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 arthr itis (RA) maps to the HLA-DR locus of the major histocompatibility com plex. Strong Linkage disequilibrium between certain HLA-DQ genes and H LA-DR genes associated with RA, however, suggests that HLA-DQ molecule s may also play a role in RA susceptibility. To examine the role of HL A-DQ molecules in arthritis, we generated transgenic mice expressing t he DQA10301 and DQB1*0302 genes from an RA predisposing haplotype (8/ DR4Dw4). The transgenes were introduced into mouse class II-deficient H-2Ab(0) mice, and their susceptibility to experimental collagen-induc ed arthritis was evaluated. The HLA-DQ8(+),H-2Ab(0) mice displayed goo d expression of the DQ8 molecule, while no surface expression of endog enous murine class II molecules could be detected. The DQ8 molecule al so induced the selection of CD4(+) T cells expressing a normal reperto ire of V-beta T cell receptors. Immunization of HLA-DQ8(+),H-2Ab(0) mi ce with bovine type II collagen (CII) induced a strong antibody respon se that was crossreactive to homologous mouse CII. Also, in vitro prol iferative responses against bovine CII, which were blocked in the pres ence of an antibody specific for HLA-DQ and mouse CD4, were detected. Finally, a severe polyarthritis developed in a majority of HLA-DQ8(+), H-2Ab(0) mice, which was indistinguishable from the disease observed i n arthritis susceptible B10.T(6R) (H-2A(q)) controls. In contrast, HLA -DQ8(-),H-2Ab(0) fullsibs did not generate CII antibody and were compl etely resistant to arthritis. Therefore, these results strongly sugges t that HLA-DQ8 molecules contribute to genetic susceptibility to arthr itis and also establish a novel animal model for the study of human ar thritis.