CD74/DQA1 dimers predispose to the development of arthritis in humanized mice.

Rheumatoid arthritis (RA) is associated with the presence of certain HLA class II genes. However, why some individuals carrying RA non-associated alleles develop arthritis is still unexplained. The trans-heterodimer between two RA non-associated HLA genes can render susceptibility to develop arthritis in humanized mice, DQA10103/DQB10604, suggesting a role for DQ α chains in pathogenesis. In this study we determined the role of DQA1 in arthritis by using mice expressing DQA10103 and lacking endogenous class II molecules. Proximity ligation assay showed that DQA10103 is expressed on the cell surface as a dimer with CD74. Upon immunization with type II collagen, DQA10103 mice generated an antigen-specific cellular and humoral response and developed severe arthritis. Structural modelling suggests that DQA10103/CD74 form a pocket with similarity to the antigen binding pocket. DQA10103 mice present type II collagen-derived peptides that are not presented by an arthritis-resistant DQA10103/DQB10601 allele, suggesting that the DQA10103/CD74 dimer may result in presentation of unique antigens and susceptibility to develop arthritis. The present data provide a possible explanation by which the DQA1 molecule contributes to susceptibility to develop arthritis.