TOLERANCE TO A SELF PEPTIDE FROM THE 3RD HYPERVARIABLE REGION OF THE E-BETA(S) CHAIN - IMPLICATIONS FOR MOLECULAR MIMICRY MODELS OF AUTOIMMUNE-DISEASE

As a first step in the analysis of a molecular mimicry model of rheumatoid arthritis, we addressed the question of whether tolerance to self-major histocompatibility complex (MHC) class II molecules includes tolerance to peptides from the third hypervariable region of their beta-chain. We studied T cell responses to a peptide from the third hypervariable region of the E-beta-s chain, E-beta-s peptide (PEFLEQRRAAVDTYC), in different mouse strains after footpad priming with peptide in complete Freund's adjuvant. Strains of mice of the k or d haplotype (B10D2; H-2d, B10BR; H-2k) mounted a vigorous T cell response to the E-beta-s peptide. In mice expressing the E-beta-s chain either on the cell surface (B10S9R) or in the cytoplasm as free unassociated chain (B10S), no response could be detected. Binding studies using purified MHC class II molecules and competition for antigen presentation showed that the E-beta-s peptide binds A(k), A(d) and A(s) but not E(k). Thus, the nonresponder status of B10S and B10S9R mice appears to reflect self tolerance. Tolerance was also suggested by the observation that responder x nonresponder F1 crosses such as (B10D2 x B10S9R) and (B10BR x B10S9R) did not respond to E-beta-s peptide. Interestingly, mice derived from the (B10BR x B10S) cross responded to the E-beta-s peptide, suggesting that the immune system may not always tolerate peptides from the third hypervariable region of self-MHC class II molecules.