Modulation of HLA-DQ-restricted collagen-induced arthritis by HLA-DRB1 polymorphism

Mouse class II-deficient HLA-DQB1*0302, DQA1*0301 (DQ8) transgenic mice are susceptible to severe collagen-induced arthritis (CIA), an animal model for rheumatoid arthritis. To examine whether polymorphism at the DRB1 locus can modulate DQ-restricted arthritis, we generated double-transgenic (DR/DQ) mice. HLA-DRB1*1502 (DR2) and DRB1*0301 (DR3) were introduced separately into CIA susceptible DQ8.A(β)(o) transgenic mice to generate DQ8/DR2.A(β)(o) and DQ8/DR3.A(β)(o) mice. The HLA-DR molecules in these mice were found to be functional on the basis of their positive/negative selection of the V(β) T cell repertoire. Introduction of the DR2 gene led to a significant decrease in disease incidence in DQ8.A(β)(o) mice, while the DR3 transgene had no effect. In vitro T cell proliferative responses against bovine CII collagen in primed mice were higher in DQ8/DR3 mice compared with DQ8/DR2 mice. Cytokine analysis showed a T(h)2 profile in DQ8/DR2 mice, while DQ8/DR3 mice showed a T(h)1 profile. These results suggest that DRB1 polymorphism can modulate the disease.