Molecular mechanisms of HLA association with autoimmune diseases

The association of human leukocyte antigen (HLA) molecules with many autoimmune diseases has been long known. Yet, the molecular basis for these associations remains unclear for most of these diseases because of the lack of identification of a primary target autoantigen or autoantigens. In two frequent autoimmune disorders, however, celiac disease and type 1 diabetes, recent progress in the identification of immunogenic antigen epitopes and analysis of crystal structure of particular HLA molecules in complex with disease-specific epitopes has allowed for a better understanding of the molecular mechanisms underlying disease association. In this review, these two diseases will be analyzed in detail to show how HLA polymorphisms may directly contribute to susceptibility to, or protection from, disease. Such analyses have significant interest in clinical practice to identify at-risk individuals and elaborate new therapeutic strategies aiming at inhibiting or preventing the autoimmune process.