Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Slowly progressive insulin-dependent diabetes mellitus (IDDM), like classical IDDM, is also associated with genetic markers. HLA-DR3 but not DR4 is associated with latent autoimmune diabetes in adults (LADA). In GAD65 antibody-positive Finnish LADA patients, DQB1*0302 is positively associated with the disease. Alleles of the MHC class I chain-related A (MICA) gene located centromeric to the HLA-B gene is associated with LADA. Allele 5.1 of MICA was associated with both LADA and adult-onset Italian IDDM patients when compared to controls. This finding was also observed in Indian and Latvian patients with LADA. These findings suggest that certain genetic markers distinguish LADA better.
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PMID:Genetics of latent autoimmune diabetes in adults. 1202 Oct 89

Genetic studies of malnutrition-related diabetes are few. We have analyzed the HLA class II gene polymorphism in malnutrition-modulated diabetes mellitus (MMDM), which was previously referred to as protein-deficient diabetes mellitus (PDDM) in the 1985 WHO classification. Insulin-dependent diabetes mellitus (IDDM) is a polygenic disorder with an autoimmune basis for disease development. In addition to HLA, a second susceptibility locus for IDDM has been identified to lie in the major histocompatibility class III region. Both IDDM and MMDM in eastern Indians are associated with DR3-DQ2 but not DR4-DQ8. The presence of autoantibodies to IDDM autoantigens in clinical MMDM either identifies the slow-onset form of IDDM or suggests autoimmunity different from that in IDDM. Our study demonstrates that the presence of GAD65 antibody and DR3-DQ2 positivity in MMDM patients identifies the underlying autoimmune mechanism in the etiology in eastern India. In autoantibody-negative MMDM patients an association with DR7-DQ2 is identified. The date obtained also indicate the possibility that MMDM can coexist with IDDM in these patients and that malnutrition could be one of the reasons for the slower onset in IDDM-prone individuals. The association of DR7-DQ2 suggests that there is a different immunogenetic background to MMDM than to IDDM. MICA is located in the MHC class I region and is expressed by monocytes, keratinocytes, and endothelial cells. Sequence determination of MICA gene identifies trinucleotide repeat (GCT) microsatellite polymorphism in exon 5. Five alleles with 4, 5, 6, and 9 repetitions of GCT or 5 repetitions of GCT with 1 additional nucleotide insertion (GGCT) are identified. The alleles are A4, A5, A5.1, A6, and A9. We studied the association of MICA alleles with IDDM (n = 52) and MMDM (n = 41) patients and healthy controls (n = 73) from Cuttack, eastern India. MICA was typed by PCR amplification, and fragment sizes were determined in an ABI prism DNA sequencer. Allele 9 of MICA is positively and allele 4 negatively associated with MMDM patients compared to controls. Allele 5 is positively associated with IDDM (OR 2.64, P < 0.05) when compared to controls. Our findings suggest that MMDM is immunogenetically different from IDDM in eastern India and that MIC-A is important in the pathogenesis of MMDM patients from Cuttack in eastern India.
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PMID:Immunogenetic studies on malnutrition-modulated diabetes mellitus. 1202 Oct 94

MHC class III genes are important in immune regulation and inflammation, and the gene products of this region are well conserved between species. Their role in diabetes is, however, unknown. We used islets from NOD mice that lacked expression of both MHC class I and class II molecules to test the effect of class III differences on the injury of transplanted NOD islets. Loss of islet MHC class I was highly protective, while deletion of MHC class II had no benefit on islet survival. However the combined absence of both MHC class I and class II expression by NOD islets resulted in a delayed form of injury, when islets were transplanted to NOD mice. As neither MHC class I or II molecules were expressed by donor islet tissue, these results suggest a previously unrecognized and important contribution of MHC class III differences on islet injury following transplantation.
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PMID:Role of donor MHC class III genes in the destruction of transplanted islets in NOD mice. 1202 Nov 1

NIDDM is one of the most common forms of diabetes. The diagnosis is based on WHO classification, which is a clinical classification and misses the autoimmune diabetes in adults. Therefore, among the clinically diagnosed NIDDM cases, there can be a certain number of patients with latent autoimmune diabetes in adults (LADA). The MICA gene is located in the MHC class I region and is expressed by monocytes, keratinocytes, and endothelial cells. Sequence determination of the MICA gene identifies trinucleotide repeat (GCT) microsatellite polymorphism, which identifies 5 alleles with 4, 5, 6, and 9 repetitions of GCT (A4, A5, A6, and A9) or 5 repetitions of GCT with 1 additional G insertion for allele A5.1. From our previous studies, we have shown that microsatellite allele A5 of MICA is associated with IDDM. The aim of this study was to test the hypothesis that certain MICA alleles are associated with LADA among clinically diagnosed NIDDM. Out of 100 clinically diagnosed NIDDM patients, 49 tested positive for GAD65 and IA-2 antibodies by use of 35S RIA. Samples from these 49 patients and 96 healthy controls were analyzed for MICA by PCR amplification, and fragment sizes were determined in an ABI prism DNA sequencer. Our results show that MICA allele A5.1 is significantly increased in antibody-positive (GAD65 or IA-2) NIDDM patients [35/49 (72%)] when compared to healthy controls [22/96 (23%)] (OR = 8.4; P < 0.0001). However, we do not see any association with each of the antibodies separately. From our study, we conclude that (a) MICA allele A5.1 is associated with LADA and (b) MICA may play an important role in the etiopathogenesis of LADA.
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PMID:Microsatellite allele A5.1 of MHC class I chain-related gene A is associated with latent autoimmune diabetes in adults in Latvia. 1202 Nov 41

Gamma interferon (IFN-gamma) has been thought to play an important role in the pathogenesis of diabetes. This report determines if rIFN-gamma administration to NOD mice paradoxically inhibits the development of diabetes. Injections of recombinant rIFN-gamma of 5 x 10(3), 20 x 10(3), and 100 x 10(3) units, dose dependently inhibited the development of diabetes. The maximal rIFN-gamma dose decreased the incidence of diabetes from 74% in control animals to 42%. 100x10(3) unit rIFN-gamma dose significantly decreased insulitis score, and increased islet number. The development of diabetes in irradiated NOD mice was slower in animals injected with spleen cells from rIFN-gamma treated than from saline treated NOD mice suggesting that rIFN-gamma decreases anti-islet effector cell activity. The susceptibility to apoptosis was increased in splenic cells of rIFN-gamma treated mice. The expressions of the co-stimulatory molecules B7-2 and ICAM-1 were significantly increased in spleen cells of rIFN-gamma treated mice while the expression of MHC class I was decreased. In vitro studies demonstrated that NOD mouse mononuclear spleen cells preincubated with rIFN-gamma and subsequently cocultured with responder cells, potently inhibited responder T-cell proliferative responses. rIFN-gamma administration decreased IL-12 and IL-2 mRNA expression in spleen cells while increasing IL-1 expression. In conclusion, rIFN-gamma inhibits the diabetic process in NOD mice by decreasing anti-islet effector activity and in turn decreasing insulitis and islet destruction. The suppression of Th1 cell related cytokines and/or augmentation of the macrophage cytokine IL-1 may play a role in the diabetes sparing effect of rIFN-gamma.
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PMID:Gamma interferon paradoxically inhibits the development of diabetes in the NOD mouse. 1241 83

Activated insulin-specific CD8(+) T cells (IS-CD8(+) cells) home to the pancreas, destroy beta cells, and cause rapid diabetes upon transfer into diabetes-prone NOD mice. Surprisingly, they also cause diabetes in mouse strains that are free of preexistent inflammation. Thus, we hypothesized that islet-specific homing may be in part dependent on IS-CD8(+) cells' recognition of the cognate major histocompatibility complex (MHC)/peptide complexes presented by pancreatic endothelial cells, which acquire the antigen (insulin) from beta cells. In fact, islet-specific homing was abrogated in mice that lack MHC class I expression, or presentation of the specific peptide, or have impaired insulin secretion. Moreover, we found that IS-CD8(+) cells directly recognized pancreatic endothelial cells in islet organ cultures. Triggering of IS-CD8(+) cells' T cell receptor (TCR) led to activation of integrins expressed by these cells. In addition, chemokines, particularly SLC (CCL21), were also required for IS-CD8(+) cells' adhesion to endothelial monolayers and for successful homing in vivo. Thus, signaling through TCR and chemokine receptors work in concert to assure firm adhesion of T cells to the pancreatic endothelium. The antigen cross-presentation ability of endothelia may therefore contribute to the specificity of homing of activated T lymphocytes to the tissues where antigens are generated by other cell types.
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PMID:Presentation of antigen by endothelial cells and chemoattraction are required for homing of insulin-specific CD8+ T cells. 1261 5

Genes in the early region 3 (E3) of the adenovirus genome allow the virus to evade host immune responses by interfering with major histocompatibility (MHC) class I-mediated antigen presentation and tumor necrosis factor-alpha (TNF-alpha)- or Fas-induced apoptosis of infected cells. Autoimmune type 1 diabetes (T1D) is inhibited in NOD mice transgenically expressing all E3 genes under control of a rat insulin promoter (RIPE3/NOD). For dissecting the protective mechanisms afforded by various E3 genes, they were subdivided into RIP-driven transgene constructs. Strong T1D protection mediated at the beta-cell level characterized DL704/NOD mice lacking the E3 gp19K gene suppressing MHC class I expression but retaining the 10.4K, 14.5K, and 14.7K genes inhibiting Fas- or TNF-alpha-induced apoptosis and TNF-alpha-induced NF-kB activation. Much weaker protection characterized DL309/NOD mice expressing the gp19K but not the 10.4K, 14.5K, and 14.7K genes. While RIPE3/NOD splenocytes had an unexpected decrease in ability to adoptively transfer T1D, splenocytes from both the DL704 and DL309 stocks efficiently did so. These findings indicate that all E3 genes must be expressed to inhibit the diabetogenic potential of NOD immune cells. They also demonstrate that the antiapoptotic E3 genes most effectively protect pancreatic beta-cells from diabetogenic immune responses.
Diabetes 2003 May
PMID:Adenovirus early region 3 antiapoptotic 10.4K, 14.5K, and 14.7K genes decrease the incidence of autoimmune diabetes in NOD mice. 1271 41

Type 1 diabetes occurs as a result of an autoimmune attack on the insulin-producing beta cells. Although CD8 T cells have been implicated both early and late in this process, the requirement for direct interaction between these cells and MHC class I on the beta cells has not been demonstrated. By using nonobese diabetic mice lacking beta cell class I expression, we show that both initiation and progression of insulitis proceeds unperturbed. However, without beta cell class I expression, the vast majority of these mice do not develop hyperglycemia. These findings demonstrate that a direct interaction between CD8 T cells and beta cells is not required for initiation or early disease progression. The requirement for class I on beta cells is a relatively late checkpoint in the development of diabetes.
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PMID:Beta cell MHC class I is a late requirement for diabetes. 1275 Apr 72

Recent evidence from several studies has suggested a genetic predisposition in the pathogenesis of ulcerative colitis (UC), which is especially related with major histocompatibility complex (MHC) genes. The aim of this study was to investigate the possible association of human leukocyte antigen (HLA-B, HLA-DR) and MHC class I chain-related-transmembrane (MICA-TM) polymorphism with the behavior and extension of UC. We selected 121 unrelated patients with UC. These were divided into two groups according to the extension of the disease: 31 patients with distal UC and 90 with wide extension UC; 116 blood donors were also selected as healthy controls, all of whom were typed for HLA-B, HLA-DR, and MICA-TM alleles. HLA-B7 was found to be overrepresented in distal UC patients compared with those with extensive UC (p(c) = 0.007, OR = 5.33) and healthy controls (p(c) = 0.03, OR = 4.09). The MICA-A5.1 allele was also increased in distal UC (p(c) = 0.015, OR = 3.82) when compared with extensive forms. These alleles are in strong linkage disequilibrium in our population. The MICA-A5 allele was significantly increased in extensive forms when compared with healthy controls(p(c) = 0.02, OR = 2.4). According to our results, MICA-A5.1 allele seems to be protective against extensive forms of UC, and MICA-A5 may condition a worse progression of the disease. These results are in agreement with other studies that suggest a similar role of such alleles in other diseases, such as insulin-dependent diabetes mellitus and celiac disease.
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PMID:MHC class I chain-related gene A transmembrane polymorphism modulates the extension of ulcerative colitis. 1287 61

Cross-presentation of self Ags by APCs is key to the initiation of organ-specific autoimmunity. As MHC class I molecules are essential for the initiation of diabetes in nonobese diabetic (NOD) mice, we sought to determine whether the initial insult that allows cross-presentation of beta cell autoantigens in diabetes is caused by cognate interactions between naive CD8(+) T cells and beta cells. Naive splenic CD8(+) T cells from transgenic NOD mice expressing a diabetogenic TCR killed peptide-pulsed targets in the absence of APCs. To ascertain the role of CD8(+) T cell-induced beta cell lysis in the initiation of diabetes, we expressed a rat insulin promoter (RIP)-driven adenovirus E19 transgene in NOD mice. RIP-E19 expression inhibited MHC class I transport exclusively in beta cells and rendered these cells resistant to lysis by CD8(+) (but not CD4(+)) T cells, both in vitro and in vivo. Surprisingly, RIP-E19 expression impaired the accumulation of CD8(+) T cells in islets and delayed the onset of islet inflammation, without affecting the timing or magnitude of T cell cross-priming in the pancreatic lymph nodes, which is the earliest known event in diabetogenesis. These results suggest that access of beta cell autoantigens to the cross-presentation pathway in diabetes is T cell independent, and reveal a previously unrecognized function of MHC class I molecules on target cells in autoimmunity: local retention of disease-initiating clonotypes.
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PMID:Cross-priming of diabetogenic T cells dissociated from CTL-induced shedding of beta cell autoantigens. 1466 97


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