Immunogenicity and arthritogenicity of recombinant CB10 in B10.RIII mice

Two major T cell determinants are recognized by I-A(r)-specific T cells in CII, the immunodominant CII610-618 (GPAG (T) under bar AG (A) under bar R) within CB10 and the subdominant CII445-453 (GPAG (P) under bar AG (E) under bar R) within CB8, Although the determinants differ by only two residues, CB8 is capable of inducing collagen-induced arthritis (CIA), while CB10 is not. We, therefore, investigated the structural differences between the two determinants that are critical to inducing arthritis. When the CB10 determ inant was mutated to that of CB8 using recombinant techniques, the resultin g mutant rCB10(T61rP,A617E) product became arthritogenic. Conversely, when the CB8 determinant was mutated to that of CB10, the resulting mutant CB8(P 449T,E452A) was no longer arthritogenic. Comparison of the epitope specific ity of the autoantibodies induced by wild-type CB10 and mutant rCBIO(T614P, A617E) revealed no qualitative differences. T cells from mice immunized wi th either CB10 or mutant rCB10 produced predominantly Th1 cytokines when cu ltured with the immunizing Ag. In contrast, when cultured with mouse CII, T cells from mice immunized with the nonarthritogenic CB10 produced predomin antly Th2 (IL-4 and IL-10) cytokines whereas the arthritogenic mutant rCB10 induced predominantly Th1 (IFN-gamma) cytokines, We conclude that the T ce ll cytokine response most critical for the induction of CIA is that induced against the corresponding homologous murine T cell determinant and, furthe r, that the structural differences between the T cell determinants in CB8 a nd -10 are important in breaking self tolerance and inducing autoimmune res ponse.