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Arthritis was induced in Lewis and DA rat strains after immunization with native homologous type II collagen (CII). Differences were noted in the clinical signs of arthritis in the 2 rat strains, which were immunized with the same arthritogenic preparation of CII. DA rats showed disease onset characterized by symmetric involvement of the interphalangeal joints of the hind feet. Lewis rats showed disease onset characterized by involvement of only the ankle or knee joints. Moreover, the arthritis tended to be chronic (i.e., persistent and variable redness and swelling seen in interphalangeal joints) in DA rats, but not in Lewis rats. Analysis of the delayed-type hypersensitivity reaction to CII and anti-CII autoantibody production demonstrated the presence of T cell, as well as B cell, reactivity to rat CII in both strains of rat. A spontaneous T cell reactivity to CII, as measured by rat CII-induced ear swelling, was observed in nonimmunized DA rats, but not in nonimmunized Lewis rats. The demonstration that clinical features of arthritis induced with identical arthritogenic stimuli are different depending on the genetic background of the affected animal may be relevant in understanding the heterogeneity of the clinical features of human inflammatory joint disease.