The Role of HLA Class I Gene Variation in Autoimmune Diabetes

Abstract

■ AbstractThe use of DNA-based genetic typing has enabled the identification of type 1 diabetes mellitus (T1DM) susceptible and protective major histocompatibility complex (MHC) class II alleles and haplotypes. The application of this approach has also progressed to locate MHC class I alleles that contribute to the clinicopathology of T1DM. Recent studies have shown a widespread involvement of genes from the MHC class I gene region in the clinicopathology of T1DM. These genes are demonstrated to be involved in contributing to progression from the preclinical stage of the disease, which is characterized by the occurrence of islet-specific antibodies, to clinical disease and also to the occurrence of autoimmunity. They can either contribute directly to disease development or indirectly in concert with other susceptible MHC class II alleles or haplotypes via linkage disequilibrium. Class I alleles may also be negatively associated with T1DM. These findings are useful for the development of future strategies in designing tolerogenic approaches for the prevention or even reversal of T1DM. In this article, the latest evidence for the different kinds of participation of HLA class I genes in the etiology of T1DM is reviewed. A metaanalysis which included existing association studies was also carried out in order to re-assess the relevance of class I genes in diabetes development. The analysis of an enlarged heterogeneous sample confirmed the involvement of previously detected serotypes in the etiology of T1DM, such as A24, B8 and B18, and revealed hitherto unknown associations with B60 and B62. The analysis points out that much of the conflicting results of previous association studies originate from inadequate sample sizes and accentuate the value of future investigations of larger samples for identifying linkage in multigenic diseases.Keywords: type 1 diabetes · HLA class I · cross-study analysis · serotype association Introduction ype 1 diabetes mellitus (T1DM) is a multifactorial and multigenic autoimmune organ disease characterized by progressive T cell-mediated destruction of the pancreatic β-cells . The major determinants of this disease are genes of the human leucocyte antigen (HLA) region, which are highly polymorphic. In a multiplicative model, they account for between 20 and 53% of T1DM susceptibility markers [1]. Gene products of HLA class I genes function as antigen presenting molecules for CD8 + cytotoxic T lymphocytes (CTL) and determine the antigen specificity of the CTL-mediated immune response against pathogens and self-antigens. T cell reactions with islet-specific self-antigens may lead to clonal proliferation of autoreactive CTLs directed against pancreatic β-cells provoking destruction of these organ cells.Initial genetic analyses clearly rejected a dominant major locus. In contrast, a series of other genes, such as the coding sequences for TAP (transporters associated with antigen processing), LMP (large multifunc- Copyright © by the SBDR tional proteases) and TNF-α, the MIC-A (MHC class I chain-r...

Islet cell autoantibodies in African patients with Type 1 and Type 2 diabetes in Dar es Salaam Tanzania: a cross sectional study

“…Significantly more patients with T1D that were autoantibody positive had a positive family history of diabetes compared with those who were autoantibody negative; this is in accordance with the well-known notion that autoimmune diabetes has a genetic basis [ 33 - 35 ]. Some studies have shown disappearance of GADA and IA2A with time [ 36 ], while others have shown an increase of autoantibodies with time, up to a point, and still others have shown seroconversion to autoantibody positivity within the first few years of the disease after being negative at diagnosis [ 31 ].…”

Genome-wide association studies: progress and potential for drug discovery and development

“…One study showed association of both rheumatoid arthritis and T1DM with specific polymorphisms (IL2RA-rs2104286 and PTPN22-rs6679677; TABLE 2) 18 . T1DM, rheumatoid arthritis and IBD also show association with MHC alleles [74][75][76] . These findings suggest common underlying aetiological pathways (and therapeutic targets) for several, common autoimmune disorders 77 .…”

The role of HLA genes: from autoimmune diseases to COVID-19

“…Молекулы Патологическая активация иммунной системы у пациентов с генетической предрасположенностью (в том числе определяемой генами HLA) может приводить к формированию аутоиммунных реакций, обуславливать развитие, влиять на тяжесть и прогноз неаутоиммунных заболеваний (таблица). В частности, определенные аллели генов системы HLA увеличивают риск развития аутоиммунных эндокринопатий: сахарного диабета 1 типа (СД1) [6], болезни Грейвса [7], аутоиммунного тиреоидита [7], первичной надпочечниковой недостаточности [8], идиопатического гипопаратиреоза [9], лимфоцитарного гипофизита [10], в том числе в составе аутоиммунных полигландулярных синдромов [11]. Кроме того, обнаружена ассоциация аллелей HLA с риском развития неэндокринных аутоиммунных заболеваний: анкилозирующего спондилоартрита [1], ревматоидного артрита (РА) [12], системной красной волчанки [13], целиакии [1], рассеянного склероза [14].…”