Immunogenetics of Type 1 Diabetes

Abstract

The T-cell mediated autoimmune process that destroys pancreatic β cells in type 1 diabetes (T1D) is a complex phenotype influenced by multiple genetic and environmental factors. Human leukocyte antigen (HLA) accounts for about half of the genetic susceptibility, through a large variety of protective and predisposing haplotypes. Other important loci associated with T1D, with much smaller effects than HLA, include the insulin variable number of tandem repeats, PTPN22, and CTLA-4. Detecting the association and confirming it beyond doubt is only the first step. Identifying the functional variant from among a block of polymorphisms in tight linkage disequilibrium and determining its biological consequences can be an even more challenging task. It is hoped that the identification of additional loci and functional analysis of known ones, no matter how small each individual effect is, will provide: (1) pathophysiological insights necessary for the development of preventive interventions; (2) risk prediction to identify individuals that can benefit from them, and (3) potentially, identification of distinct subgenotypes, with different immune dysregulation pathways leading to the common disease phenotype that may respond to different preventive interventions.

Autoimmunity: Basic Mechanisms and Implications in Endocrine Diseases

“…A recent review by Mimi and Polychronakos [9] analyzed the correlation between HLA haplotypes and the risk for T1D. Polymorphisms in HLA DRB, HLA DQB and HLA DQA genes appear to be critical in T1D, where polymorphisms in the insulin gene seem to be the strongest candidate for insulin-dependent diabetes mellitus type 2 (IDDM2).…”

“…Polymorphisms in HLA DRB, HLA DQB and HLA DQA genes appear to be critical in T1D, where polymorphisms in the insulin gene seem to be the strongest candidate for insulin-dependent diabetes mellitus type 2 (IDDM2). HLA alleles may be markers for T1D susceptibility but they do not themselves represent the susceptibility genes, which are still unknown [9,10,11,12]. …”

Apoptosis of pancreatic β-cells in type 1 diabetes: The role of Caspase-3 in β-cell apoptosis

“…dendritic cells, macrophages and B-lymphocytes) including DR, DQ and DP and some specific combination of alleles for DQA1 and DQB1 genes and DRB1 genes (DRB1*03 and DRB1*04) significantly increase the development of T1D [2][3][4][5] . The earliest sign of autoimmunity against β-cells are often detectable months or years of clinical T1D and the most common autoantibodies in pre-diabetic subjects are directly against glutamic acid decarboxylase (GAD65), tyrosine phosphatase-like protein (IA-2) and insulin 6 . Up to 90 % of newly diagnosed T1D subjects have autoantibodies to one or more of these antigens 6 and autoimmunity detection rates increase to 98% when combining the detection of these three antibodies plus antibodies against the newly discovered β-cell autoantigen ZnT8 7,8 .…”

Toll-like receptor 3 (TLR3) and the development of type 1 diabetes mellitus

“…This may lead to induction and amplification of the inflammatory process, but in some cases, may lead to the resolution of insulitis (2). Furthermore, the course of beta-cell inflammation and its potential progression to clinical T1DM depend on a complex interaction between a strong genetic component and a diversity of environmental triggers (3,4).…”