to the ovarian target antigens during the development of autoimmune orchitis and autoimmune oophoritis. However, the precise role of antibody in these autoimmune diseases has not been critically explored. In this study, I have described a novel mechanism of autoantibody induction. Immunization of female mice with a pure T cell peptide from ZP3 can lead to the production of antibodies against ZP3 domains outside the immunogenic ZP3 peptide. Evidently, endogenous antigens from normal and pathologic ovaries may reach peripheral immune tissues, and provide the antigenic stimulus to trigger an autoantibody response. This occurs at the same time when activation of ZP3 specific T cells is detected, and it is not simply a consequence of tissue injury. Importantly, the autoantibodies react with native antigenic determinants, and are potentially important in autoimmune disease pathogenesis.

Key words

Autoimmunity - Tolerance - Ovary - Testis