Amino Acids in the Peptide‐Binding Groove Influence an Antibody‐Defined, Disease‐Associated HLA‐DR Epitope

Abstract

A shared amino‐acid sequence on the a helix of certain DRβ1 chains is predicted to generate a ‘shared epitope’ that is implicated in susceptibility to the development of rheumatoid arthritis (RA). Different relative risks (RR) for disease susceptibility and severity conferred by these DRβ31 chains suggest that their ‘shared epitopes’ are not equivalent. A set of monoclonal antibodies (MoAb) that map to the critical region, and for which optimal binding depends on DR context and cell lineage, was used to test this idea. Mapping experiments using mutated DRβ1* molecules showed that the antibody‐binding epitopes are overlapping; residue 70Q is pivotal for each, but neighbouring residues on the a helix and on the floor of the groove are also involved. Importantly, these epitopes are profoundly modified by peptide loading of DRβ31*0401 molecules. These data suggest that ‘shared epitopes’ on DR molecules that are associated with RA are influenced by their context; such structural modifications may be the basis for the varying susceptibilities conferred by these DR molecules for the development of RA.