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)

Tumor necrosis factor beta (TNF-beta) (lymphotoxin) may play an important role in the immune response and pathologic inflammatory diseases. Insulitis is an important early step in the development of insulin-dependent diabetes mellitus. To understand better the role of TNF-beta in the regulation of inflammation and type 1 diabetes, we produced transgenic mice in which the murine TNF-beta gene was regulated by the rat insulin II promoter. The transgene was expressed in the pancreas, kidney, and skin of transgenic mice. The expression of TNF-beta in the pancreas of transgenic mice resulted in a leukocytic inflammatory infiltrate consisting primarily of B220+ IgM+ B cells and CD4+ and CD8+ T cells. The insulitis is reminiscent of the early stages of diabetes, though the mice did not progress to diabetes.
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PMID:Insulitis in transgenic mice expressing tumor necrosis factor beta (lymphotoxin) in the pancreas. 127 67

HLA antigens have been shown to be associated with several immunoinflammatory diseases. The mechanisms by which these antigens confer susceptibility to disease continue to be of major interest. Rapid progress has been made in the elucidation of the structure and function of class I and II MHC molecules, and several genes located within the HLA complex have been identified which are potentially involved in immunologic processes. Because of the HLA localization of the TNF-alpha and -beta genes and the biologic activities of the gene products, recent investigation has focused on a possible role of polymorphic TNF genes in the pathogenesis of HLA-associated diseases. Allelic variations have only been detected in the TNF-beta gene. No evidence has been found so far that a particular TNF-beta allele contributes significantly in the susceptibility to the diseases studied. Although it has been postulated that the TNF beta*2 allele contributes to susceptibility to IDDM in HLA-DR3, 4 heterozygous individuals, a larger group of HLA-typed patients and controls is needed to provide more conclusive evidence for this hypothesis. The increasing number of genes of unknown function encoded by the class III region leaves the possibility that the observed HLA associations in some diseases may be related to the presence of these genes. In AS, the lack of association with the TNF-beta alleles furthermore supports the function of the HLA-B27 molecule in the disease and underlines the improbability that HLA-B27 is merely a marker for a closely linked susceptibility gene.
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PMID:Polymorphism of the tumor necrosis factor region in relation to disease: an overview. 134 86

The genes located between class II and class I HLA genes including polymorphic tumour necrosis factor (TNF) genes may contribute to the disease susceptibility in IDDM. Restriction fragment polymorphisms of the TNF-beta gene have been found to be fixed in the major IDDM susceptibility haplotypes, the B62,DR4 haplotype being associated with the 10.5-kb fragment and the B8,DR3 haplotype with a 5.5-kb fragment. We studied this TNF polymorphism in a sample of diabetic families. In all IDDM-associated haplotypes (n = 129) the 5.5-kb allele was more frequent than in haplotypes found only in healthy family members (n = 112) (58.1% versus 40.2%, P < 0.01). Among IDDM haplotypes the B62,DR4 haplotype was characterized by the 10.5-kb TNF fragment, whereas two other common Finnish IDDM-associated DR4 haplotypes--A24,B39,DR4 and A2,B56,DR4--had the 5.5-kb TNF fragment. Both IDDM-associated and non-associated DR3 positive haplotypes were linked to the 5.5-kb fragment. The distribution of various combinations of TNF alleles in IDDM probands (n = 63) did not differ from that expected according to the Hardy-Weinberg distribution. Our results indicate that the 10.5-kb allele of TNF-beta gene as such is not a risk factor contributing to DR4/DQ8-associated susceptibility. Alternatively, there may be heterogeneity in pathogenetic effector mechanisms.
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PMID:Tumour necrosis factor-beta gene RFLP alleles in Finnish IDDM haplotypes. The Childhood Diabetes in Finland (DiMe) Study Group. 136 Oct 76

Tumour necrosis factors alpha and beta (TNF-alpha and TNF-beta) and gamma interferon (IFN-gamma) were measured by ELISA in the supernatants of phytohaemagglutinin (PHA)-activated peripheral blood mononuclear cells (PBMNC) from 98 individuals (60 controls and 38 patients with insulin-dependent diabetes mellitus [IDDM]). The PBMNC were incubated with varying concentrations of PHA (0, 1, 5, and 10 micrograms/ml) for 72 h. In our population study we observed a correlation between the levels of secretion of TNF-alpha and IFN-gamma but not TNF-beta. The complete data set was analysed by non-parametric tests, and no associations with HLA phenotypes existed. Reduced levels of TNF-beta, but not TNF-alpha or IFN-gamma, secretion were found in IDDM patients stimulated with 1 and 5 micrograms/ml of PHA (P = 0.001 and 0.02 respectively). None of the lymphokine secretion levels at any PHA concentration correlated with particular HLA phenotypes. Analysis of the natural log-transformed data indicated that only for the TNF-beta levels (at 5 micrograms/ml PHA) could subjects be divided into high and low secretors, which also did not correlate with a particular HLA-B or -DR antigen.
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PMID:The effect of HLA and insulin-dependent diabetes mellitus on the secretion levels of tumour necrosis factors alpha and beta and gamma interferon. 212 64

The inappropriate expression of HLA Class II molecules by the target cells of endocrine autoimmune diseases is a recent observation that has been intensively studied in thyroid autoimmunity and type I diabetes mellitus. In vitro studies have shown that interferon-gamma can induce Class II expression, either alone, as in thyrocytes, or in combination with other mediators like tumour necrosis factor or lymphotoxin, as in islet cells, pointing to possible mechanisms operating in vivo. Endocrine cells expressing Class II molecules are able to present their autoantigens to helper T cells, thus possibly inducing the autoimmune process. However, until now it is still unclear if the expression of Class II molecules by the target cells is the primary immune phenomenon, which might possibly be triggered by a latent viral infection of the endocrine cell. Alternatively, it might be a secondary response in an ongoing autoimmune process. Particularly data obtained in the diabetic pancreas favour the first possibility, but only progress in our understanding of the role of HLA antigens in immunoregulation will make it possible to interpret the phenomenon properly.
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PMID:[Recent aspects of the pathogenesis of endocrine autoimmune diseases in the human: what role does expression of class II HLA molecules in the endocrine target cell play?]. 268 54

The genes encoding tumour necrosis factors (TNF) are located within the major histocompatibility complex. Since TNF may be involved in the pathogenesis of autoimmune disease the purpose of the present study was to investigate TNF beta gene polymorphism in two types of immune complex mediated glomerulonephritis, IgA nephropathy (IgAN) and idiopathic membranous glomerulonephritis (IMN) and to compare them with IDDM and healthy controls. DNA was studied by Southern-blot hybridisation methods using Nco I digestion and a TNF beta probe; two alleles were detected size 5.5 kb and 10.5 kb. In healthy controls (n = 107), 9% were 5.5 homozygotes, 47% heterozygotes and 44% 10.5 homozygotes. The corresponding figures in IMN (n = 51) were 21.5%, 61% and 17.5% (p = 0.002), in IDDM (n = 42) 24%, 50% and 26% (p = 0.027) and in IgAN (n = 77) 2.5%, 65% and 32.5% (p = 0.025). The increase in 5.5 homozygotes in both IMN and IDDM was found to be due to an increased frequency of the haplotype A1-B8-TNF beta 5.5-DR3 seen in both these diseases; whereas in IgAN the increased frequency of the 10.5 kb allele can be explained by an association of a Taq 1DQB1-T2 allele with the TNF beta 10.5 allele. These results demonstrate an association of TNF beta gene polymorphism with IMN and IgAN and confirm the associations found in IDDM. Although these disease associations can be explained by linkage disequilibrium with extended MHC haplotypes, a direct role of genetically determined TNF production in the etiology of these diseases remains to be excluded.
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PMID:Autoimmune renal disease and tumour necrosis factor beta gene polymorphism. 822 74

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease in which cytokines are thought to play an important role in beta-cell destruction and immune regulation. A major target of beta-cell autoimmunity in IDDM is the enzyme glutamate decarboxylase (GAD). We hypothesized that cytokines in the insulitis lesion modulate the synthesis of GAD. This may, in turn, modify the rate of beta-cell destruction. Accordingly we cultured rat islets in the presence and absence of cytokines, and measured synthesis of both isoforms of GAD, GAD65 and GAD67, by [35S]methionine incorporation and immunoprecipitation with a rabbit antiserum that recognizes both GAD65 and GAD67. Incubation of islets with interleukin (IL)-1 beta (1 ng/ml, 24 h), tumour necrosis factor alpha (TNF-alpha; 200 units/ml, 24 h) or interferon gamma (IFN-gamma; 500 units/ml, 72 h) significantly decreased the synthesis of both GAD65 and GAD67, but reduced neither total protein synthesis nor insulin accumulation in the medium or content. Incubation of islets for 24 h in IFN-alpha (1000 units/ml), TNF-beta (50 ng/ml), IL 2 (1000 units/ml), IL-4 (100 ng/ml), IL-6 (10 ng/ml), IL-10 (20 ng/ml), IL-12 (10 ng/ml) or transforming growth factor beta 2 (TGF-beta 2; 5 ng/ml) did not significantly alter GAD65 or GAD67 synthesis. Inhibition of GAD65 and GAD67 protein synthesis by IL-1 beta, TNF-alpha or IFN-gamma was reversed by co-incubation with the nitric oxide synthase inhibitor, NG-monomethyl arginine (NMMA). Expression of both GAD65 and GAD67 mRNA, measured by RNase protection assay, was also decreased by IL-1 beta and completely restored to baseline levels by NMMA. Thus the synthesis of both isoforms of islet GAD is selectively decreased in the presence of IL-1 beta, TNF-alpha or IFN-gamma by a NO-mediated mechanism, probably at the level of cytokine gene transcription. As GAD autoimmunity has been previously shown to have a pathogenic role in an animal model of IDDM, its inhibition by cytokines might limit the immune response, thereby regulating the rate of beta-cell destruction in IDDM.
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PMID:Cytokine regulation of glutamate decarboxylase biosynthesis in isolated rat islets of Langerhans. 876 Mar 54

The TNF region within the MHC includes a number of immunologically important genes. Microsatellites TNFa and TNFb adjacent to TNF exhibit extensive polymorphism. Employing a PCR-based technique, we identified TNFab haplotypes and defined their distribution in 97 controls and 48 diabetics of Caucasoid origin in a search for other genes within the MHC potentially associated with IDDM. Twenty-five different TNFab haplotypes were identified. A significant difference (p < 0.0005) in frequency between patients and controls was found for TNFa1b5 (relative risk 53). However, no other TNFab microsatellites demonstrated significantly different frequencies. Among diabetics TNFa1b5 was found to be in linkage disequilibrium with HLA-DR3-B18, a haplotype known to be associated with IDDM. Thus the increased frequency of TNFa1b5 among diabetics could reflect a linkage disequilibrium with a gene within the TNF region or with other genes, including the HLAs, which characterize this haplotype. In both controls and diabetics TNFa2b3 and TNFa7b4 were in linkage disequilibrium with DR3-B8 and DR7, respectively. Among diabetics, TNFa2b1 and TNFa6b5 were in linkage disequilibrium with DR4-B62 and DR4-B44, respectively. It is intriguing that TNFab haplotypes, represented by a short piece of about 200 nucleotides in the untranslated region upstream of TNF beta gene, maintain strong linkage disequilibria with different HLA haplotypes extending over 1 million base pairs. The identification of TNFab microsatellites exhibiting a high polymorphic index in a region lacking known polymorphic markers may provide potentially important information regarding the association of HLA haplotypes with autoimmune diseases, as they are in close proximity to other genes of immunologic importance.
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PMID:Genetic polymorphism of the human tumor necrosis factor region in insulin-dependent diabetes mellitus. Linkage disequilibrium of TNFab microsatellite alleles with HLA haplotypes. 884 31

In IDDM an association between diabetic retinopathy and polymorphic markers of MHC has been described. However, these associations are complicated by a primary association between the MHC and IDDM. Because the pathogenesis of retinopathy is likely to be the same in IDDM and NIDDM, NIDDM subjects with retinopathy would be the ideal population to study for an association with MHC markers. The following South Indian subjects were therefore studied: unselected NIDDM (n = 76), unselected IDDM (n = 99), non-diabetic controls (n = 96), NIDDM subjects with maculopathy (MAC), n = 55, NIDDM subjects with proliferative retinopathy (PR), n = 53, and without retinopathy (LTD), n = 46. DNA was amplified and studied using a microsatellite polymorphism located 3.5 kb upstream of TNF-beta within the MHC class III region on the short arm of chromosome 6. No differences in allelic distribution were observed between the random NIDDM subjects and controls (p = 0.17). Differences in allelic distribution were found between unselected IDDM and controls (P = 0.016) and between the NIDDM subjects with maculopathy and/or proliferative retinopathy and no retinopathy (P = 0.006). This association could be accounted for by those patients with proliferative retinopathy (MAC vs LTD, p = 0.23; MAC vs PR, p = 0.07; and PR vs LTD, p = 0.002).
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PMID:An association in non-insulin-dependent diabetes mellitus subjects between susceptibility to retinopathy and tumor necrosis factor polymorphism. 915 89

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


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