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) is viewed as a thymus-dependent autoimmune disease, although the specific beta-cell autoantigen or autoantigens remain unknown. The recent identification of the beta-cell 64K antigen as the enzyme glutamic acid decarboxylase (GAD) permits investigation of GAD as a candidate for the autoantigen associated with beta-cell destruction, mediated by T-lymphocytes, in susceptible individuals. In this study, we describe the isolation of GAD-specific T-lymphocyte lines from BB rats, an animal model of IDDM. GAD (Escherichia coli) was inoculated into the footpads of diabetes-resistant BB rats, and after 10 days, a popliteal lymph node cell culture suspension was prepared. GAD-specific T lymphocytes were obtained by culture with interleukin 2 and repeated stimulation with GAD in the presence of BB rat thymic antigen-presenting cells. Four stable, CD4+, MHC (RT1u)-restricted T-lymphocyte lines were isolated. They proliferate selectively in the presence of GAD and secrete interleukin 2 and interferon-gamma. T-lymphocyte lines such as these could be important in the definition of pathogenetic epitopes associated with GAD.
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PMID:T-lymphocyte lines specific for glutamic acid decarboxylase (GAD) the 64K beta-cell antigen of IDDM. 172 31

Production of and response to interleukin 2 (IL-2) were studied using peripheral blood mononuclear cells (PBMC) from 23 patients with type 1 diabetes. When compared to PBMC from 18 control subjects, mean PHA-stimulated IL-2 synthesis in the diabetic group was found unimpaired (1.2 +/- 0.1 vs 1.5 +/- 0.2 U/ml). However, 3 subgroups could be distinguished with regard to IL-2 synthesis: IL-2 production was significantly increased in 5 patients and decreased in 2 patients, while the remaining 16 diabetics produced normal levels of IL-2. The diabetic group displayed a curve of PBMC proliferation in response to a range of recombinant IL-2 which was not significantly altered. However, an abnormally high blastogenic response was detected in 5 patients, correlating to an increased percentage of Ia-bearing T lymphocytes, while a markedly low response was seen in 2 other patients. These alterations of the IL-2 system could be related duration of diabetes. Indeed, high synthesis of IL-2 was more frequent in patients with long-standing disease than in recent onset diabetics: 44% and 7%, respectively. Conversely, increased response to IL-2 was found more often in the latter group than in the former (28% vs 11%) while decreased sensitivity was seen only in the latter group (14%). No correlations were found between these results and basal or glucagon-stimulated C peptide levels, percent of glycosylated hemoglobin, presence of autoantibodies, lymphocyte subsets, or HLA typing.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Production of and response to interleukin 2 by blood mononuclear cells from some type 1 diabetic patients. 349 40

Blood T-cells from 28 patients with type I (insulin-dependent) diabetes (IDDM) of variable duration were examined for the Tac antigen by immunofluorescence, and for proliferation in the presence of interleukin 2 (IL 2). The mean percentage of Tac+ cells in patients whose IDDM was of less than 2-yr duration was 6.2% compared with 2% in patients whose IDDM was of 3 or more years' duration, or in healthy controls. The percentage of Tac+ cells in the patients' blood correlated positively with the amount of thymidine uptake in a 24-h culture of blood mononuclear cells and with the percentage of T-cell blasts generated in a 6-day culture. The patients' T-cell blasts stained with OKT 4 or OKT 8, suggesting that each of these subsets is present in the activated T-cell population in the patients' blood. The T-cell blasts did not show specificity for pork insulin in an antigen restimulation assay. There was no correlation between increased Tac+ cells and the presence or absence of islet cell antibodies. If T-cell activation in IDDM occurs as a result of recognition of islet cell antigens, our results suggest that both HLA-DR-restricted (OKT 4+) and A-, B-, and C-restricted (OKT 8+) T-cell subsets contribute.
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PMID:Culture and phenotype of activated T-cells from patients with type I diabetes mellitus. 636 90

Insulin-dependent diabetes mellitus (IDDM) is a disease that results from autoimmune destruction of the insulin-producing beta-cells in the pancreatic islets of Langerhans. The autoimmune response against islet beta-cells is believed to result from a disorder of immunoregulation. According to this concept, a T helper 1 (Th1) subset of T cells and their cytokine products, i.e. Type 1 cytokines--interleukin 2 (IL-2), interferon gamma (IFNgamma), and tumor necrosis factor beta (TNFbeta), dominate over an immunoregulatory (suppressor) Th2 subset of T cells and their cytokine products, i.e. Type 2 cytokines--IL-4 and IL-10. This allows Type 1 cytokines to initiate a cascade of immune/inflammatory processes in the islet (insulitis), culminating in beta-cell destruction. Type 1 cytokines activate (1) cytotoxic T cells that interact specifically with beta-cells and destroy them, and (2) macrophages to produce proinflammatory cytokines (IL-1 and TNFalpha), and oxygen and nitrogen free radicals that are highly toxic to islet beta-cells. Furthermore, the cytokines IL-1, TNFalpha, and IFNgamma are cytotoxic to beta-cells, in large part by inducing the formation of oxygen free radicals, nitric oxide, and peroxynitrite in the beta-cells themselves. Therefore, it would appear that prevention of islet beta-cell destruction and IDDM should be aimed at stimulating the production and/or action of Type 2 cytokines, inhibiting the production and/or action of Type 1 cytokines, and inhibiting the production and/or action of oxygen and nitrogen free radicals in the pancreatic islets.
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PMID:Cytokines and their roles in pancreatic islet beta-cell destruction and insulin-dependent diabetes mellitus. 971 67

Type 1 diabetes in the NOD mouse is under polygenic control, with a major susceptibility gene, Idd1, in the major histocompatibility complex (MHC). To investigate the contribution of the NOD MHC to type 1 diabetes susceptibility, a B6.NOD-H-2 congenic strain, in which the NOD MHC was introgressed onto the genetic background of the C57BL/6 strain, was established. Despite possession of the diabetogenic MHC from the NOD mouse, none of the B6.NOD-H-2 mice developed type 1 diabetes, indicating that the NOD MHC alone is not sufficient for type 1 diabetes and that non-MHC genes are also necessary. One of the strongest non-MHC genes is Idd3, and Il2 which encodes interleukin 2, is a candidate gene for Idd3. To test whether a combination of the NOD MHC with the NOD allele of Il2 is sufficient for type 1 diabetes, B6.NOD-H-2 mice were crossed with C3H mice, which possess the NOD allele at Il2, and F2 mice homozygous for NOD alleles at both the MHC and Il2 were produced. None of the F2 mice developed type 1 diabetes, suggesting that NOD alleles at MHC (Idd1) and Il2 (Idd3) are not sufficient for type 1 diabetes in the NOD mouse.
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PMID:Idd1 and Idd3 are necessary but not sufficient for development of type 1 diabetes in NOD mouse. 1556 87

Brx-019 (acetic acid 3,6a,9-triacetoxy-6, 6a,7,11b-tetrahydro-indeno [2,1-c] chromen-10-yl ester) was derived from brazilin (CAS 474-07-7) during a trial designed to search for immunomodulators with lower toxicity and more effective immunomodulating activities than brazilin. Brx-019 was selected as a potential immunomodulator based on its effects on Concanavalin A (Con A)-induced proliferation of splenocytes and the 3-[14,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Intraperitoneally administered Brx-019 significantly improved delayed type hypersensitivity and increased immunoglobulin M (IgM) plaque forming cells (PFCs) in multiple low dose streptozotocin-induced diabetic mice (MLDS-diabetic mice). This finding suggests that Brx-019 may increase suppressed humoral and cell-mediated immunity in type 1 diabetes. Brx-019 also significantly increased Con A- or alloantigen-induced proliferation of splenocytes, Con A-induced interleukin 2 (IL-2) production from splenocytes, and IL-2-induced proliferation of Con A-activated splenocytes in MLDS-diabetic mice. These results suggest that Brx-019 might improve immunity in diabetic mice by increasing IL-2 production in splenocytes and responsiveness of splenocytes to IL-2, which were suppressed in MLDS-diabetes.
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PMID:Effects of Brx-019 (acetic acid 3,6a,9-triacetoxy-6,6a,7, 11b-tetrahydro-indeno [2,1-c] chromen-10-yl ester), a Brazilin derivative, on T cell-mediated immune responses in multiple low dose streptozotocin-induced diabetic C57BL/6 male mice. 1622 19

Prevention of type 1 diabetes mellitus (T1DM) requires early intervention in the autoimmune process directed against beta-cells of the pancreatic islets of Langerhans, which is believed to result from a disorder of immunoregulation. According to this concept, a T-helper lymphocyte of type 1 (Th1) subset of T-lymphocytes and their cytokine products, the type 1 cytokines [e.g. interleukin 2 (IL-2), interferon gamma (IFN-gamma) and tumour necrosis factor beta (TNF-beta)] prevail over immunoregulatory (anti-inflammatory) Th2 subset and its cytokine products, i.e. type 2 cytokines (e.g. IL-4, IL-6 and IL-10). This allows type 1 cytokines to initiate a cascade of immune/inflammatory processes in the islet (insulitis), culminating in beta-cell destruction. Activation of sympathetic-corticotropin-releasing hormone (CRH) axis by psychological stress induces specifically Th1 cell overactivity that determines enhanced glutamine utilization and consequent poor L-arginine supply for nitric oxide (NO)-assisted insulin secretion. This determines the shift of intraislet glutamate metabolism from the synthesis of glutathione (GSH) to that of L-arginine, leading to a redox imbalance that activates nuclear factor kappaB exacerbating inflammation and NO-mediated cytotoxicity. Physical exercise is capable of inducing changes in the pattern of cytokine production and release towards type 2 class and to normalize the glutamine supply to the circulation, which reduces the need for glutamate, whose metabolic fate may be restored in the direction of GSH synthesis and antioxidant defence. Also, the 70-kDa heat shock protein (hsp70), which is immunoregulatory, may modulate exercise-induced anti-inflammation. In this work, we envisage how exercise can intervene in the mechanisms involved in the autoimmune process against beta-cells and how novel therapeutic approaches may be inferred from these observations.
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PMID:Type 1 diabetes: can exercise impair the autoimmune event? The L-arginine/glutamine coupling hypothesis. 1838 59

Variants within the IL-2 (interleukin 2) and CD25 genes are associated with T1DM (Type 1 diabetes mellitus) in mice and humans respectively. Both gene products are essential for optimal immune tolerance and a partial failure to tolerize is linked to the autoimmune responses to insulin and other beta-cell proteins that precede T1DM onset. Gene variants that contribute to common disease susceptibility often alter gene expression only modestly. Small expression changes can be technically challenging to measure robustly, especially since biological variation usually contributes negatively to this goal. The present review focuses on allele-specific expression assays that can be used to quantify genotype-determined expression differences such as those observed for IL-2, where the susceptibility allele is transcribed 2-fold less than the resistance allele.
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PMID:Commonality in the genetic control of Type 1 diabetes in humans and NOD mice: variants of genes in the IL-2 pathway are associated with autoimmune diabetes in both species. 1848 48

Type 1 diabetes mellitus (T1DM) is a widespread, severe disease which results from the immunologically mediated destruction of the beta-cells of pancreatic Langerhans islets. To date the several loci involved to the T1DM development have been reliably identified by means of a number of approaches: MHC locus, VNTR within 5'-nontranscibed region of insulin (INS) gene, CTLA4 gene, encoding surface receptor of T cells, PTPN22 and PTPN2 genes, encoding tyrosine phosphatases of T lymphocytes, interleukin 2 (IL2) gene and alpha-chain of its receptor gene (IL2RA), as well as KIAA0350 gene (unknown function) and IFIH1 gene, encoding receptor of double-stranded DNA generated during viral infections. The functional analysis of proteins encoded by the genes, which are involved to the T1DM development, performed to confirm the hypothesis that on the one hand the origin of T1DM development is founded on the some deregulation of mechanisms of the immune tolerance formation and on the other hand the cause is founded on the formation of destructive immune response against own proteins of organism after virus infection or some other immune stress. Thus the protein products of MHC, INS, PTPN22 and PTPN2 genes involve in the formation in thymus of T-lymphocyte repertoire, which provides the immune defense of organism. On the other hand the nonspecific activation of T cells, from that starts the autoimmune destruction of beta-cells of Langerhans islets of pancreas, in all probability, connects with the protein products of CTLA4, IL2, IL2RA genes, and, perhaps, PTPN22 and PTPN2 genes. The only exception, if not considering the genes with unknown function,--is the IFIH1 gene, but its association with T1DM confirms that fact, that the certain types of virus infection can lead to the activation of autoreactive T cells and T1DM development.
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PMID:[Molecular genetics of type 1 diabetes mellitus: achievements and future trends]. 1898 35

The immune system must balance the need to maintain a diverse repertoire of lymphocytes to be able to fight infection with the need to maintain tolerance to self-proteins. The immune system places strict regulation over the ability of T cells to produce the major T cell growth factor interleukin 2 as this cytokine can influence a variety of immune outcomes. T cells require the delivery of two signals, one through the antigen receptor and a second through the costimulatory receptor CD28. The immune system uses a variety of E3 ubiquitin ligases to target signaling proteins that function downstream of the TCR and CD28 receptors. Mutations in these E3 ligases can lead to a breakdown in immune tolerance and development of autoimmunity. This paper will examine the role of a range of E3 ubiquitin ligases and signaling pathways that influence the development of T-cell effector responses and the development of organ-specific autoimmune diseases such as type 1 diabetes.
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PMID:Mechanisms that regulate peripheral immune responses to control organ-specific autoimmunity. 2160 4


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