HLA-DRB1 encoded predisposition to rheumatoid arthritis: the anchor hypothesis

Antigenic peptides anchor by amino acid residues to pockets within the antigen-binding groove of the HLA-DRB1 molecule. In order to assess whether a pocket-wise analysis of HLA-encoded susceptibility might provide a better fit to the immunogenetic data in rheumatoid arthritis (RA) than the shared epitope hypothesis, HLA-DRB1 typing findings in 167 patients with recent onset RA and in 166 controls were analyzed.

The shared epitope (residues 67–74) borders pockets 4 and 7. After stratification for pocket 4, polymorphisms in pocket 7 did not influence RA risk. However, after stratification for pocket 7, both substitutions in the α helix bordering pocket 4 and substitutions at position 13 in the floor of this pocket independently and significantly influenced RA risk. Furthermore, substitutions at position 86 in pocket 1 also had an effect on RA risk. Pairs of HLA-DRB1 alleles that only differ in the glycine/valine dimorphism showed a consistent tendency toward increased risk for the glycine variant in a pooled analysis (pooled OR 1.66; p1 = 0.08). This observation is also strongly supported by data from previous publications.

Structural data indicate that HLA disease association may be determined by the make-up of individual pockets within the antigen-binding groove of the HLA molecule. In RA, susceptibility is influenced by genetic polymorphisms in pocket 4 of the HLA-DRB1 molecule, both in the floor of this pocket and in the α helix bordering this pocket. In addition, genetic variation in pocket 1 modifies RA risk.

Affiliations

1. Division of Clinical Immunology and Rheumatology F4-218, AMC/University of Amsterdam, Amsterdam, The Netherlands
   • N de Vries
   •  & PP Tak
2. Blood Transfusion and Transplantation Immunology, UMC, St Radbond, The Netherlands
   • H Tijssen
3. Rheumatology, UMC, St Radboud, Nijmegen, The Netherlands
   • PLCM van Riel
   •  & LBA van de Putte

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