HLA and disease: guilt by association

It is now over forty years since the first associations between particular HLA antigens and disease susceptibility were described, and the identification of large numbers HLA-associated diseases parallels our increased understanding of the genetic complexity of the HLA system and its extensive polymorphism. However, surprisingly and frustratingly, clear identification of the underlying mechanisms resulting in a causative role for HLA polymorphism in the molecular immunopathogenesis of individual HLA-associated diseases remains the exception rather than the rule. This review, while not intended to be a comprehensive catalogue of HLA-associated diseases, aims to revisit a number of well known and more recently described HLA-associated diseases as exemplars of our current understanding of the underlying molecular mechanisms which may result in genetic disease predisposition. Such mechanisms may act as pointers for further investigations in other HLA-associated diseases. The clinical utility of specific HLA disease associations in disease diagnosis/exclusion is also considered.