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)

Since their demonstration in 1975, ICSAs have been proposed as serological markers and pathogenic elements in IDDM. ICSAs are detected in the sera of most newly diagnosed IDDM patients by indirect IFL that uses viable preparations of rat islet or insulinoma cells as substrate, but they also can be detected by using human insulinoma or fetal islet cells. We have tried to demonstrate ICSAs in the sera of 31 newly diagnosed diabetic patients, including 6 positive samples on human fetal islet cells, which used their natural target for the first time: normal human islet cells. In spite of using different types of preparations of these cells (i.e., freshly dispersed cell suspensions, monolayer cultures, or dispersed islets after culture), ICSAs could not be detected by IFL under the UV microscope, nor by flow cytometry. In contrast, 9 of 29 of the sera gave a positive staining on the RIN rat insulinoma cells. In an attempt to establish whether the putative ICSA autoantigen is present in the surface of human islet cells in the diabetic pancreas, the insulitis microenvironment was emulated by exposing the islets to three types of stress: 1) cytokines (IFN-gamma and TNF-alpha); 2) heat shock; and 3) hyperglycemia. However, diabetic sera failed again to recognize membrane antigens on the islet cells after either of these treatments. Neither were islet cells from a newly diagnosed diabetic patient stained by its autologous serum (ICA titer > 80 JDF U). These results suggest that ICSA autoantigen is not expressed in the membrane of human islet cells and therefore raises doubts about their proposed pathogenic role.
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PMID:Reevaluation of autoantibodies to islet cell membrane in IDDM. Failure to detect islet cell surface antibodies using human islet cells as substrate. 144 4

The role of TNF-alpha and IFN-gamma in various models of autoimmune disease were analyzed. These include murine models of lupus, type 1 diabetes in NOD mice and the adjuvant arthritis model in rats. Rather than being involved mainly in the effector arm of the inflammatory process of autoimmune organ destruction, our data suggest a primary involvement of these cytokines in some of the basic mechanisms of the autoimmune process. Evidence has been presented that emphasizes the possibility of the involvement of TNF-alpha in the genetic predisposition to SLE. Based on the data presented, one should be cautious in extrapolating the effects of these cytokines in various in vitro systems to the in vivo situation.
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PMID:Tumor necrosis factor and interferon gamma: relevance for immune regulation and genetic predisposition to autoimmune disease. 162 86

Pancreatic beta cell destruction in the non-obese diabetic (NOD) mouse is mediated by T lymphocytes and macrophages and accelerated by cyclophosphamide. We purified pancreatic T lymphocytes from the NOD mouse for comparative phenotypic and functional analysis with T lymphocytes from spleen, peripheral blood and regional lymph nodes. Pancreatic T lymphocytes from NOD-Wehi mice, which have an incidence of spontaneous diabetes of less than 5%, had a CD4:CD8 ratio of 1.25 +/- 0.23 compared with 2.44 +/- 0.31 for peripheral blood lymphocytes. After cyclophosphamide, the CD4:CD8 ratio of pancreatic lymphocytes increased to 2.30 +/- 0.24 at day 7. T lymphocytes bearing IL-2 receptors increased two- to three-fold in number and their secretion of GM-CSF/IL-3 and IFN-gamma increased to a maximum on day 7. Pancreatic insulin content and mRNA levels declined sharply between days 10 and 12, at which time the majority of pancreatic T lymphocytes in hyperglycaemic mice were CD8+ (CD4:CD8 ratio 0.63 +/- 0.04 compared to 4.14 +/- 1.05 in peripheral blood). The pancreatic T lymphocyte CD4:CD8 ratio in prediabetic NOD-Lt mice, which have an incidence of spontaneous diabetes of about 60% at 150 days, was similar to that in untreated NOD-Wehi mice, but 25% of their pancreatic CD8 T lymphocytes were IL-2-receptor positive. Thus, significant changes in the phenotype of NOD pancreatic T lymphocytes following cyclophosphamide were not reflected in peripheral blood or spleen T lymphocytes. The earliest change after cyclophosphamide was an increase in activated, predominantly CD4+ T lymphocytes; with the development of beta cell destruction and hyperglycaemia, pancreatic T lymphocytes were, as in human IDDM, predominantly CD8+.
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PMID:Characterization of pancreatic T lymphocytes associated with beta cell destruction in the non-obese diabetic (NOD) mouse. 167 32

In insulin dependent diabetes mellitis (IDDM) beta cell destruction is associated with infiltration of the pancreatic islets by T lymphocytes and macrophages. Cytokine products from the infiltrating immunocytes not only have powerful immunoregulatory actions but also are capable of impairing islet cell functions and have thus been postulated to assume a central role in mediating anti-beta cell immunity and beta cell destruction. In an effort to explore further the role of cytokines in the pathogenesis of IDDM, we examined clinical, metabolic and pathological features of NOD/Wehi mice injected intraperitoneally with multiple doses of IFN-gamma and/or TNF-alpha. Blood glucose profiles were not significantly altered by injection of cytokines alone or in combination. Except for a hypoglycaemic rebound in mice injected with TNF-alpha, arginine stimulation tests revealed no disturbances in islet secretory function in cytokine injected mice. Compared with vehicle and cytokines alone, injection of IFN-gamma + TNF-alpha was associated with a variety of clinical and pathological changes including abdominal distention, piloerection, ascites, oedema, thymic atrophy, splenic enlargement and pancreatic distention. Histological examination of the pancreas in these mice revealed moderate to severe pancreatitis which included focal haemorrhagic necrosis, oedema and polymorphonuclear and mononuclear cell infiltration. The islets in these mice appeared normal morphologically and when stained for insulin. The injection of IFN-gamma + TNF-alpha, and to a lesser extent TNF-alpha alone, was associated with a significant reduction in the severity of insulitis. Examination of pancreatic MHC-class I and class II molecule expression revealed in mice given IFN-gamma + TNF-alpha, as compared with controls, significant and uniform induction of both these molecules on ductal and acinar cells; low level MHC-class II expression was also detectable on beta cells in these mice. MHC-class I molecules which were expressed at high levels by beta cells in control mice did not appear to change following administration of the cytokines alone or in combination. We conclude that despite their immunostimulatory actions in vitro and in other models in vivo, systemic administration of the cytokines IFN-gamma and/or TNF-alpha to NOD/Wehi mice does not activate or enhance, and may actually suppress, anti-beta cell immunity in this model.
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PMID:Reduction in insulitis following administration of IFN-gamma and TNF-alpha in the NOD mouse. 190 36

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

IFN-gamma and TNF-alpha injure the pancreatic beta-cell and may be involved in the pathogenesis of autoimmune type 1 diabetes. Because the induction of IL-6 appears to be an important host cell response to injury, we have examined whether IL-6 is produced by murine pancreatic islets or rat insulinoma (RIN-m5F) cells after their exposure to IFN-gamma and TNF-alpha. Islet culture supernatants contained detectable IL-6 activity which was increased 6-fold when islets were exposed to IFN-gamma and 40- and 115-fold when islets were exposed to TNF-alpha and TNF-alpha + IFN-gamma, respectively. A mAb against murine IL-6 abolished (control and IFN-gamma) or significantly reduced (TNF-alpha and TNF-alpha + IFN-gamma) the IL-6 activity in islet supernatants. The magnitude for the effects of IFN-gamma and TNF-alpha on the production of IL-6 from mouse islets was found to be both time and dose dependent. Northern blot hybridization analysis of islet total cytoplasmic RNA with a cDNA probe to murine IL-6 revealed a band at 1.3 kb, the intensity of which increased in islets exposed to IFN-gamma + TNF-alpha. IL-6 activity was also detected in culture supernatants from RIN-m5F cells exposed to TNF-alpha + IFN-gamma. Islets cultured with rIL-6 secreted higher levels of insulin compared with control islets. Pancreatic islet cells, in all probability beta-cells, produce IL-6, the expression of which is up-regulated by IFN-gamma and/or TNF-alpha. In addition to a possible role in regulating pancreatic beta-cell function we propose that IL-6 produced by the pancreatic beta-cell may act as a costimulator for autoreactive B and T lymphocytes in autoimmune diabetes.
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PMID:Evidence for IL-6 production by and effects on the pancreatic beta-cell. 250 90

Anti-class II ag mAb (DR and DQ) inhibited, in a dose-dependent manner, LPS-induced IL-1 and TNF secretions from human monocytes (34 to 95% inhibition). The potentiating effect of IFN-gamma on LPS-induced TNF secretion (15.3 +/- 0.7 to 44 +/- 0.6 ng/ml) was also blocked by anti-class II ag mAb (44 +/- 0.6 to 0.3 +/- 0.03 ng/ml). We also report a relationship between interindividual differences in monocyte IL-1 and TNF secretions and the HLA-D-encoded genetic polymorphism. Heterozygotes were, in general, higher secretors of those cytokines than homozygotes. Analysis of these secretions in heterozygotes demonstrated a differential effect of certain haplotype combinations (i.e., DR2-DR4 vs DR2-DR3) that could be arbitrarily characterized as being "low" or "high" secretors (6,230 +/- 2,950 vs 13,029 +/- 6,541 cpm for IL-1, and 12 +/- 10 vs 25 +/- 15 ng/ml for TNF, p = 0.006 and 0.048). DR-associated Dw subtypes appeared to account for differences within certain haplotype combinations (Dw18 vs Dw19 in DRw13/DR4) (11,227 +/- 3,648 vs 17,166 +/- 3,176 cpm for IL-1, and 13 +/- 9 vs 25 +/- 10 ng/ml for TNF, p = 0.02 and 0.047). Interindividual differences were better explained by differences in LPS sensitivity than by differences in the kinetics of secretion and related not to the secretory process itself but to the rate of cytokine synthesis. Finally, there were no relationships between high secretor genotypes and IDD high risk genotypes. Thus, we conclude that, a) LPS-induced IL-1 and TNF secretions are, at least in part, regulated by class II MHC molecules, b) that HLA-D region-encoded genetic polymorphism accounts for interindividual differences in these secretions, and c) that the HLA-associated risk to develop IDD is not explained by these cytokine secretory differences as previously proposed.
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PMID:Involvement of class II MHC molecules in the LPS-induction of IL-1/TNF secretions by human monocytes. Quantitative differences at the polymorphic level. 278 51

Acid-stable interferons (IFN-alpha or IFN-beta) are produced by nucleated cells infected by virus, while acid-labile interferon (IFN-gamma) is synthesized by activated T-lymphocytes. IFN-gamma or an atypical form of acid-labile IFN-alpha have been observed in the circulation of some patients with autoimmune disease. It is believed that autoimmunity and/or viral infections are involved in the pathogenesis of insulin dependent diabetes mellitus. We therefore examined the sera of newly diagnosed diabetic children for the presence of virus-induced or acid-labile IFN. Significant IFN levels (greater than or equal to 8 U/ml) were observed in 11 of 29 patients when compared to 31 healthy children in the same age range. The inhibitor is characterized by species specificity, acid-lability and neutralization with anti-serum for IFN-gamma.
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PMID:Evidence of circulating interferon-gamma in newly diagnosed diabetic children. 644 49

Insulin-dependent diabetes mellitus in nonobese diabetic (NOD) mice results from selective destruction of pancreatic islet beta-cells following islet infiltration by mononuclear leukocytes. Cytokines produced by islet-infiltrating mononuclear cells may be involved in beta-cell destruction. Therefore, we analyzed cytokine mRNA expression, by reverse-transcriptase PCR (RT-PCR) assay, in mononuclear leukocytes isolated from pancreatic islets of four groups of mice: diabetes-prone female NOD mice; female NOD mice protected from diabetes by injection of CFA at an early age; male NOD mice with a low diabetes incidence; and female BALB/c mice that do not develop diabetes. We found that mRNA levels of IL-1 beta, IL-2, IL-4, IL-10, and IFN-gamma in mononuclear cells from islets of diabetes-prone female NOD mice increased progressively as these cells infiltrated the islets from age 5 wk to diabetes onset (> 13 wk). However, only IFN-gamma mRNA levels were significantly higher in islet mononuclear cells from 12-wk-old diabetes-prone female NOD mice than from less diabetes-prone NOD mice (CFA-treated females, and males) and normal mice (BALB/c). In contrast, IL-4 mRNA levels were lower in islet mononuclear cells from diabetes-prone female NOD mice than from NOD mice with low diabetes incidence (CFA-treated females and males). Splenic cell mRNA levels of IFN-gamma and IL-4 were not different in the four groups of mice. These results suggest that islet beta-cell destruction and diabetes in female NOD mice are dependent upon intra-islet IFN-gamma production by mononuclear cells, and that CFA-treated female NOD mice and male NOD mice may be protected from diabetes development by down-regulation of IFN-gamma production in the islets.
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PMID:IFN-gamma gene expression in pancreatic islet-infiltrating mononuclear cells correlates with autoimmune diabetes in nonobese diabetic mice. 772 37

Insulin-dependent diabetes mellitus (IDDM), in which only the pancreatic beta cells are destroyed by the autoimmune response, is the paradigm of organ-specific autoimmunity. As a result of a combination of factors, the number of immunohistologic/cellular/molecular studies of pancreas in IDDM is very limited. We report here studies conducted in the pancreata of two IDDM patients: one newly diagnosed (case 1) and one long standing (case 2). In case 1, we demonstrated the presence of morphologically normal viable beta cells without evidence of viral infection. In both cases the expression of the autoantigens defined by islet cell Abs and by glutamic acid decarboxylase was markedly reduced in the islet cells whereas expression of hsp60, another putative autoantigen, was normal. Over-expression of HLA class I was detected in 58% of the islets in pancreatic sections and in cultured beta cells in case 1 and also in 30% of islets in case 2 but it was not restricted to any insular cell type. In case 1, there was "inappropriate" HLA class II expression in islets cells but it was a rare finding and not beta cell specific. The analysis of the correlation between class I overexpression, residual insulin, and insulitis suggests that the first event is the increase of HLA class I expression. Of adhesion molecules, ICAM-1, VLA, VCAM, and LFA-3 were normal and only ICAM-1 was moderately overexpressed in and around the islets of case 1 insulitis, as was detected by immunofluorescence which showed that 18% of the islets of case 1 had CD8+ lymphocytes as the predominant population. Reverse transcription-PCR demonstrated moderate V beta skewing and the profile of cytokines expected in CTLs: IL-2, IL-4, IL-10, and IFN-gamma negative, perforin positive. In addition, IFN-alpha, IFN-beta, and IL-6 transcripts were detected in the case 1 pancreas, consistent with the existence of a silent viral infection. Overall, the results indicated that, differently from spontaneous animal models of diabetes, in the pancreas of IDDM patients there are no elements of the inductive phase of the autoimmune response.
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PMID:Pancreas in recent onset insulin-dependent diabetes mellitus. Changes in HLA, adhesion molecules and autoantigens, restricted T cell receptor V beta usage, and cytokine profile. 791 15


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