Relapsing polychondritis, a human autoimmune disease of unknown etiology, is characterized by episodes of mononuclear infiltration of cartilage-rich sites resulting in the destruction of cartilaginous tissues and elevated mortality. HLA-DQ transgenic mice expressing for the mixed haplotype HLA-DQ6alpha8beta molecule develop experimental polychondritis following immunization with bovine type II collagen with several similarities to relapsing polychondritis including development of both auricular chondritis and polyarthritis. The studies proposed here will characterize the disease processes of experimental polychondritis by the evaluation of clinical, humoral, and cellular responses of DQ6alpha8beta expressing transgenic mice following immunization with bovine, chick, porcine and human type II collagen to determine potential species specific differences and thus, identifying potential chondritic or arthritogenic epitopes presented by the DQ6alpha8beta molecule based on differences in the type II collagen sequences. Type II collagen specific T cell clones will also be generated from chondritis ears for further characterization of the potentially pathogenic epitopes of type II collagen and the potential of these clones to induce disease in naive syngeneic mice. The mechanisms of cartilage destruction associated with auricular chondritis will be examined in diseased ears by assessment of localized cytokine production both by measuring the levels of cytokine transcript produced by reverse phase polymerase chain reaction and in situ hybridization of cytokine RNA, with a particular emphasis on the potential of macrophage derived cytokines, the predominate mononuclear cell present during disease in this model and relapsing polychondritis. The potential of type IX collagen, another putative autoantigen in relapsing polychondritis, will also be examined. Type IX collagen specific antibody production detected in type II collagen immunized DQ6alpha8beta expressing transgenic mice and relapsing polychondritis will be further characterized as well as T cell reactivity and the ability of immunization with native type IX collagen to induce experimental polychondritis.
