AMINO-ACIDS IN THE PEPTIDE-BINDING GROOVE INFLUENCE AN ANTIBODY-DEFINED, DISEASE-ASSOCIATED HLA-DR EPITOPE

A shared amino-acid sequence on the alpha helix of certain DR beta 1 c hains is predicted to generate a 'shared epitope' that is implicated i n susceptibility to the development of rheumatoid arthritis (RA). Diff erent relative risks (RR) for disease susceptibility and severity conf erred by these DR beta 1 chains suggest that their 'shared epitopes' a re not equivalent. A set of monoclonal antibodies (MoAb) that map to t he critical region, and for which optimal binding depends on DR contex t and cell lineage, was used to test this idea. Mapping experiments us ing mutated DR beta 1 molecules showed that the antibody-binding epit opes are overlapping; residue 70Q is pivotal for each, but neighbourin g residues on the a helix and on the floor of the groove are also invo lved. Importantly, these epitopes are profoundly modified by peptide l oading of DR beta 10401 molecules. These data suggest that 'shared ep itopes' 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 devel opment of RA.