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)

To examine humoral and mucosal immune responses to food antigens and their relation to the pathophysiology of type 1 diabetes mellitus, IgA and IgG antibodies to cow's milk antigens (bovine serum albumin (BSA) and beta-lactoglobulin (BLG)) and another food antigen (ovalbumin, (OVA)) in human serum were assessed by enzyme-linked immunosorbent assay (ELISA). If anti-idiotype antibodies to the antibodies were present in serum, they might interfere with the ELISA assay, so suitable microtiter plates were employed to minimize such interference. The levels of IgA and IgG antibodies to the above antigens (P<0.001-P<0.01) and the prevalence of positive sera (P<0.001-P<0.05) in the patient group (n=52, aged 14.5+/-4.1 (S.D.) years) were significantly higher than those in the control group (n=41, aged 13.3+/-6.8 (S.D.) years). Interestingly, the levels of IgA antibodies to all the food antigens examined were elevated in 26 (50%) patients, while the elevation was seen in 3 (7%) healthy controls. The elevation of IgA antibodies in the patients was well correlated with increased concentrations of IgA and transforming growth factor (TGF)-beta, which induces IgA-producing B-cells, in serum. Although the cytokine TGF-beta is secreted from regulatory T-cells (Th3), and is related to oral tolerance, the interleukin-2 (IL-2, Th1)/IL-4 (Th2) ratio in the patient group was significantly elevated (P<0.001), which might indicate that the oral tolerance is impaired in patients. Thus, we demonstrated that both IgA and IgG antibodies to several food antigens are elevated in patients. We suggest that impairment of oral tolerance might be related to the pathogenesis of type 1 diabetes mellitus.
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PMID:Antibodies to food antigens in Japanese patients with type 1 diabetes mellitus. 1175 73

Recently, a newly identified human HERV-K18 like endogenous retrovirus (IDDMK(1,2)22) has been associated to the etiology of type I diabetes (IDDM). Although the exact mechanism remains unclear, it was postulated that the 3' end ORF product of the env gene of IDDMK(1,2)22 would trigger a V beta 7-specific human T cell expansion leading to their infiltration in the pancreas of afflicted patients and to the autoimmune destruction of the insulin-producing beta cells. Since then, such superantigen (SAg)-like activity as well as the association between the IDDMK(1,2)22 virus and IDDM pathogenesis have been challenged. To further characterize functionally the putative IDDMK(1,2)22-encoded SAg, we have cloned from human DNA the identical 462bp ORF sequence originally described. The IDDMK(1,2)22 ORF fragment was transfected in the same human B cell line (Raji) originally used as APC to demonstrate the V beta 7 specificity. The immunostimulatory potential of IDDM ORF was tested on murine T cell hybridomas and compared to the well-characterized mouse mammary tumor virus Mtv7 SAg transfected in the same conditions. A panel of 16 T cell hybridomas encompassing 14 different V betas was analyzed. We have failed to detect IDDMK(1,2)22-induced IL-2 production from any of these hybridomas, even those bearing the murine V beta 1 mV beta 1, V beta 4 or V beta 10 TcR beta chains which are most closely related to the human V beta 7 (hV beta 7). Our results suggest that IDDMK(1,2)22 ORF is devoid of superantigenic activity as defined by classical criteria.
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PMID:Human endogenous retrovirus IDDMK(1,2)22 and mouse mammary tumor virus superantigens differ in their ability to stimulate murine T cell hybridomas. 1184 50

In human type 1 diabetes (T1D) autoantibodies to insulin precede clinical disease, while little is known about the contribution of insulin-specific T lymphocytes-in particular, T helper (Th) subsets. Here we have studied the in vivo primed cytokine response to preproinsulin in peripheral blood mononuclear cells (PBMCs) and two major Th cell subsets-CD45RO+ memory cells and CD45RA+ naive/resting cells-in 35 individuals with HLA-DRB1*04, DQB1*0302 diabetes risk marker: 12 patients with T1D, 12 autoantibody-positive (Ab+) individuals, and 11 healthy controls. Cytokine secretion (TNF-alpha, IFN-gamma, IL-2, IL-4, IL-5, and IL-10) was measured in the supernatants of the cultures stimulated with 21 overlapping preproinsulin peptides as well as proinsulin and insulin. In Ab+ individuals our results reveal higher IL-4 levels in CD45RO+ memory cells and higher IL-5 levels in CD45RA+ naive/resting cells, while higher IL-2 production was found in PBMCs. In contrast, in PBMCs of T1D patients higher IFN-gamma and IL-10 secretion was found. Our data delineate characteristic cytokine patterns in peripheral T lymphocytes from patients at different stages of the T1D development.
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PMID:Th2 dominance of T helper cell response to preproinsulin in individuals with preclinical type 1 diabetes. 1202 Nov 8

Cytokines released from activated antigen-presenting cells and T-lymphocytes are crucially involved in the pathogenesis of type 1 diabetes. Previous studies have shown that proinflammatory cytokines play an important role in the induction of autoimmunity and beta-cell damage. Inhibition of insulin expression has been described, but their effects on other major target autoantigens, such as the tyrosine phosphatase-like protein IA-2, is not known. In the present study, we established sensitive real-time RT-PCR to measure IA-2, insulin, and inducible nitric oxide (NO) synthase (iNOS) mRNA expression. Rat insulinoma INS-1 cells were stimulated with IL-1beta, TNF-alpha, interferon (IFN)-gamma, and IL-2 as well as with two combinations of these cytokines (C1: IL-1beta + TNF-alpha + IFN-gamma; C2: TNF-alpha + IFN-gamma). Treatment with IL-1beta, TNF-alpha, or IFN-gamma alone caused a significant down-regulation of IA-2 and insulin mRNA levels in a time and dose-dependent manner, whereas IL-2 had no effect. Exposure to cytokine combinations strongly potentiates the inhibitory effects. Incubation of cells with C1 and C2 for 24 h induces a significant inhibition of IA-2 mRNA levels by 78% and 58%, respectively. Under these conditions, an up to 5 x 10(4)-fold increase of iNOS gene expression was observed. The hypothesis that the formation of NO is involved in IA-2 regulation was confirmed by the finding that the coincubation of C1 with 4 mM L-N(G)-monomethyL-L-arginine, an inhibitor of the iNOS, partly reversed the down-regulation of IA-2. Further, incubation with the synthetic NO-donor S-nitroso-N-acetyl-D-L-penicillamine significantly decreased IA-2 mRNA level to 51% of basal levels. In conclusion, we have demonstrated for the first time that IL-1beta, TNF-alpha, and IFN-gamma exert a strong inhibitory effect on expression of the diabetes autoantigen IA-2. The action of IL-1beta may be partly mediated by the activation of the NO pathway.
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PMID:Effect of proinflammatory cytokines on gene expression of the diabetes-associated autoantigen IA-2 in INS-1 cells. 1223 95

We have proposed a unifying hypothesis of the etiopathogenesis of autoimmunity that defines autoimmunity as a type I interferon (IFN) immunodeficiency syndrome. We have examined toxicity and potential efficacy in three phase I (type 1 diabetes, rheumatoid arthritis, multiple sclerosis) and one phase II clinical trials in multiple sclerosis. In a phase I open-label trial in type 1 diabetes, ingested IFN-alpha preserved residual beta-cell function in recent onset patients. In a second phase I trial, treatment of rheumatoid arthritis with ingested IFN-alpha reduced the secretion of interleukin (IL)-1, a pro-inflammatory cytokine. In a third phase I trial in multiple sclerosis, there was a significant decrease in peripheral blood mononuclear cell IL-2 and IFN-gamma production after ingesting IFN-alpha. In a phase II randomized, placebo-controlled, double-blind trial in multiple sclerosis, 10,000 IU ingested IFN-alpha significantly decreased gadolinium enhancements compared with the placebo group at month 5. Tumor necrosis factor-alpha and IFN-gamma cytokine secretion in the 10,000 IU group at month 5 showed a significant decrease that corresponded with the effect of ingested IFN-alpha on decreasing gadolinium enhancements. Ingested IFN-alpha was not toxic in any of these clinical trials. These studies suggest that ingested IFN-alpha may have a potential role in the treatment of autoimmunity.
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PMID:Ingested type I interferon: state of the art as treatment for autoimmunity. 1248 7

We have proposed a unifying hypothesis of the etiopathogenesis of autoimmunity that defines autoimmunity as a type I interferon (IFN) immunodeficiency syndrome. We have examined toxicity and potential efficacy in three phase I (type 1 diabetes, rheumatoid arthritis, multiple sclerosis) and one phase II clinical trials in multiple sclerosis (MS). In a phase I open-label trial in type 1 diabetes, ingested IFN-alpha preserved residual beta cell function in recent onset patients. In a second phase I trial, treatment of rheumatoid arthritis (RA) with ingested IFN-alpha reduced the secretion of interleukin-1 (IL-1), a proinflammatory cytokine. In a third phase I trial in MS, there was a significant decrease in peripheral blood mononuclear cell (PBMC) IL-2 and IFN-gamma production after ingesting IFN-alpha. In a phase II randomized, placebo-controlled, double-blind trial in MS, 10,000 IU ingested IFN-alpha significantly decreased gadolinium enhancements compared with the placebo group at month 5. Tumor necrosis factor-alpha (TNF-alpha) and IFN-gamma cytokine secretion in the 10,000 IU group at month 5 showed a significant decrease that corresponded with the effect of ingested IFN-alpha on decreasing gadolinium enhancements. Ingested IFN-alpha was not toxic in any of these clinical trials. These studies suggest that ingested IFN-alpha may have a potential role in the treatment of autoimmunity.
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PMID:Ingested type I interferon: a potential treatment for autoimmunity. 1258 87

Type 1 diabetes mellitus (DM) develops as a result of autoimmune destruction of the pancreatic beta-cells. The aim of this study was to explore possible associations between serum levels of cytokines, IL-1, IL-2, TNFalpha and INFgamma and metabolic parameters in children with type 1 DM and their non-diabetic siblings to determine whether these cytokines could be indicators of disordered immune regulation. The study population consisted of 41 children with type 1 DM, 32 non-diabetic siblings, and 28 healthy controls. Children with DM were divided into three subgroups: 1) newly diagnosed patients with diabetic ketoacidosis (ND + DKA), 2) newly diagnosed patients without DKA (ND - DKA), and 3) previously diagnosed patients (PD). The highest serum IL-1alpha level was found in the ND - DKA group, which was significant compared to both the ND + DKA (p < 0.05) and the siblings (S) (p < 0.005). IL-2 levels were similar among all groups. The highest TNFalpha level was observed in the ND + DKA group, which was significant against the ND - DKA (p < 0.05), PD (p < 0.001), S (p < 0.05), and control (C) (p < 0.005) groups. TNFalpha concentration in the PD group was significantly lower than those of S (p< 0.005) and C (p < 0.001) groups. The ND - DKA group had the highest INFgamma and this was statistically significant when compared with the S (p < 0.005) and C (p < 0.05) groups. Both the newly diabetics and all diabetics as a group had statistically significantly higher INFgamma levels than both the S (p < 0.01 for both) and C (p < 0.05 for both) groups. In the diabetics as a whole group, TNFalpha showed correlations with INFgamma (r = 0.370, p < 0.05). IL-1 showed correlation with TNFalpha (r = 0.368, p < 0.05) INFgamma (r = 0.796, p < 0.001) and IL-2 (r = 0.862, p < 0.001) in the all diabetics group. IL-2 was correlated with TNFalpha (r = 0.320, p < 0.05) and INFgamma (r = 0.754, p < 0.01) in the all diabetics group. In conclusion, our results suggest that proinflammatory cytokines TNFalpha, INFgamma, IL-1alpha and IL-2 may play important roles alone or in combination in the pathogenesis of type 1 diabetes mellitus.
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PMID:Serum IL-1, IL-2, TNFalpha and INFgamma levels of patients with type 1 diabetes mellitus and their siblings. 1271 58

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is expressed in different tissues and cells, including pancreas and lymphocytes, and can induce apoptosis in various tumor cells but not in most normal cells. The specific roles of TRAIL in health and disease remain unclear. Here we show by cDNA array analyses that TRAIL gene expression is upregulated in pancreatic islets during the development of autoimmune type 1 diabetes in nonobese diabetic (NOD) mice and in Min6 islet beta-cells activated by TNF-alpha + interferon-gamma. However, stimulation of freshly isolated pancreatic islets or Min6 cells with TRAIL did not induce their apoptosis. TRAIL blockade exacerbates the onset of type 1 diabetes in NOD.Scid recipients of transferred diabetogenic T-cells and in cyclophosphamide-treated NOD mice. TRAIL inhibits the proliferation of NOD diabetogenic T-cells by suppressing interleukin (IL)-2 production and cell cycle progression, and this inhibition can be rescued in the presence of exogenous IL-2. cDNA array and Western blot analyses indicate that TRAIL upregulates the expression of the cdk inhibitor p27(kip1). Our data suggest that TRAIL is an important immune regulator of the development of type 1 diabetes.
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PMID:Blockade of tumor necrosis factor-related apoptosis-inducing ligand exacerbates type 1 diabetes in NOD mice. 1288 12

Involvement of gut immune system has been implicated in the pathogenesis of type 1 diabetes. However, few studies have been performed on the gut mucosa from patients with type 1 diabetes. Thus, we characterized the stage of immune activation in jejunal biopsy samples from 31 children with type 1 diabetes by immunohistochemistry, in situ hybridization, and RT-PCR. We found enhanced expressions of HLA-DR, HLA-DP, and intercellular adhesion molecule-1 by immunohistochemistry even on structurally normal intestine of patients with type 1 diabetes and no signs of celiac disease. In addition, the densities of IL-1 alpha- and IL-4-positive cells detected by immunohistochemistry and IL-4 mRNA-expressing cells evaluated by in situ hybridization were increased in the lamina propria in patients with type 1 diabetes and normal mucosa. Instead, the densities of IL-2, gamma-interferon (IFN-gamma), and tumor necrosis factor alpha-positive cells, the density of IFN-gamma mRNA positive cells, and the amounts of IFN-gamma mRNA detected by RT-PCR correlated with the degree of celiac disease in patients with type 1 diabetes. Our study supports the hypothesis that a link exists between the gut immune system and type 1 diabetes.
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PMID:Immunologic activity in the small intestinal mucosa of pediatric patients with type 1 diabetes. 1294 68

Genetic association with type 1 diabetes (T1D) has been established for two chromosomal regions: HLA DQ/DR (IDDM1) and INS VNTR (IDDM2). To identify additional genetic markers, we tested polymorphisms in regulatory regions of several cytokine and important metabolic genes. These polymorphisms exhibit functional consequences for expression and function. Functional genetic polymorphisms of proinflammatory (T-helper-1: IL-2, IL-12 and IFN-gamma), anti-inflammatory (T-helper-2: IL-4, IL-6 and IL-10) and metabolic (IGF-I, VDR and INS) genes were determined in 206 Dutch simplex families with juvenile onset T1D and the results were analysed using the transmission disequilibrium test. Significantly increased transmission to T1D probands was observed for the loci IDDM1, IDDM2 and the vitamin D receptor. Although none of the other individual polymorphisms was associated with disease individually, the combination of T-helper-2 and metabolic/growth alleles IL-10(*)R2, IL-4(*)C, VDR(*)C and IGF-I(*)wt was found to be transmitted more frequently than expected (67%, P(c)=0.015). We conclude that additional genetic predisposition to T1D is defined by combinations of markers (eg Th2 and metabolic) rather than by a single marker. The consequences of the increased transmission of a low Th2 expressing genotypes together with a normal Th1 profile may result in a net proinflammatory cytokine expression pattern.
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PMID:Functional genetic polymorphisms in cytokines and metabolic genes as additional genetic markers for susceptibility to develop type 1 diabetes. 1473 47


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