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

Interleukin-1 (IL-1), tumor necrosis factor (TNF), and interferon-gamma (IFN gamma) inhibit insulin release and may be cytotoxic to isolated rodent pancreatic islets. In this study we examined the effects of IL-1, TNF, and IFN gamma on the viability and hormone secretion of islets isolated from adult human pancreas and maintained in monolayer culture. IL-1 and TNF were cytotoxic to the islet cells (20-30% cell lysis) in a 51Cr release cytotoxicity assay, and IFN gamma had only small effects (less than 10% lysis). Combination of maximally cytotoxic concentrations of IL-1 (10 U/mL) and TNF (10(3) U/mL) produced an additive cytotoxic effect. IFN gamma (10(3) U/mL) acted synergistically with IL-1 and TNF, and the three cytokines added together produced maximal islet cell lysis (46.4 +/- 4.3%). Assay of insulin and glucagon in the islet monolayers revealed that IL-1, TNF, and IFN gamma inhibited both B- and A-cell secretory functions; however, only IL-1 and TNF produced permanent decreases in insulin and glucagon contents in the islet cultures. These findings indicate that IL-1 and TNF, as single agents, are cytotoxic to human islet cells, and that this cytotoxicity can be amplified by combining the cytokines and/or adding IFN gamma. However, the lack of specificity for B-cells in vitro suggests that additional factors might be operative in vivo for the cytokine products of macrophages and lymphocytes infiltrating islets to produce the B-cell-specific damage characteristic of type 1 diabetes.
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PMID:Cytotoxic effects of cytokines on human pancreatic islet cells in monolayer culture. 211 42

In order to analyze the first steps of T cell activation in type 1 diabetes we studied in vitro IL-2 and gamma-IFN production by peripheral blood mononuclear cells after 24 h PHA stimulation. There was a significant decrease in IL-2 production by mononuclear cells of the diabetic patients with respect to the controls. No significant difference was observed between the diabetic patients and the healthy subjects as regards gamma-IFN production. These observations may be interesting in relation to the pathogenetic mechanisms involved in type 1 diabetes. In particular, normal gamma-IFN production may indicate integrity of the natural killer circuit.
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PMID:Dissociated production of interleukin-2 and immune gamma-interferon by phytohaemoagglutinin stimulated peripheral mononuclear cells in type 1 (insulin-dependent) diabetes. 315 11

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 (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

We report a case of IDDM which occurred during interferon therapy for chronic hepatitis. A 31-year-old man intermittently received 2.5 x 10(8) units of alpha-IFN and 1 x 10(8) units of beta-IFN for treatment of chronic viral hepatitis type B. Four years after the beginning of IFN therapy, he acutely developed moderate hyperglycemia and severe ketonuria with positive islet cell antibody, and then 28 units/day of insulin injection was started. After the start of insulin therapy, there was a remission period for about 3 years but insulin-dependency recurred thereafter. The clinical course of this case indicates that IFN therapy precedes IDDM. During and after IFN therapy we should consider the possibility of occurrence of IDDM as well as other autoimmune diseases and observe the clinical course carefully.
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PMID:Occurrence of IDDM during interferon therapy for chronic viral hepatitis. 801 61

Interferon-alpha (IFN-alpha) is important in the innate immune defense, particularly in viral infections. IFN-alpha induces 2',5'A synthetase, the products of which, 2',5'-oligoadenine nucleotides, activate mRNA degrading enzymes. IFN-alpha is the first detectable cytokine in the insulitis lesion seen in recent-onset IDDM, and insulin promoter directed expression of IFN-alpha in transgenic mice leads to development of IDDM. Here, we demonstrate that IFN-alpha induces 2',5'A synthetase activity only in insulin-producing betaTC3 cells and in isolated single rat beta-cells but not in alphaTC3 cells or in isolated rat non-beta-cells. The increased responsiveness of beta-cells but not non-beta-cells to IFN-alpha with the ensuing activation of the mRNA-degrading 2',5'A synthetase system suggests why only the beta-cells are destroyed in the diabetogenic process.
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PMID:Differential responsiveness to interferon-alpha in beta-cells and non-beta cells. 863 59

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

Development of type 1 insulin-dependent diabetes mellitus has been recently reported in patients who underwent interferon-alpha (IFN-alpha) therapy because of chronic viral hepatitis. Furthermore IFN-alpha seems to be involved in the immunological events that lead to beta-cell destruction and development of type 1 diabetes. To evaluate whether IFN-alpha treatment could elicit an autoimmune response against beta-cell antigens, we determined the occurrence of islet cell antibodies and insulin autoantibodies in the sera of 60 patients with HCV- or HBV-related chronic hepatitis who had been treated with IFN-alpha for 6 or 12 months. The presence of antibodies against thyroglobulin, thyroid microsomal antigen, gastric parietal cells, and non-organ-specific antigens was also investigated. Insulin autoantibody positivity was observed in 2/60 (3.3%), 8/60 (13.3%), and 4/30 (13.3%) patients, before IFN-alpha treatment, and after 6 months and 12 months of therapy, respectively. None of the studied patients developed islet cell antibodies or type 1 diabetes. Before IFN-alpha therapy four patients showed thyroid autoantibodies and four others developed antibodies against thyroglobulin and/or thyroid microsomal antigen during the treatment. Coexistence of insulin autoantibodies and thyroid autoantibodies was observed in only two patients. Our results showed that IFN-alpha therapy in patients with chronic viral hepatitis is capable of inducing development of autoantibodies against insulin. This event seems to be not related to other autoimmune disorders.
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PMID:Interferon-alpha therapy may induce insulin autoantibody development in patients with chronic viral hepatitis. 876

We evaluated the role of the costimulatory molecule B7-1 in overcoming peripheral ignorance in transgenic mice, which expressed the glycoprotein (GP) or nucleoprotein (NP) of lymphocytic choriomeningitis virus (LCMV) as the self-antigen in pancreatic beta cells. The viral transgenes or B7-1 alone did not induce autoimmune diabetes (IDDM). However, in bigenic mice expressing B7-1 and LCMV-GP, anti-self (viral) cytotoxic T lymphocytes (CTL) were activated without viral infection and spontaneous IDDM occurred. In contrast, bigenic RIP-B7-1 x RIP-NP mice with thymic expression of the self (viral-NP) antigen deleted the majority of their autoreactive CTL and did not develop spontaneous IDDM. However, these mice developed fast-onset IDDM 14 days after LCMV infection, whereas single-transgenic RIP-NP littermates developed IDDM only within 4-5 months. Rapid IDDM was associated with increased numbers of anti-self CTL and a predominance of IFN gamma produced by islet-infiltrating lymphocytes, whereas single transgenic RIP-NP littermates with slow-onset IDDM displayed less anti-self CTL and more IL-4- and IL-10-producing T lymphocytes in pancreatic infiltrates.
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PMID:Coexpression of B7-1 and viral ("self") transgenes in pancreatic beta cells can break peripheral ignorance and lead to spontaneous autoimmune diabetes. 877 18


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