Having previously determined the amino acid sequences of human, mouse, rat, and bovine retinal S-antigen and rat pineal gland S-antigen, we also determined the immunogenic sites and four uveitopathogenic sites of S-antigen. Two of the immunogenic sequences were highly conserved among these species. Many proteins in the National Biomedical Research Foundation data base have a similar sequence with a uveitopathogenic site. We chemically synthesized many peptides and some of them induced experimental autoimmune uveitis (EAU) and experimental autoimmune pinealitis (EAP) in Lewis rats. Those synthesized include synthetic peptides from yeast (Saccharomyces cerevisiae) histone H3, Escherichia coli hypothetical protein, potato proteinase inhibitor, hepatitis virus protein, Moloney murine sarcoma virus protein, and Moloney murine leukemia virus protein. In addition, we found that native yeast histone H3 was also capable of inducing EAU. The animals which were administrated yeast histone by the oral route suppressed the induction of EAU and EAP induced by either yeast histone H3 peptide or a S-antigen peptide. Thus, the peptides which have molecular mimicry cross-induced the tolerance. These findings provide a basis for understanding autoimmune inflammatory diseases of the eye in humans. To elucidate the role in autoimmunity of infectious microorganisms that have cross-reactive antigens, we injected Lewis rats with peptide M together with one of six different killed bacteria, either with or without incomplete Freund's adjuvant (IFA). The rats injected with IFA developed EAU, but most rats injected without IFA did not develop EAU. To assess the impact of infection by live microorganisms, we injected rats several times with low doses of both live Escherichia coli that express S-antigen and baker's yeast that has a cross-reactive antigen. The rats injected with either live Escherichia coli or live yeast developed EAU. We conclude that infection by microorganisms that have cross-reactive antigens can break immune tolerance to self-antigens and induce inflammatory autoimmune diseases.
