CRITICAL RESIDUES ON HLA-DRB1-ASTERISK-0402 HV3 PEPTIDE FOR HLA-DQS-RESTRICTED IMMUNOGENICITY - IMPLICATIONS FOR RHEUMATOID-ARTHRITIS PREDISPOSITION

Recently, we have proposed that the combination of HLA-DQ and -DR alle les is responsible for the association of the HLA class II region with rheumatoid arthritis (RA). According to this model, some HLA-DQ allel es, namely DQ4, DQ7, DQ8, and DQ9, predispose carriers to severe RA, b ut a self peptide of sequence KDILEDERAAVDTYC from the third hypervari able (HV3) region of some DRB1 alleles, including DRB10402, can prote ct from the disease if presented by DQ molecules. This model implies t hat DQ4, DQ7, DQ8, and DQ9 should be able to present a set of common p eptides, despite polymorphisms in their Ag binding groove. In the pres ent study, we have further analyzed the immunogenicity of the DRB1040 2 HV3 peptide in DQ8-transgenic mice. We found that the motif DERAA gu arantees DQ8-restricted immunogenicity, and that R is the main anchor residue for binding of the DRB10402 peptide to DQ. Interestingly, the p1 pocket that probably controls binding of the R residue is identica l in all four RA-associated DQ molecules. Our results imply that the a ssociation of RA with some DR subtypes can be explained by their linka ge with DQ alleles displaying a binding site for similar ''arthritogen ic'' peptides.