Pathogenesis of type 1 diabetes: genetics

There has been much progress in the identification of genes and molecular pathways involved in the pathogenesis of type 1 diabetes. Human histocompatibility (HLA) complex genes are the most powerful susceptibility determinants. The stronger effect is from alleles coding for selected HLA class I and class II antigen-presenting molecules, which are restricting elements for autoreactive CD8 and CD4 Tcells, respectively. Insulin is an autoantigen in type 1 diabetes and insulin gene polymorphisms have been linked to diabetes susceptibility and shown to regulate insulin expression in the thymus. Thus, predisposing HLA and insulin gene variants may drive autoimmunity towards pancreatic islets by synergistically influencing the selection and restriction of Tcells reacting with insulin. Several non-HLA loci are associated with type 1 diabetes susceptibility. Among these are CTLA-4, PTPN22 and IL2RA, all modulating basic pathways of T cell activation, function and regulation. Predisposing variants at these loci create a significant propensity to immune reactivity and less effective control over Tcell selection, activation and perhaps differentiation into memory and regulatory phenotypes. Polymorphisms at these loci are not necessarily diseasespecific, rather providing a generic predisposition to autoimmunity and often conferring increased risk for multiple autoimmune disorders. Finally, the IFIH1 locus may control the magnitude of viral-induced responses, linking the innate immune system to disease pathogenesis. Further studies to fine-map additional susceptibility genes and better define functional effects on immune regulation are ongoing and will help to identify novel therapeutic targets.