Trans heterodimer between two non-arthritis-associated HLA alleles can predispose to arthritis in humanized mice.

OBJECTIVE

Certain HLA class II alleles are associated with susceptibility to the development of arthritis. However, the development of arthritis in some persons carrying non-rheumatoid arthritis (RA)-associated alleles remains unexplained. An individual who is heterozygous for the DQA1 and DQB1 genes can express the DQ molecule in cis or trans heterodimers. In a cis heterodimer, the α-chain interacts with the β-chain coded by the same chromosome, while in a trans heterodimer it interacts with the β-chain on the other chromosome. In this study, we used a humanized mouse model of arthritis in an attempt to determine whether a trans heterodimer of 2 nonassociated alleles, DQB10601 and DQB10604, can predispose to arthritis.

METHODS

DQB10601 and 0604 occur in linkage with DQA10103 and 0102, respectively. To understand the role of trans heterodimers, we generated DQB10604/DQA10103-transgenic mice lacking endogenous HLA class II molecules.

RESULTS

Severe arthritis developed in the DQB10604/A10103-trangenic mice, and an antigen-specific response was generated in vitro. DQB10604/DQA10103 presented type II collagen-derived peptides that were not presented by the arthritis-resistant DQB10601 allele, suggesting that trans heterodimer molecules between 2 DQB1 and DQA1 molecules may result in the presentation of unique antigens and susceptibility to the development of arthritis. Molecular modeling of type II collagen peptides showed that DQB10604/DQA10103 shares a p4 pocket with the arthritis-susceptible DQB10302 allele, suggesting a critical role of the p4 and p9 pockets in susceptibility to arthritis.

CONCLUSION

These results provide a possible explanation for the parental inheritance of nonsusceptibility alleles in some patients with RA and a mechanism by which they can predispose to the development of arthritis.