Specific overexpression of rheumatoid arthritis-associated HLA-DR alleles and presentation of low-affinity peptides

Objective. To compare levels of HLA-DR expression in rheumatoid arthritis ( RA) patients and healthy controls for whom an ordered expression according to the DR alleles is demonstrated and to test the functional consequences o f this expression on peptide presentation. Methods. Using monoclonal antibodies that recognize different DRB1 alleles, DR molecules were quantitated at the surface of the peripheral blood B cel ls of 23 RA patients and 17 healthy subjects. The functional consequences o f the level of DR surface expression was tested using a universal model of antigen presentation and mutated peptides with variable affinities for the T cell receptor. Results. In healthy subjects, surface HLA-DR molecules were expressed at di fferent levels according to allele (DR53, DR4, and DR11 less than DR1 less than DR7 less than DR15). In RA patients, this hierarchy was not conserved and, furthermore, the density of RA-associated DR4 and DR1 molecules was en hanced in patients compared with the basal density in healthy individuals. We demonstrated that an increased expression of DR molecules at the surface of antigen-presenting cells allowed a noteworthy presentation of low-affin ity peptides that under normal conditions are not efficient in generating a T cell response at physiologic surface density of the DR molecules. Conclusion. Our results suggest that the specific overexpression of RA-asso ciated HLA molecules could be responsible for the presentation of low-affin ity auto-peptides and therefore the activation of peripheral autoreactive T cells.