Critical residues on HLA-DRB1*0402 HV3 peptide for HLA-DQ8-restricted immunogenicity: implications for rheumatoid arthritis predisposition.

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 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.

• Authors: E Zanelli, C J Krco, C S David
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 158 Issue 7 Pg. 3545-51 (Apr 01 1997) ISSN: 0022-1767 [Print] United States
• PMID: 9120317 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• HLA-DQ Antigens
• HLA-DR Antigens
• HLA-DRB1 Chains
• HLA-DRB1*04:02 antigen
• Immunodominant Epitopes
• Peptide Fragments

Topics

• Amino Acid Sequence
• Animals
• Arthritis, Rheumatoid (genetics, immunology)
• Disease Susceptibility
• HLA-DQ Antigens (genetics, immunology)
• HLA-DR Antigens (chemistry, immunology)
• HLA-DRB1 Chains
• Immunodominant Epitopes (immunology)
• Mice
• Mice, Transgenic
• Molecular Sequence Data
• Peptide Fragments (immunology)