Retinal S-antigen (S-Ag) is capable of inducing experimental autoimmune uveitis (EAU) in laboratory animals. EAU may serve as an animal model for studying human uveitis. As a first step we have determined the nucleotide sequence of an S-Ag gene and its cDNAs. The amino acid sequences were deduced from the cDNAs of various animals and human. Four uveitopathogenic sites in bovine S-Ag were characterized. One of the sites (peptide M) has sequence homology with non-self proteins from baker's yeast, potato, E. coli, hepatitis B virus, moloney murine leukemia virus, Moloney murine sarcoma virus, AKR murine leukemia virus and baboon endogenous virus. Mononuclear cells from animals immunized with peptide M showed significant proliferation when incubated with synthetic peptides corresponding to the amino acid sequences of the above-mentioned foreign proteins. In addition, all the peptides induced EAU in Lewis rats with a dose of 10-2000 micrograms. Moreover, native histone H3 from baker's yeast histone H3 induced EAU in Lewis rats. Thus, we found several examples of antigenic mimicry between self and non-self proteins. These findings establish a base to study further the mechanism of autoimmune inflammation.