title: Type 1 diabetes genetic susceptibility and dendritic cell function: potential targets for treatment.
abstract: Type 1 diabetes is an autoimmune disease that results from the defective induction or maintenance of T cell tolerance against islet β cell self-antigens. Under steady-state conditions, dendritic cells with tolerogenic properties are critical for peripheral immune tolerance. Tolerogenic dendritic cells can induce T cell anergy and deletion and, in some contexts, induce or expand regulatory T cells. Dendritic cells contribute to both immunomodulatory effects and triggering of pathogenesis in type 1 diabetes. This immune equilibrium is affected by both genetic and environmental factors that contribute to the development of type 1 diabetes. Genome-wide association studies and disease association studies have identified >50 polymorphic loci that lend susceptibility or resistance to insulin-dependent diabetes mellitus. In parallel, diabetes susceptibility regions known as insulin-dependent diabetes loci have been identified in the nonobese diabetic mouse, a model for human type 1 diabetes, providing a better understanding of potential immunomodulatory factors in type 1 diabetes risk. Most genetic candidates have annotated immune cell functions, but the focus has been on changes to T and B cells. However, it is likely that some of the genomic susceptibility in type 1 diabetes directly interrupts the tolerogenic potential of dendritic cells in the pathogenic context of ongoing autoimmunity. Here, we will review how gene polymorphisms associated with autoimmune diabetes may influence dendritic cell development and maturation processes that could lead to alterations in the tolerogenic function of dendritic cells. These insights into potential tolerogenic and pathogenic roles for dendritic cells have practical implications for the clinical manipulation of dendritic cells toward tolerance to prevent and treat type 1 diabetes.
authors.affiliation: Immune Tolerance Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Chie
authors.initials: C
authors.lastname: Hotta-Iwamura
authors.affiliation: Immune Tolerance Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA tarbellk@niddk.nih.gov.
authors.forename: Kristin V
authors.initials: KV
authors.lastname: Tarbell
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*
keywords: antigen presentation; genetic polymorphism; innate immunity; insulin-dependent diabetes mellitus susceptibility; tolerance