DIVERSIFICATION OF RESPONSE TO HSP65 DURING THE COURSE OF AUTOIMMUNE ARTHRITIS IS REGULATORY RATHER THAN PATHOGENIC

Determinant spreading has been implicated in the pathogenesis of certa in autoimmune diseases in animal models. We have observed that during the course of adjuvant arthritis (AA) in the Lewis rat, there is 'dive rsification' of response to the bacterial 65-kDa heat shock protein (B hsp65) towards its carboxy-terminal determinants (BCTD). Strikingly, p retreatment of naive Lewis rats with BCTD affords significant protecti on from AA. Our preliminary studies indicate that the diversification of response to BCTD in the Lewis rat is probably triggered in vivo by the induction and enhanced processing of self(rat) hsp65. Thus, the se lf hsp65 directed T-cell responses appear to be involved in mediating natural remission from acute inflammatory arthritis induced by a forei gn antigen, Mycobacterium tuberculosis. This the first report describi ng that the new T-cell specificities arising during the course of an a utoimmune disease are regulatory/protective rather than pathogenic. Mo reover, our results suggest that a final common mechanism involving BC TD might be recruited by other rat strains which either are resistant to AA (WKY rats) or whose susceptibility to AA is modulated significan tly by microbial flora (Fisher rats). The results of this study would contribute significantly to understanding of the pathogenesis of human rheumatoid arthritis, and in devising new therapeutic strategies for this disease.