Critical Residues on HLA-DRB1*0402 HV3 Peptide for HLA-DQ8-Restricted Immunogenicity: Implications for Rheumatoid Arthritis Predisposition

Eric Zanelli, Christopher J. Krco, Chella S. David

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

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 DQS-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.

Original languageEnglish (US)
Pages (from-to)3545-3551
Number of pages7
JournalJournal of Immunology
Volume158
Issue number7
StatePublished - Apr 1 1997

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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