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, DQB1*0601 and DQB1*0604, can predispose to arthritis. Methods DQB1*0601 and *0604 occur in linkage with DQA1*0103 and *0102, respectively. To understand the role of trans heterodimers, we generated DQB1*0604/DQA1*0103‐transgenic mice lacking endogenous HLA class II molecules. Results Severe arthritis developed in the DQB1*0604/A1*0103‐trangenic mice, and an antigen‐specific response was generated in vitro. DQB1*0604/DQA1*0103 presented type II collagen–derived peptides that were not presented by the arthritis‐resistant DQB1*0601 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 DQB1*0604/DQA1*0103 shares a p4 pocket with the arthritis‐susceptible DQB1*0302 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.