Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 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 shown 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 meta-analysis 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.
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PMID:The role of HLA class I gene variation in autoimmune diabetes. 1749 85

We have previously mapped a separate type 1 diabetes (T1D) association in the extended MHC class I region, marked by D6S2223, on the DRB1*03-DQA1*0501-DQB1*0201 haplotype. The associated region encompasses a gene encoding a thymus-specific serine protease (PRSS16), presumably involved in positive selection of T cells or in T-cell regulation. Fourteen PRSS16 polymorphisms were genotyped in two steps using a total of six T1D family data sets, as well as case-control materials for both T1D and celiac disease (CD). An association with a 15 base-pair deletion in exon 12 of PRSS16 was found on the DRB1*03-DQA1*0501-DQB1*0201 haplotype for both T1D and CD, but it could not explain the more pronounced disease associations observed at marker D6S2223. We compared the performance of the 14 tested PRSS16 polymorphisms, selected after our previous comprehensive screen, against HapMap selected tag SNPs. Use of a HapMap based SNP selection strategy would result in loss of a large proportion of the genetic variation in PRSS16. Our data suggest that it is unlikely that polymorphisms within the PRSS16 gene are involved in the predisposition to T1D. However, we cannot rule out that regulatory polymorphisms located some distance away from the gene may be involved.
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PMID:Association analysis in type 1 diabetes of the PRSS16 gene encoding a thymus-specific serine protease. 1758 81

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods-recursive partitioning and regression-to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; P(combined) = 2.01 x 10(-19) and 2.35 x 10(-13), respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes.
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PMID:Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. 1806 92

Dendritic cell (DC) differentiation is abnormal in type 1 diabetes mellitus (T1DM). However, the nature of the relationship between this abnormality and disease pathogenesis is unknown. We studied the LPS response in monocytes and monocyte-derived DCs isolated from T1DM patients and from non-T1DM controls. In T1DM patients, late LPS-mediated nuclear DNA binding by RelA, p50, c-Rel, and RelB was impaired as compared with type 2 DM, rheumatoid arthritis, and healthy subjects, associated with impaired DC CD40 and MHC class I induction but normal cytokine production. In TIDM monocytes, RelA and RelB were constitutively activated, and the src homology 2 domain-containing protein tyrosine phosphatase (SHP-1), a negative regulator of NF-kappaB, was overexpressed. Addition of sodium stibogluconate, a SHP-1 inhibitor, to DCs differentiating from monocyte precursors restored their capacity to respond to LPS in approximately 60% of patients. The monocyte and DC NF-kappaB response to LPS is thus a novel phenotypic and likely pathogenetic marker for human T1DM. SHP-1 is at least one NF-kappaB regulatory mechanism which might be induced as a result of abnormal inflammatory signaling responses in T1DM monocytes.
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PMID:Abnormal NF-kappa B function characterizes human type 1 diabetes dendritic cells and monocytes. 1829 40

CD8(+) T cells play an important role in the initiation of insulitis and in the destructive stage leading to insulin-dependent diabetes mellitus. A string of recent studies has led to the identification of numerous HLA-A2-restricted epitopes derived from pancreatic beta cell Ags. It is hoped that assays detecting responses of patient PBMC to such epitopes might be instrumental for early diagnosis of beta cell-directed autoimmunity and for monitoring trials of immunointervention. However, it remains unclear whether the results of assays studying PBMC reflect responses of islet-infiltrating lymphocytes, and to what extent they correlate with disease risk and/or activity. We have used female and male humanized NOD mice expressing HLA-A2 in addition to murine MHC class I molecules to study spontaneous responses of islet-infiltrating blood, spleen, and lymph node lymphocytes of various age groups to a panel of 16 epitopes. Twelve of these are restricted by HLA-A2, have previously been shown to be recognized by patient CTL, and have identical sequences in human and murine autoantigens. Using an IFN-gamma ELISPOT assay, we find highly similar hierarchies of epitope immunodominance in the different T cell compartments, including peripheral blood and pancreatic islets. Moreover, we demonstrate that most of the epitopes eliciting dominant responses in humans display similar status in the mouse model. These results emphasize the potential of humanized mice as tools for studying spontaneous autoimmune CTL responses, and they provide a strong rationale for the development and use of assays monitoring responses of CD8(+) PBMC in human type 1 diabetes.
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PMID:Equivalent specificity of peripheral blood and islet-infiltrating CD8+ T lymphocytes in spontaneously diabetic HLA-A2 transgenic NOD mice. 1839 Jul 25

Cytotoxic T lymphocytes (CTL) are believed to play an essential role in beta-cell destruction leading to development of type 1 diabetes and allogeneic islet graft failure. We aimed to identify the mechanisms used by CTL to kill human beta cells. CTL clones that recognize epitopes from influenza virus and Epstein-Barr virus restricted by human leukocyte antigen (HLA)-A0201 and -B0801, respectively, were used to investigate the susceptibility of human beta cells to CTL. In a short-term (5-hour) assay, CTL killed human islet cells of the appropriate major histocompatibility complex (MHC) class I type that had been pulsed with viral peptides. Killing was increased by pretreating islets with interferon gamma that increases MHC class I on target cells. Killing was abolished by incubation of CTL with the perforin inhibitor concanamycin A. The Fas pathway did not contribute to killing because blocking with neutralizing anti-Fas ligand antibody did not significantly reduce beta-cell killing. In conclusion, we report a novel way of investigating the interaction between CTL and human islets. Human islets were rapidly killed in vitro by MHC class I-restricted CTL predominantly by the granule exocytosis pathway.
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PMID:Cytotoxic T-lymphocyte-mediated killing of human pancreatic islet cells in vitro. 1863 98

The contribution of SNPs in TNF genes to type 1 diabetes (T1D) is not well established and may be confounded by the linkage disequilibrium within the HLA genes. Seven SNPs in the TNF genes (TNFA and TNFB) were genotyped in a Korean cohort (398 T1D patients and 1422 nondiabetic controls), along with HLA DRB1, DQB1, and MICA (MHC class I chain-related genes). Among them, three SNPs (TNFB+318, TNFA-857, and TNFA-308) and two common TNF haplotypes showed significant association with the risk of T1D (P= 5 x 10(-3)-10(-5)). T1D patients were more often heterozygous for the alleles at the TNFB+318 (OR = 1.7, P= 10(-3)) and TNFA-308 (OR = 1.7, P < 10(-5)) than were the controls. Genetic association analyses of the DRB1, DQB1, and MICA alleles with the risk of T1D revealed dramatic associations in several alleles as expected. Independent analyses to discern the genetic effects of TNF polymorphisms on the risk of T1D suggested that these genetic influences might be not totally dependent on the nearby HLA genes. Our results support the hypothesis that two susceptibility loci in the MHC (one in the HLA class II and another in the central MHC region) act epistatically to increase susceptibility to T1D.
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PMID:Independent association of tumor necrosis factor polymorphism with type 1 diabetes susceptibility. 1912 Feb 72

Type 1 diabetes is an autoimmune disorder characterized by progressive destruction of insulin-secreting beta cells of the pancreas, in which CD8(+) T cells play a critical role. The diversity in the HLA alleles expressed among various racial and ethnic groups leads to great variability in antigen presentation and recognition by CD8(+) T cells in the context of MHC class I molecules. To date, studies aimed at identifying disease-relevant antigenic epitopes have focused on using mice transgenic for HLA-A*0201, a common allele, particularly among Caucasians. We present HLA class I typing data from 88 children with type 1 diabetes at the Children's Hospital at Montefiore, where the patient population is ethnically diverse, but largely minority. When categorized into the HLA supertypes A2, A3, B7, and C1, 77% of those studied have alleles belonging to at least one supertype, and of these patients, 65% do not belong to the A2 supertype, which is the supertype represented by the HLA-A*0201 allele. These results support the need for studies using HLA transgenic mice expressing MHC molecules representative of a variety of HLA supertypes, particularly when searching for antigenic epitopes applicable for study among largely urban, minority pediatric populations.
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PMID:HLA class I supertypes in type 1 diabetic children in an urban children's hospital. 1912 Feb 73

An important prerequisite for development of insulitis and beta-cell destruction in type 1 diabetes is successful transmigration of autoreactive T cells across the islet endothelium. Previous work suggests that antigen presentation to T cells by endothelium, which requires endothelial cell expression of major histocompatibility complex (MHC) molecules, promotes tissue-specific T cell migration. We therefore tested the hypothesis that the level of endothelial MHC class I molecule expression in diabetes-prone mice directly influences autoreactive CD8 T cell migration. We investigated the immune phenotype of endothelial cells, focusing on endothelial MHC class I molecule expression in a range of different tissues and mouse strains, including non-obese diabetic (NOD) mice. In addition, we examined whether the level of expression of MHC class I molecules influences autoantigen-driven CD8 T cell transmigration. Using endothelial cell lines that expressed 'high' (NOD mouse), medium (NOD x C3H/HeJ F(1) generation mice) and no (C3H/HeJ) H-2K(d), we demonstrated in vitro that MHC levels have a profound effect on the activation, adhesion and transmigration of pathogenic, islet autoreactive CD8 T cells. The expression level of MHC class I molecules on endothelial tissues has a direct impact upon the efficiency of migration of autoreactive T cells. The immune phenotype of microvascular endothelium in NOD mice may be an additional contributory factor in disease predisposition or development, and similar phenotypes should be sought in human type 1 diabetes.
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PMID:Level of major histocompatibility complex class I expression on endothelium in non-obese diabetic mice influences CD8 T cell adhesion and migration. 1965 77

There is compelling evidence that self-reactive CD8(+) T cells are a major factor in development and progression of type 1 diabetes in animals and humans. Hence, great effort has been expended to define the specificity of autoimmune CD8(+) T cells and to alter their responses. Much work has focused on tolerization of T cells using proteins or peptides. A weakness in this approach is that residual autoreactive T cells may be activated and exacerbate disease. In this report, we use a novel approach, toxin-coupled MHC class I tetramers. Used for some time to identify Ag-specific cells, in this study, we use that same property to delete the Ag-specific cells. We show that saporin-coupled tetramers can delete islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-reactive T cells in vitro and in vivo. Sequence analysis of TCRbeta-chains of IGRP(+) cells reveals the repertoire complexity in the islets is markedly decreased as NOD mice age and significantly altered in toxic tetramer-treated NOD mice. Further tetramer(+) T cells in the islets are almost completely deleted, and, surprisingly, loss of tetramer(+) T cells in the islets is long lasting. Finally, we show deletion at 8 wk of age of IGRP(+) CD8(+) T cells, but not dystophia myotonica kinase- or insulin B-reactive cells, significantly delays diabetes in NOD mice.
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PMID:Toxin-coupled MHC class I tetramers can specifically ablate autoreactive CD8+ T cells and delay diabetes in nonobese diabetic mice. 2022 85


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