Critical residues on HLA-DRB1*0402 HV3 peptide for HLA-DQ8-restricted immunogenicity: implications for rheumatoid arthritis predisposition.
Recently, we have proposed that the combination of HLA-DQ and -DR alleles is responsible for the association of the HLA class II region with rheumatoid arthritis (RA). According to this model, some HLA-DQ alleles, namely DQ4, DQ7, DQ8, and DQ9, predispose carriers to severe RA, but a self peptide of sequence KDILEDERAAVDTYC from the third hypervariable (HV3) region of some DRB1 alleles, including DRB1*0402, can protect from the disease if presented by DQ molecules. This model implies that DQ4, DQ7, DQ8, and DQ9 should be able to present a set of common peptides, despite polymorphisms in their Ag binding groove. In the present study, we have further analyzed the immunogenicity of the DRB1*0402 HV3 peptide in DQ8-transgenic mice. We found that the motif DERAA guarantees DQ8-restricted immunogenicity, and that R is the main anchor residue for binding of the DRB1*0402 peptide to DQ. Interestingly, the p1 pocket that probably controls binding of the R residue is identical in all four RA-associated DQ molecules. Our results imply that the association of RA with some DR subtypes can be explained by their linkage with DQ alleles displaying a binding site for similar "arthritogenic" peptides.
Zanelli
E
E
Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA.
Krco
C J
CJ
David
C S
CS
D000595:Amino Acid Sequence; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology*; D004198:Disease Susceptibility; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology*; D006684:HLA-DR Antigens / Q000737:chemistry* / Q000276:immunology*; D059811:HLA-DRB1 Chains; D016056:Immunodominant Epitopes / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology*
D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553506:HLA-DRB1*04:02 antigen; D016056:Immunodominant Epitopes; D010446:Peptide Fragments