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)

Subtypes of HLA-DR4 are associated with susceptibility or protection against type 1 diabetes (T1DM). We addressed whether this reflects linkage disequilibrium with the true susceptibility locus by studying broader MHC haplotypes marked by alleles of HLA-B, IKBL (adjacent to TNFA) and complement C4. The study used a largely Caucasian cohort from Western Australia. HLA-DRB1*0401 and HLA-DRB1*0405 marked susceptibility to T1DM. In Caucasians, DRB1*0401 occurs predominantly in the 44.1 ancestral haplotype (AH; HLA-A2,B44, DRB1*0401,DQB1*0301) and the 62.1AH (HLA-A2,B15(62),DRB1*0401,DQB1*0302). HLA-B15 marked susceptibility and HLA-B44 marked with resistance to T1DM in patients and controls preselected for HLA-DRB1*0401. A gene between TNFA and HLA-B on the 8.1AH (HLA-A1,B8,;DR3,DQ2) modifies the effects of the class II alleles. Here, alleles characteristic of the 62.1AH (C4B3, IKBL+446*T and HLA-A2,B15) were screened in donors preselected for HLA-DRB1*0401. C4B3 was associated with diabetes, consistent with a diabetes gene telomeric of MHC class II. However, increases in carriage of IKBL+446*T and HLA-A2,B15 were marginal, as too few control subjects were available with the diabetogenic alleles. However, with these tools, selection of HLA-DRB1*0401, DQB1*0302 donors who are positive and negative for C4B3 will allow bidirectional mapping of diabetes genes in the central MHC.
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PMID:Does a central MHC gene in linkage disequilibrium with HLA-DRB1*0401 affect susceptibility to type 1 diabetes? 1585 1

Enteroviruses such as coxsackievirus B4 (CVB4) are proposed as possible environmental triggers or accelerants of the autoimmune process that leads to type 1 diabetes mellitus. One putative mechanism to account for this association is mimicry between virus components and islet autoantigens. Particular interest has focused on the CVB4 non-structural protein P2C, which we previously showed to be a major target of the effector memory anti-CVB4 CD4 T-cell response, and which harbours a region of sequence similarity with the islet autoantigen, glutamic acid decarboxylase (GAD65). Since several distinct human leucocyte antigen (HLA) Class II molecules are associated with development of type 1 diabetes, we hypothesized that for functional mimicry to be important, any potential region(s) of mimicry in P2C should bind to each of these susceptibility molecules. In the present study therefore we examined the affinity of 20-mer overlapping P2C peptides for soluble HLA-DR4, -DR3, -DQ2 and -DQ8. We identified one discrete region of P2C with high binding affinities for all of these HLA Class II molecules. Moreover, the binding affinity of P2C peptides was significantly correlated between HLA molecules present on the same susceptibility haplotype (e.g. DR4 and DQ8, P =0.0076; DR3 and DQ2 P = 0.002). We conclude that possession of these haplotypes favours restricted presentation of viral epitopes, and speculate that this could promote the potential for mimicry between microbial proteins and islet autoantigens.
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PMID:HLA Class II molecules on haplotypes associated with type 1 diabetes exhibit similar patterns of binding affinities for coxsackievirus P2C peptides. 1623 23

Enteroviruses, particularly Coxsackie virus B4 (CVB4), are considered to be involved in the pathogenesis of type 1 diabetes. We wanted to compare the characteristics of T-cell immune response to CVB4 in children with type 1 diabetes and healthy children with and without HLA risk-associated haplotypes (HLA-DR3-DQ2 or HLA-DR4-DQ8) for type 1 diabetes. Peripheral blood mononuclear cells (PBMCs) were isolated and cultured with CVB4 and analyzed for cytokine and chemokine receptors by flow cytometry and for expression of transcription factors Tbet and GATA-3 by RT-PCR and Western blot. Culture supernatants were analyzed for secretion of gamma-interferon (IFN-gamma). In children with type 1 diabetes, a decreased percentage of T-cells expressed CCR2, CXCR6, interleukin (IL)-18R, and IL-12Rbeta2-chain after in vitro stimulation with CVB4 in comparison with healthy children with or without HLA risk genotype. Moreover, we found that children with type 1 diabetes had decreased IFN-gamma secretion and expression of Tbet, both on mRNA and protein level, in CVB4-stimulated PBMCs. Accordingly, children with type 1 diabetes show an impaired type 1 immune response against CVB4 compared with healthy children. This may lead to a delayed clearance of the virus and, at least partly, explain why children with type 1 diabetes may be more prone to CVB4 infections and related complications, such as beta-cell damage.
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PMID:Decreased in vitro type 1 immune response against coxsackie virus B4 in children with type 1 diabetes. 1656 21

Recently, we have identified proinsulin (P-Ins)(73-90) as an immunodominant T cell epitope of HLA-DRB1*0401 (DR4) subjects with beta-islet cell autoimmunity and of HLA-DR4/CD4 double-transgenic mice immunized with human P-Ins. We have compared the fine specificities of one human CD4 T cell clone and two mouse T cell hybridoma clones recognizing this epitope, and, although these three clones all recognized the same core region (LALEGSLQK), there were major differences in how they interacted with the peptide (p)/HLA complex, reflecting the fact that human P-Ins is a foreign antigen in the mouse and an autoantigen in the type 1 diabetes patient. The human T cell clone was forkhead transcription factor 3 (Foxp3)-positive, a marker for regulatory T cell lineages, and secreted predominantly IL-5, IL-10, and low levels of IFNgamma in response to P-Ins(73-90). This finding is compatible with the previously detected regulatory cytokine pattern in subjects with beta-cell autoimmunity. However, added N- or C-terminal amino acids drastically changed HLA and tetramer binding capacity as well as T cell reactivity and the cytokine phenotype of the P-Ins(73-90)-specific human CD4 T cell clone, suggesting a potential for this P-Ins epitope as a target for therapeutic intervention in HLA-DR4-positive humans with beta-islet cell autoimmunity or recent-onset type 1 diabetes.
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PMID:DRB1*0401-restricted human T cell clone specific for the major proinsulin73-90 epitope expresses a down-regulatory T helper 2 phenotype. 1686 84

We had earlier hypothesized, if parents originated from previously isolated populations that had selected against different critical susceptibility genes for a polygenic disease, their offspring could have a greater risk of that disease than either parent. We therefore studied parents of patients with type 1 diabetes (T1D). We found that parents who transmitted HLA-DR3 to HLA-DR3/DR4 patients had different HLA-A allele frequencies on the non-transmitted HLA haplotype than HLA-DR4-transmitters. HLA-DR3-positive parents also had different insulin (INS) gene allele frequencies than HLA-DR4-positive parents. Parent pairs of patients had greater self-reported ethnicity disparity than parent pairs in control families. Although there was an excess of HLA-DR3/DR4 heterozygotes among type 1 diabetes patients, there were significantly fewer HLA-DR3/DR4 heterozygous parents of patients than expected. These findings are consistent with HLA-DR and INS VNTR alleles marking both disease susceptibility and separate Caucasian parental subpopulations. Our hypothesis thus explains some seemingly disconnected puzzling phenomena, including (1) the rising world-wide incidence of T1D, (2) the excess of HLA-DR3/DR4 heterozygotes among patients, (3) the changing frequency of HLA-DR3/DR4 heterozygotes and of susceptibility alleles in general in patients over the past several decades, and (4) the association of INS alleles with specific HLA-DR alleles in patients with T1D.
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PMID:A genetic explanation for the rising incidence of type 1 diabetes, a polygenic disease. 1705 89

Aberrancies in T-cell polarization including expression of chemokine receptors have been reported in human leucocyte antigen (HLA) class II associated autoimmune diseases, such as type 1 diabetes (T1D) and rheumatoid arthritis. We asked whether these aberrancies are present at birth in newborn infants carrying the HLA risk haplotypes for T1D. Sixty-seven cord blood (CB) samples from infants were screened for T1D-associated HLA risk genotypes (HLA-DR4-DQ8 and/or DR3-DQ2 without protective alleles). CB lymphocytes were stimulated with phytohaemagglutinin in type 1 (interleukin (IL)-12, anti-IL4) or type 2 (IL-4, anti-IL12) cytokine environment for 6 days. The expression of chemokine and cytokine receptors on T cells was determined by flow cytometry, secretion of cytokines was analysed with enzyme-linked immunosorbent assay, and transcription factors were analysed using real-time reverse transcriptase-polymerase chain reaction. After culture of CB lymphocytes in type 2 cytokine environment newborn infants carrying DR4-DQ8 haplotype (n=18) showed reduced percentage of CD4 T cells expressing CCR4 (P=0 x 009) and the level of CCR4 mRNA was decreased (P=0 x 008). In addition, lower secretion of IL-13 and expression of GATA-3 in CB lymphocytes cultured in type 2 cytokine environment were found in the infants with DR4-DQ8 haplotype (P=0 x 020 and P=0 x 004, respectively) in comparison to newborn infants without DR4-DQ8 and DR3-DQ2 haplotypes (n=37). Poor in vitro induction of type 2 immune responses in newborn infants with DR4-DQ8 haplotype suggests that the HLA genotype associated with risk of autoimmunity may affect the T cell polarization already at birth, which in turn may contribute to the risk for autoimmunity later in life.
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PMID:Reduced CCR4, interleukin-13 and GATA-3 up-regulation in response to type 2 cytokines of cord blood T lymphocytes in infants at genetic risk of type 1 diabetes. 1724 54

Autoimmune diabetes mellitus, called type 1 diabetes mellitus (T1DM), is caused by autoimmune destruction of islet beta cells in the pancreas. T1DM susceptibility loci mapped by different genome screening are IDDM1-IDDM18. It has been estimated that HLA (IDDM1) provides up to 40-50 % of the familial clustering of T1DM (LOD score of 65.8). Many studies have verified that DQB1*0302 is a strong susceptibility gene and that the heterozygous combination of DQA1*0301-DQB1*0302 on the HLA-DR4 haplotype and DQA1*0501-DQB1*0201 on the HLA-DR3 haplotype results in a synergistically increased risk of T1DM. The presence of predisposing genes in autoimmune diabetes decreases with age, probably due to increasing influence of environmental factors. Autoimmune diabetes with manifestation in adults may have partly different immunogenetic etiopathogenesis than autoimmune diabetes with manifestation in childhood. Compared to fast progressing adult-onset T1DM, slowly progressing adult-onset type 1 diabetes (LADA) might involve genes leading to a slow progressive beta-cells destruction.
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PMID:Genetics of autoimmune diabetes mellitus. 1828 44

Previous studies have shown that enteroviral RNA can be detected in blood at the onset of type 1 diabetes (T1D). The infection may play a role in triggering T1D and genetic host factors may contribute to this process. We investigated (1) whether enterovirus is present at the onset of T1D in peripheral blood mononuclear cells (PBMC), plasma, throat, or stool, and (2) whether enteroviral presence is linked with HLA-DR type and/or polymorphisms in melanoma differentiation-associated gene 5 (MDA5) and 2'-5' oligoadenylate synthetase 1 (OAS1), factors of antiviral immunity. To this end, PBMC, plasma, throat, and stool samples from 10 T1D patients and 20 unrelated controls were tested for the presence of enteroviruses (RT-PCR), for HLA-DR type, and polymorphisms in MDA5 and OAS1. Enterovirus RNA was detected in PBMC of 4/10 T1D patients, but none of 20 controls. Plasma was positive in 2/10 T1D patients and none of 20 controls, suggesting that enteroviruses found at the onset of T1D are mainly present in PBMC. All throat samples from positive T1D patients were virus-negative and only 1 fecal sample was positive. The negative results for all throat and most stool samples argues against acute infection. Enterovirus presence was linked with HLA-DR4, but not with polymorphisms in MDA5 or OAS1.
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PMID:Detection of enterovirus RNA in peripheral blood mononuclear cells of type 1 diabetic patients beyond the stage of acute infection. 2012 7

Extract: Autoreactive T cells are part of the normal immune system and are kept under control by mechanisms known as anergy. Autoimmune diseases are caused by the breakdown of this tolerance, and T cell activation leads to severe inflammation and tissue damage. For example, in rheumatoid arthritis, synovial joints will be destroyed whereas in insulin-dependent diabetes mellitus (IDDM, type 1 diabetes), insulin-producing beta cells in the pancreatic islets of Langerhans will be the focus of the attack. The genetic makeup of susceptible individuals and the environmental factors leading to autoimmunity are complex and largely unknown. In many instances, the main genetic locus that has been determined is the MHC (major histocompatibility complex) class II locus. In the case of IDDM this locus encodes alleles such as HLA-DR4, -DR3, and -DQ8 in humans and I-Ag7 in the non-obese diabetic (NOD) mouse. Since MHC class II molecules present peptides to CD4 positive T cells, it is tempting to link genes and function and to study closely CD4+ T cells in the context of autoimmunity. It is now well established that, indeed, these cells are essential for the initiation and development of autoimmunity, however, in-depth investigation of them has been impeded by two major roadblocks. First, potential antigens, and therefore relevant peptides, are scarce and difficult to isolate. Secondly, reagents able to detect T cells in an antigen-specific fashion have remained elusive.
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PMID:Getting a grip on antigen-specific CD4 T cells: Tracking autoimmune T cells in vivo. 2070 62

The aim of this study was to evaluate the humoral autoreactivity to zinc transporter 8 (ZnT8) depending on the clinical phenotype of type 1 diabetes (T1D). ZnT8 autoantibodies (ZnT8A) were determined by radioimmunoassay using carboxy-terminal ZnT8 constructs in 57 childhood-onset, 97 adult-onset, and 85 fulminant T1D. The ZnT8A frequency was higher in childhood-onset patients and decreased with increasing age of onset from 70% to 24% (P(trend)<0.005). None of the patients with fulminant T1D was positive for ZnT8A. There were at least two distinct ZnT8A epitope patterns associated with the aa325-restriction, childhood-onset patients have aa325-nonrestricted response more frequently compared to the adult-onset group (P<0.05). The level of ZnT8A was inversely associated with the copy number of HLA-DR4 allele (P<0.05). These results suggest differences in the humoral autoreactivity to ZnT8 depending on the clinical phenotype, which should provide strategy for autoantibody measurement in subjects to allow early diagnosis of autoimmune T1D.
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PMID:Differences in the humoral autoreactivity to zinc transporter 8 between childhood- and adult-onset type 1 diabetes in Japanese patients. 2106 78


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