HLA-DR risk variants in rheumatoid arthritis: what we know and still do not know

Rheumatoid arthritis (RA) susceptibility is strongly influenced by genetic variations within the major histocompatibility complex, with HLA-DRB1 risk alleles representing the largest contributors to heritability, particularly in seropositive (anti-citrullinated protein antibody positive) disease. The shared epitope (SE) hypothesis, first proposed more than three decades ago, explained the clustering of susceptibility within HLA-DRB1*04 subtypes. Subsequent fine-mapping expanded HLA-DRB1 disease associations beyond the SE motif, identifying key amino acid residues at positions 11/13, in addition to 71 and 74, that account for much of the genetic contribution to susceptibility in seropositive RA. Recent studies demonstrate that these residues not only determine risk of developing seropositive RA but also stratify disease outcome (ie, radiographic progression or mortality), with valine at position 11 or histidine at position 13 as central determinants. However, their role in response to treatment remains unclear. Structural work has partially elucidated the molecular basis of these associations, showing that SE-bearing HLA-DR molecules preferentially bind nonpolar or negatively charged amino acids and directly engage T cell receptors, while genetic data support a role in shaping thymic repertoire selection. However, only a few RA autoantigens have been identified so far. Beyond professional antigen-presenting cells, HLA-DR expression is found on fibroblasts in the inflamed synovium and activated lymphocytes, where its function remains unknown. Importantly, HLA-DRB1 association to RA is not unique; HLA-DRB1 alleles contribute pleiotropically to the susceptibility of a wide range of autoimmune diseases, reflecting fundamental roles in immune regulation. This review synthesises established findings and current uncertainties in HLA-DRB1 research, identifying outstanding challenges and opportunities for translation into precision medicine.