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)

Insulin-dependent diabetes mellitus (IDDM) and Graves' disease (GD) are autoimmune endocrinopathies and associated with distinct HLA-DR and -DQ alleles as well as several tumor necrosis factor alpha (TNF-alpha) and beta (TNF-beta) alleles. TNF-alpha and TNF-beta interact with TNF receptor (TNF-R), of which two subtypes have been described: TNF-R1 and TNF-R2. We investigated TNF-R2 alleles in 90 patients with IDDM, 101 with GD and 70 healthy controls. Genomic DNA was amplified with specific flanking primers for the untranslated 3' region of TNF-R2. SSCP analysis revealed two alleles by different fragment patterns: TNF-R2*1 and TNF-R2*2. Patients with IDDM or Graves' disease and controls did not differ significantly: TNF-R2*1/*1:IDDM(8%)/GD(2%)/KO(4%); TNF-R2*2/*2:IDDM(34%)/GD(48%)/KO(42%), heterozygosity TNF-R2*1/*2:IDDM(58%)/GD(50%)/KO(54%) (IDDM vs KO: P=0.46, chi2=1.57; GD vs KO: P=0.59, chi2=1.05). In conclusion, the studied polymorphism of TNF-R2 was associated with neither IDDM nor GD in a German population.
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PMID:Polymorphisms of tumor necrosis factor receptor 2 are not associated with insulin-dependent diabetes mellitus or Graves' disease. 917 53

The purposes of this study were 1) to compare soluble tumor necrosis factor-alpha receptors, which are thought to reflect the degree of TNF-alpha activation, in nondiabetic subjects and type 1 diabetic patients, and 2) to evaluate the effects of smoking and microvascular complications on soluble tumor necrosis factor-alpha receptor levels in type 1 diabetic individuals. Plasma soluble tumor necrosis factor-alpha receptor levels (R1 and R2) were measured in 50 young type 1 diabetic patients without clinical macroangiopathy and in a matched group of 20 healthy volunteers. When diabetic patients were grouped according to smoking and microvascular complication status, the groups of patients had similar values of age, sex, body mass index, blood pressure, lipids, creatinine, and glycometabolic control. Nevertheless, soluble tumor necrosis factor-alpha receptor-R1 levels but not R2 levels, were markedly elevated (P < 0.05 or less) in complicated vs. uncomplicated (2.40 +/- 0.3 vs. 1.80 +/- 0.1 ng/ml) patients and in smokers vs. nonsmokers (2.66 +/- 0.4 vs. 1.76 +/- 0.1 ng/ml). In a two-factor ANOVA, both smoking (P < 0.01) and microvascular complications (P < 0.05) were independent predictors of soluble tumor necrosis factor-alpha receptor-R1. Soluble tumor necrosis factor-alpha receptor levels of diabetic patients who did not smoke or without complications were similar to those of healthy controls. In conclusion, smoking and microvascular complications seem to exert an additive and deleterious impact on TNF-alpha activation, as reflected by levels of soluble tumor necrosis factor-alpha receptors, in young adults with type 1 diabetes.
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PMID:Elevated plasma levels of soluble receptors of TNF-alpha and their association with smoking and microvascular complications in young adults with type 1 diabetes. 1150 15

Insulin-dependent diabetes mellitus (IDDM), also known as type 1 diabetes, is an organ-specific autoimmune disease resulting from the destruction of insulin-producing pancreatic beta cells. The hypothesis that IDDM is an autoimmune disease has been considerably strengthened by the study of animal models such as the BioBreeding (BB) rat and the nonobese diabetic (NOD) mouse, both of which spontaneously develop a diabetic syndrome similar to human IDDM. Beta cell autoantigens, macrophages, dendritic cells, B lymphocytes, and T cells have been shown to be involved in the pathogenesis of autoimmune diabetes. Among the beta cell autoantigens identified, glutamic acid decarboxylase (GAD) has been extensively studied and is the best characterized. Beta cell-specific suppression of GAD expression in NOD mice results in the prevention of IDDM. Macrophages and/or dendritic cells are the first cell types to infiltrate the pancreatic islets. Macrophages play an essential role in the development and activation of beta cell-cytotoxic T cells. B lymphocytes play a role as antigen-presenting cells, and T cells have been shown to play a critical role as final effectors that kill beta cells. Cytokines secreted by immunocytes, including macrophages and T cells, may regulate the direction of the immune response toward Th1 or Th2 as well as cytotoxic effector cell or suppressor cell dominance. Beta cells are destroyed by apoptosis through Fas-Fas ligand and TNF-TNF receptor interactions and by granzymes and perforin released from cytotoxic effector T cells. Therefore, the activated macrophages and T cells, and cytokines secreted from these immunocytes, act synergistically to destroy beta cells, resulting in the development of autoimmune IDDM.
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PMID:Cellular and molecular pathogenic mechanisms of insulin-dependent diabetes mellitus. 1179 11

Our previous results have suggested that genes outside the human leukocyte antigen (HLA) class II locus may affect the phenotype of type 2 diabetic patients from families with both type 1 and type 2 diabetes (mixed type 1/2). To study whether the TNF alpha gene could be such a modifying gene, we studied TNF alpha promoter polymorphisms (G-->A substitution at positions -308 and -238) in relation to HLA-DQB1 genotypes in type 2 patients from mixed type 1/2 families or common type 2 diabetes families as well as in patients with adult-onset type 1 diabetes and control subjects. The TNF alpha(308) AA/AG genotype frequency was increased in adult onset type 1 patients (55%, 69 of 126), but it was similar in type 2 patients from type 1/2 families (35%, 33/93) or common type 2 families (31%, 122 of 395), compared with controls (33%, 95/284; P < 0.0001 vs. type 1). The TNF alpha(308) A and DQB1*02 alleles were in linkage disequilibrium in type 1 patients (Ds = 0.81; P < 0.001 vs. Ds = 0.25 in controls) and type 2 patients from type 1/2 families (Ds = 0.59, P < 0.05 vs. controls) but not in common type 2 patients (Ds = 0.39). The polymorphism was associated with an insulin-deficient phenotype in the type 2 patients from type 1/2 families only together with DQB*02, whereas the common type 2 patients with AA/AG had lower waist to hip ratio [0.92 (0.12) vs. 0.94 (0.11), P = 0.008] and lower fasting C-peptide concentration [0.48 (0.47) vs. 0.62 (0.46) nmol/liter, P = 0.020] than those with GG, independently of the presence of DQB1*02. In conclusion, TNF alpha is unlikely to be the second gene in the HLA area responsible for our previous findings in type 1/2 patients. However, we could show an association between TNF alpha(308) polymorphism and the phenotype of common type 2 diabetes.
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PMID:A combination of human leukocyte antigen DQB1*02 and the tumor necrosis factor alpha promoter G308A polymorphism predisposes to an insulin-deficient phenotype in patients with type 2 diabetes. 1278 86

Immunization with mycobacterial preparation such as Bacille Calmette-Guerin (BCG) or complete Freund's adjuvant (CFA) prevents the onset and recurrence of type 1 diabetes in non-obese diabetic (NOD) mice. In this study, we explored the mechanism underlying the down-regulation of diabetogenic T cells by BCG treatment. We found that the potential of splenocytes from BCG-immunized diabetic NOD mice to adoptively transfer diabetes was significantly impaired. BCG immunization sequentially induced the production of TNF-alpha, IFN-gamma and IL-4 by splenocytes, increased the expression of Fas(high) (Apo-1/CD95), Fas ligand (FasL, CD95L) and TNF receptor (TNFR) on T cells leading to T cell apoptosis. The primary role of IFN-gamma and TNF-alpha in BCG-immunotherapy was demonstrated by (i) reversing the immune regulatory effect of BCG by in vivo treatment with neutralizing anti-cytokine antibodies, (ii) inducing effect similar to BCG by treatment with these cytokines. We show that Fas and TNF are two pathways in BCG-induced apoptosis of diabetogenic T cells, since in vitro blocking FasL or TNFR1 with antibody reduced T cell apoptosis and increased T cell proliferative response. In addition, TNF-alpha and agonistic anti-Fas antibody had a synergistic effect on the in vitro apoptosis of diabetogenic T cells. Our results suggest that BCG down-regulates destructive autoimmunity by TNF-alpha/IFN-gamma-induced apoptosis of diabetogenic T cells through both Fas and TNF pathways. These studies provide a novel mechanism for blocking disease recurrence and immune modulating effect of BCG immunization in type 1 diabetes.
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PMID:In vivo apoptosis of diabetogenic T cells in NOD mice by IFN-gamma/TNF-alpha. 1549 21

Idd9.3, a locus that determines susceptibility to the autoimmune disease type 1 diabetes (T1D) in the nonobese diabetic (NOD) mouse, has been mapped to the distal region of chromosome 4. In the current report we reduce the size of the Idd9.3 interval to 1.2Mb containing 15 genes, including one encoding the immune signaling molecule, 4-1BB, which shows amino acid variation between diabetes sensitive and resistant strains. 4-1BB, a member of the TNF receptor superfamily expressed by a variety of immune cells, mediates growth and survival signals for T cells. Functional analyses demonstrate that purified T cells from NOD congenic mice with the C57BL/10 (B10) allele at Idd9.3 produce more IL-2 and proliferate more vigorously in response to anti-CD3 plus immobilized 4-1BB ligand than T cells from NOD mice with the NOD allele at Idd9.3. In contrast, the response to anti-CD3 plus anti-CD28 costimulation was indistinguishable between the congenic strains, pinpointing the differences in NOD versus NOD.B10 Idd9.3 T cell responses to the 4-1BB costimulatory pathway. These data provide evidence in support of Idd9.3 as the locus encoding 4-1BB and suggest that the 4-1BB signaling pathway could have a primary function in the etiology of autoimmune disease.
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PMID:Genetic and functional association of the immune signaling molecule 4-1BB (CD137/TNFRSF9) with type 1 diabetes. 1599 81

D-hormone [1,25(OH)2 D3] is an important immune system regulator that has been shown to inhibit development of autoimmune diseases including experimental inflammatory bowel disease (IBD), rheumatoid arthritis (RA), multiple sclerosis (MS), and type 1 diabetes. Paradoxically, other immune mediated diseases (experimental asthma) and immunity to infectious organisms were not found to be affected by D-hormone treatment. The effectiveness of D-hormone treatment of autoimmune diseases is due to inhibition of the development and function of Th1 cells and the induction of other Th cells including Th2 cells. We report results of microarray analysis of colons from D-hormone treated mice with experimental IBD. Two hundred thirty-nine genes were inhibited and 298 genes were upregulated in the colon by D-hormone treatment of mice with IBD. Of interest was the D-hormone mediated inhibition of 3 tumor necrosis factor-alpha (TNF-alpha, lipopolysaccharide-induced TNF-alpha factor, and TNF receptor) related genes in the colon. It is likely that the effectiveness of D-hormone treatment of experimental autoimmunity is due in part to the inhibition of the TNF family of genes. D-hormone is a selective regulator of the immune system, and the outcome of D-hormone treatment depends on the nature (infectious disease, asthma, autoimmune disease, etc.) of the immune response.
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PMID:D-hormone and the immune system. 1614 46

IDDM results from pancreatic beta cell destruction by islet-reactive T cells, a process that involves beta cell apoptosis. Fas-FasL pathway plays a major role in pancreatic beta cell death. Fas-associated death domain protein (FADD), the component of the tumor necrosis factor receptor type 1 (TNFR1) and Fas signaling complexes, is involved in TNFR1- and Fas-induced apoptosis. Inhibiting the function of FADD will lead to blocking downstream apoptosis signal, which protects pancreatic beta cells from destruction by Fas-FasL pathway. In this study we constructed eukaryotic expressing vector of fusional protein FADDdel-GFP named pFADDdel-GFP. After pFADDdel-GFP was transfected into NIT, the expression of FADDdel-GFP in NIT was detected by fluorescence microscopy and the resistance of NIT transfected with pFADDdel-GFP to cytotoxicity mediated by special T cells was detected by FACS and MTT. The results showed that NIT modified by pFADDdel-GFP obviously resisted cytotoxicity mediated by special T cells. Therefore, it may be useful in the prevention or treatment of IDDM by intervening Fas-FasL pathway.
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PMID:FADDdel-GFP modified mouse insulinoma cells counteract the cytotoxicity of reactive T cells. 1628 99

Apoptotic beta-cell death is central to the pathogenesis of type 1 diabetes and may be important in islet graft rejection. Despite this, genetic control of beta-cell apoptosis is only poorly understood. We report that inhibition of gene transcription sensitized beta-cells to tumor necrosis factor (TNF)-alpha-induced apoptosis, indicating the presence of a regulated antiapoptotic response. Using oligonucleotide microarrays and real-time PCR, we identified TNFAIP3/A20 as the most highly regulated antiapoptotic gene expressed in cytokine-stimulated human and mouse islets. Cytokine induction of A20 mRNA in primary islets and insulinoma cells was rapid and observed within 1 h, consistent with A20 being an immediate early response gene in beta-cells. Regulation of A20 was nuclear factor-kappaB (NF-kappaB)-dependent, two NF-kappaB sites within the A20 promoter were found to be necessary and sufficient for A20 expression in beta-cells. Activation of NF-kappaB by TNF receptor-associated factor (TRAF) 2, TRAF6, NF-kappaB-inducing kinase, or protein kinase D, which transduce signals downstream of Toll-like receptors, TNF receptors, and free radicals, respectively, were all potent activators of the A20 promoter. Moreover, A20 expression was induced in transplanted islets in vivo. Finally, A20 expression was sufficient to protect beta-cells from TNF-induced apoptosis. These data demonstrate that A20 is the cardinal antiapoptotic gene in beta-cells. Further, A20 expression is NF-kappaB dependent, thus linking islet proinflammatory gene responses with protection from apoptosis.
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PMID:Nuclear factor-kappaB regulates beta-cell death: a critical role for A20 in beta-cell protection. 1693 97

TNF-alpha is a pleiotropic cytokine that is constitutively expressed in the thymus. This cytokine has opposing effects on type 1 diabetes mellitus (T1DM) as non-obese diabetic (NOD) mice administered TNF-alpha early in life experience an acceleration in disease onset while TNF-alpha administered to adult NOD mice are rescued from disease entirely. Using fetal thymus organ culture (FTOC) as a model of T cell development and an associated in vitro T1DM model, we set out to reconcile the role of TNF-alpha in thymic development with its role in the pathogenesis of T1DM. Our data indicate that NOD derived FTOC produce a smaller percentage of double negative (CD4(-)/CD8(-)) thymocytes expressing TNF receptors compared to non-diabetic C57BL/6 (B6) derived FTOC. NOD FTOC produce more TNF-alpha than B6 FTOC during days 6-9 of culture, a time when negative selection of T cells is known to occur. Neutralization of this endogenous TNF-alpha production in NOD derived FTOC with soluble TNF receptor (sTNF R1) rescued insulin production in our in vitro T1DM model. Flow cytometric analysis of NOD FTOC treated with recombinant TNF-alpha (rTNF-alpha) or sTNF R1 demonstrated that the relative levels of TNF-alpha in the culture during the selection window (days 6-9) influence the ratio of immature vs. mature T cells that emerge from FTOC.
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PMID:TNF-alpha mediated modulation of T cell development and exacerbation of in vitro T1DM in fetal thymus organ culture. 1771 60


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