COLLAGEN-INDUCED ARTHRITIS IN NONHUMAN-PRIMATES - MULTIPLE EPITOPES OF TYPE-II COLLAGEN CAN INDUCE AUTOIMMUNE-MEDIATED ARTHRITIS IN OUTBREDCYNOMOLGUS MONKEYS

Objective. To define which regions of the type II collagen (CII) molec ule result in anticollagen antibody production and the subsequent deve lopment of autoantibodies in a collagen-induced arthritis (CIA) nonhum an primate model. Methods. Male and female cynomolgus monkeys (2-6 of each sex per group) were immunized with either chicken (Ch), human, or monkey (Mk) CII, or with cyanogen bromide (CB)-generated peptide frag ments of ChCII emulsified in Freund's complete adjuvant, Monkeys were observed for the development of arthritis, and sera were collected and analyzed for anticollagen antibody specificity by enzyme-linked immun osorbent assay. Results. Overt arthritis developed in all groups of mo nkeys immunized with intact CII and with all major CB peptide fragment s of ChCII except CB8. Onset and severity of arthritis correlated best with serum anti-MkCII antibody levels, The levels of IgG autoantibody to MkCII were a result of the cross-reactivity rate of anti-heterolog ous CII antibodies with MkCII, which was based on the genetic backgrou nd of individual monkeys rather than on sex differences. Conclusion. C II from several species and disparate regions of the CII molecule were able to induce autoantibody-mediated arthritis in outbred cynomolgus monkeys, The strong anti-MkCII response suggests that epitope spreadin g or induction of broad-based CII cross-reactivity occurred in these a nimals, Autoantibody levels to MkCII were higher in CIA-susceptible mo nkeys than in resistant monkeys, despite comparable antibody levels in response to the various immunizations of CII, These results closely p arallel the type of anticollagen responses found in sera from rheumato id arthritis patients. Perhaps this can be accounted for by similar ma jor histocompatibility complex heterogenicity associated with an outbr ed population, or maybe this is a primate-specific pattern of reactivi ty to CII.