Cellular and molecular pathogenesis of type 1A diabetes

Abstract

Type 1A diabetes is an organ-specific autoimmune disease resulting from destruction of insulin-producing pancreatic beta-cells. The main susceptibility genes code for polymorphic HLA molecules and in particular alleles of class II MHC genes (DR, DQ and DP). Polymorphisms of individual genes outside the MHC also contribute to diabetes risk but recent evidence suggests that there are additional non-HLA genes determining susceptibility linked to the MHC. It is now possible using genetic and autoantibody assays to predict the development of type 1A diabetes in the majority of individuals, and trials of diabetes prevention are underway.

Mediators and mechanisms of pancreatic beta-cell death in type 1 diabetes

“…These antibodies are used as markers of diabetes risk (2). The most common auto-antibodies in pre-diabetic patients are directed against glutamic acid decarboxylase (GAD65), tyrosine phosphatase-like protein (IA-2) and insulin (IAA).…”

“…Up to 90 % of newly diagnosed T1D subjects have autoantibodies to one or more of these antigens (8), and autoimmunity detection rates raise to 98% when combining the detection of these antibodies with detection of antibodies against the newly discovered beta-cell autoantigen ZnT8 (9). Epidemiological studies have shown that antibodies against beta-cell antigens can appear after a few months/years of life, tion combines with environmental trigger(s) to induce the activation of a specific autoimmune destruction of pancreatic beta-cells (1)(2)(3). Several loci, increasing the risk to develop T1D, have been identified (2)(3)(4)(5).…”

“…Epidemiological studies have shown that antibodies against beta-cell antigens can appear after a few months/years of life, tion combines with environmental trigger(s) to induce the activation of a specific autoimmune destruction of pancreatic beta-cells (1)(2)(3). Several loci, increasing the risk to develop T1D, have been identified (2)(3)(4)(5). Among them, the human leukocyte antigen (HLA) locus is by far the most common predisposing polymorphism (2,4).…”

“…Several loci, increasing the risk to develop T1D, have been identified (2)(3)(4)(5). Among them, the human leukocyte antigen (HLA) locus is by far the most common predisposing polymorphism (2,4). Other well documented predisposing loci include the insulin locus, the cytotoxic T-lymphocyte antigen 4 (CTLA4) locus and the phosphatase non-receptor type 22 (PTPN22) locus (2,3).…”

“…Among them, the human leukocyte antigen (HLA) locus is by far the most common predisposing polymorphism (2,4). Other well documented predisposing loci include the insulin locus, the cytotoxic T-lymphocyte antigen 4 (CTLA4) locus and the phosphatase non-receptor type 22 (PTPN22) locus (2,3). In addition, a recent genome wide association study of ~2000 T1D subjects suggested several new candidate loci, encoding for genes involved in immune signaling, such as the receptor tyrosine kinase ErbB3 (ERBB3), the SH2B adaptor protein 3 (SH2B3/ LNK), the TRAF-type zinc finger domain containing 1 (TRAFD1) and the protein tyrosine phosphatase nonreceptor type 11 (PTPN11) (4,5).…”