HLA-DQ8 transgenic mice are highly susceptible to collagen-induced arthritis: A novel model for human polyarthritis

Genetic studies have indicated that susceptibility to rheumatoid arthritis (RA) maps to the HLA-DR locus of the major histocompatibility complex. Strong linkage disequilibrium between certain HLA-DQ genes and HLA-DR genes associated with RA, however, suggests that HLA-DQ molecules may also play a role in RA susceptibility. To examine the role of HLA-DQ molecules in arthritis, we generated transgenic mice expressing the DQA1*0301 and DQB1*0302 genes from an RA predisposing haplotype (DQ8/DR4Dw4). The transgenes were introduced into mouse class II-deficient H-2Ab⁰ mice, and their susceptibility to experimental collagen induced arthritis was evaluated. The HLA-DQ8⁺,H-2Ab⁰ mice displayed good expression of the DQ8 molecule, while no surface expression of endogenous murine class II molecules could be detected. The DQ8 molecule also induced the selection of CD4⁺ T cells expressing a normal repertoire of V(β) T cell receptors. Immunization of HLA-DQ8⁺,H-2Ab⁰ mice with bovine type II collagen (CII) induced a strong antibody response that was cross-reactive to homologous mouse CII. Also, in vitro proliferative responses against bovine CII, which were blocked in the presence of an antibody specific for HLA-DQ and mouse CD4, were detected. Finally, a severe polyarthritis developed in a majority of HLA-DQ8⁺,H-2Ab⁰ mice, which was indistinguishable from the disease observed in arthritis susceptible B10.T(6R) (H-2A(q)) controls. In contrast, HLA-DQ8, H-2Ab⁰ fullsibs did not generate CII antibody and were completely resistant to arthritis. Therefore, these results strongly suggest that HLA-DQ8 molecules contribute to genetic susceptibility to arthritis and also establish a novel animal model for the study of human arthritis.