Polymorphism in hla-dqbl locus determine susceptibility and severity to collagen induced arthritis (CIA) in transgenic mice

We have recently reported that transgenic mice expressing HLA-DQ8 are highly susceptible to collagen induced arthritis (CIA), a mouse model of human polyarthritis. This result suggests that HLA-DQ genes, in linkage disequilibrium with rheumatoid arthritis (RA)-linked DRB1 genes may play an important role in determining predisposition to RA in humans. To investigate the contribution of DQ polymorphism in CIA, DQ8 and DQ6 genes, linked to RA-susceptible DR4 and resistant DR2 respectively, were introduced into MHC class II -/- mice. While DQ8 mice were very susceptible to CIA, DQ6 mice were relatively resistant to the onset of CIA. To more closely recreate the usual HLA heterozygosity in human RA patients, double transgenic DQ6/8 mice were bred. DQ6/8 mice generated an intermediate DQ-restricted CIIspecific cellular response, compared to the high response in DQ8 mice and low response in DQ6 mice (6 cpm's of 2534 compared to 5160 and 1132, respectively). While the incidence of arthritis was slightly reduced in DQ6/8 mice compared to DQ8 mice (60% vs. 70%), the severity of disease was significantly diminished, with arthritic scores of 3.8 compared to 7.6. The results are similar to human RA patients who are heterozygous for an RA predisposing and neutral HLA haplotypes. The introduction of multiple DQ or DR transgenes should provide an excellent model to further investigate the interaction of the different alleles during human disease.