We have generated transgenic (tg) mice expressing HLA-DQ8alphabeta (DQA1*0301/DQB*0302) or HLA-DQ6alphabeta (DQA1*0103/DQB1*0601) molecules lacking endogenous murine class II expression (A beta0) to investigate the ability of these HLA class II to present type II collagen (CII) and induce collagen-induced arthritis. The DQ8alphabeta tg mice responded strongly to CII, developing severe arthritis, while DQ6alphabeta tg mice were nonresponsive to CII. The addition of the mixed haplotype DQ8alpha6beta molecule did not significantly influence CII reactivity. To examine the interaction of DQ6alphabeta and DQ8alphabeta molecules in vivo, we generated double tg DQ6alphabeta/8alphabeta (A beta0) mice expressing both the alpha- and beta-chains of DQ6 and DQ8 molecules by mating DQ6alphabeta (A beta0) and DQ8alphabeta (A beta0) tg mice. CII-immunized DQ6alphabeta/8alphabeta tg mice developed severe experimental polychondritis, exhibiting both polyarthritis and auricular chondritis. The clinical, serologic, and histologic manifestations of experimental polychondritis are similar to those symptoms in human relapsing polychondritis. The susceptibility of DQ6alphabeta/8alphabeta tg mice compared with resistance in the parental strains suggests that expression of both the DQ6alphabeta and DQ8alphabeta tgs, unique to the DQ6alphabeta8alphabeta tg strain, is important in susceptibility to experimental polychondritis. The DQ6alphabeta/8alphabeta tg mice provide a model to investigate putative autoantigens and the mechanisms of pathogenesis involved in relapsing polychondritis as well as the influence of the expression of multiple HLA class II molecules on the disease process.