Reshaping Cinderella's slipper: the shared epitope hypothesis

This issue of Arthritis Research and Therapy contains a succinct and elegant paper by Michou and colleagues [1] that advances our understanding of the genetic basis of RA by reclassifying the contribution of RA susceptibility alleles according to their structure. This line of research is potentially important in our conceptualization of the mechanism of disease in RA, in predicting disease course and severity, and as a model for further studies on this topic.More than 10 different HLA-DRB alleles predispose to the development of rheumatoid arthritis (RA) and this number alone distinguishes RA from many other autoimmune diseases. Over two decades ago the existence of common structural features of the HLA-DR4 and DR1 molecules encoded by these multiple susceptibility alleles emerged from pioneering sequencing efforts and this structure was termed the shared epitope (SE) [2]. The SE hypothesis was a simple conceptual framework that sought to redirect thinking about disease susceptibility towards a unifying molecular susceptibility structure that would aide in the search for peptides driving the T cell immune response underlying RA, a sort of Cinderella's slipper. The original notion of SE was modified by the concepts of protective alleles [3] and 'homozygosity' or allelic interaction [4]. Additional support for the SE hypothesis came from other unrelated alleles in different populations that encode a SE motif that were identified as RA susceptibility alleles, for example, DRB1*1402 [5] and DRB1*1001 [6].Although a Google search reveals over 40,000 hits for 'shared epitope', reflecting the efforts by many to advance RA genetics, both knowledge of the inciting peptide, and how the nature and conformation of the peptide-binding groove predispose to RA eludes our grasp. Difficulties in identifying which alleles are implicated in RA susceptibility or protection and which regions of molecules encoded by these alleles are functionally important has resulted in several differe