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)

The non-obese diabetic (NOD) mouse develops insulin dependent diabetes mellitus (IDDM) spontaneously with a higher incidence in females than in males. There are many similarities to the human disease, making it an ideal model. Our group is examining the role that CD4(+) and CD8(+) T cells play in IDDM in the NOD mouse, as it is known that both T cell subsets are required for onset of disease. Although IDDM has an autoimmune etiology, the initial triggering event is unknown and the autoantigen involved has not been identified. This investigation focussed on one of the potential autoantigens involved, the enzyme glutamic acid decarboxylase (GAD). We raised GAD peptide-specific CD8(+) T cells by immunising NOD mice with the GAD peptide alongside an irrelevant peptide that induced a CD4(+) T cell response. In order to maintain these peptide specific T cells in vitro and generate clones, it was found that antibodies specific to CD4(+) and MHC class II molecules needed to be included in the culture medium. This paper outlines the methods we employed to generate and maintain these CD8(+) T cells in vitro.
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PMID:Generation and maintenance of autoantigen-specific CD8(+) T cell clones isolated from NOD mice. 1055 46

During immune responses, antigen-presenting cells (APCs) process antigens and present peptide epitopes complexed with human leukocyte antigen (HLA) molecules. CD4 cells recognize these naturally processed and presented epitopes (NPPEs) bound to HLA class II molecules. Epitope identification is important for developing diagnostic and therapeutic tools for immune-mediated diseases and providing insight into their etiology, but current approaches overlook effects of natural processing on epitope selection. We have developed a technique to identify NPPEs using mass spectrometry (MS) after antigen is targeted onto APCs using a lectin-based antigen delivery system (ADS). We applied the technique to identify NPPEs of the intracellular domain of the type 1 diabetes mellitus-associated (type 1 DM-associated) autoantigen insulinoma-associated-2 (IA-2ic), presented by HLA-DR4 (0401). IA-2ic-derived NPPEs eluted from HLA-DR4 constitute 6 sets of peptides nested around distinct core regions. Synthetic peptides based on these regions bind HLA-DR4 and elicit primary T-cell proliferation frequently in HLA-DR4-positive type 1 DM patients, but rarely in non-HLA-DR4 patients, and in none of the HLA-DR4 nondiabetic controls we tested. This flexible, direct approach identifies an HLA allele-specific map of NPPEs for any antigen, presented by any HLA class II molecule. This method should enable a greater understanding of epitope selection and lead to the generation of sensitive and specific reagents for detecting autoreactive T cells.
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PMID:Naturally processed and presented epitopes of the islet cell autoantigen IA-2 eluted from HLA-DR4. 1058 9

In this article, we report the identification of a new autoantigen in type 1 diabetes originating from the exocrine pancreas. This antigen is a pancreatic enzyme termed bile salt-dependent lipase (BSDL). We show that antibodies present in the sera of newly diagnosed type 1 diabetic patients recognize BSDL and more specifically the COOH-terminal mucin-like region of the protein. Therefore, we engineered the COOH-terminal peptide of BSDL and demonstrated that autoreactivity was linked to specific glycosylation sites by at least two glycosyltransferases: the Core 2 beta(1-6)N-acetylglucosaminyltransferase and the alpha(1-3) fucosyltransferase FUT7. We next examined the prevalence of circulating anti-BSDL antibodies in type 1 diabetic patients and found 73.5% positivity (25 sera among 34 patients tested) at onset, whereas only 8.4% of normal individuals (7 of 83) were positive. Within a cohort of first-degree relatives of diabetic patients followed prospectively until development of diabetes, 6 of 19 (31.6%) were also positive. Interestingly, two prediabetic individuals were already positive for anti-BSDL antibodies (Abs), while islet cell cytoplasmic Abs and antibodies to GAD65, IA-2, and insulin were not detected. Anti-BSDL autoantibodies were weakly or not detected in patients suffering from pancreatitis or pancreatic adenocarcinoma or in patients with Graves' disease. Although autoreactivity to BSDL in prediabetic and newly diagnosed diabetic patients might reflect cross-reactivity, our results strongly suggest that in addition to pancreatic beta-cells, acinar cells may be also affected in type 1 diabetes.
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PMID:Circulating antibodies against an exocrine pancreatic enzyme in type 1 diabetes. 1058 Apr 19

Major questions are still unanswered in the understanding of the pathogenesis of type 1 diabetes, including the important question of the nature of the autoantigen(s) recognised in the development of disease. In the nonobese diabetic mouse model, there is new evidence that insulin plays an important role: not only is it an antigen for pathogenic CD4+ T cells but also it is recognised by highly diabetogenic CD8+ T cells. Further studies using transgenic mice have also highlighted the role of glutamic acid decarboxylase as an autoantigen. It remains to be seen whether one or both of these autoantigens can be used in strategies to prevent human diabetes.
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PMID:Insulin-dependent diabetes mellitus and its animal models. 1063 49

The tyrosine phosphatase like protein IA-2 is an important autoantigen in insulin-dependent diabetes mellitus (type 1 diabetes). Autoantibodies to IA-2 (IA-2A) are present in the serum of patients with type 1 diabetes even before the onset of the disease. Previously, we reported on a radioimmune assay to detect IA-2A, using E. coli-derived 125I-labelled IA-2 as antigen. Although this assay could be shown to be equivalent to the common reference method for IA-2A detection (radioligand assays using in vitro synthesised 35S-methionine labelled antigen), the disadvantages of both assays with respect to synthesis and handling of the radioactive antigen limit their use in routine laboratories. In this study, we have evaluated a non-radioactive enzyme-linked immunosorbent assay (ELISA) for the simple detection of IA-2A. We report on an ELISA where the biotinylated intracytoplasmic part of IA-2 (IA-2ic) is captured on streptavidin-coated plates. The sensitivity of the ELISA was similar to the validated radioligand assay, as it detected 47 of 69 (69%) patients with type 1 diabetes as compared to 46 of 68 (67 %) with the reference method for IA-2A detection (radioligand assays using in vitro synthesised 35S-methionine labelled antigen). Only 2 of 50 (4%) patients with autoimmune thyroid disease and 1 of 114 (1 %) healthy controls were detected in the ELISA, confirming specificity. There was a significant correlation between the ELISA and the radioligand assay (r = 0.64, p<0.001). We conclude that this ELISA is suitable to detect IA-2A in the serum of patients with type 1 diabetes with a similar sensitivity and specificity to the radioligand assay. This ELISA will allow rapid and simple measurement of IA-2A where the radioligand assay is inconvenient or not available.
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PMID:Detection of autoantibodies to the diabetes-associated antigen IA-2 by a sensitive enzyme-linked immunosorbent assay. 1066 23

Although CD8+ T cells play a major role in beta cell destruction in insulin-dependent diabetes in the non-obese diabetic mouse, the T cell autoantigen(s) recognized by such cells remains to be identified. Therefore, an islet-reactive, CD8+ T cell line was generated from islet-infiltrating cells and hybridized by fusion with a CD8+ alphabeta TCR- BW5147 thymoma. In the presence of islets, none of the 12 CD3+ CD8+ T cell hybridomas isolated secreted IL-2/IL-4 or IFNgamma but three were islet specific, as shown by activation induced cell death. Subclone 4A7.7.15 recognized only islets expressing H-2Kd, demonstrated islet-specific inhibition of proliferation and concomitant partial arrest in the G2/M phase of the cell cycle. Further analysis using a panel of cell lines, expressing H-2Kd, and transfected with the cDNA for various putative autoantigens in type 1 diabetes showed that 4A7.7.15 recognizes insulin as an antigen.
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PMID:An islet-specific CD8+ T cell hybridoma generated from non-obese diabetic mice recognizes insulin as an autoantigen. 1074 64

Premature ovarian failure (POF) is a disorder of heterogeneous etiology, and autoimmunity has been suspected as one cause of POF. The steroidogenic enzyme, 3beta-hydroxysteroid dehydrogenase (3betaHSD), has been characterized as a potential autoantigen in POF as well as in insulin-dependent diabetes mellitus (type 1 diabetes). Here we studied the presence of steroid cell antibodies (SCA), autoantibodies to 3betaHSD and to two other known autoantigens in ovarian failure, steroidogenic enzymes 17alpha-hydroxylase (P450c17), and side-chain cleavage enzyme (P450scc) in POF patients and patient groups with autoimmune polyendocrinopathy syndromes type 1 and 2 (APS1 and -2), isolated Addison's disease, type 1 diabetes, and healthy controls. The SCA were found in 2 of 48 POF, 11 of 15 APS1, and 1 of 9 APS2, and autoantibodies to in vitro translated 3betaHSD protein were detected in 1 POF serum associated with Addison's disease and 3 APS1 sera. All 3betaHSD precipitating sera were also positive for SCA. However, no SCA or 3betaHSD autoantibodies were found in 38 Addison's disease, 28 type 1 diabetes, and 71 healthy control sera. In analysis of autoantibodies to P450c17 and P450scc, antibodies to these enzymes were not found in POF sera, but were found in 10 and 12 APS1 patient sera, respectively, and 1 APS2 patient serum contained anti-P450c17 antibodies. Our results show that autoantibodies to 3betaHSD in POF patients are rare and are also found in patients with APS1.
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PMID:3beta-hydroxysteroid dehydrogenase autoantibodies are rare in premature ovarian failure. 1085 71

Pancreas transplantation in patients with type 1 diabetes presents allogeneic beta-cell autoantigens to the immune system long after the initial beta-cell destruction that leads to diabetes has occurred. The aims of this study were to determine whether re-exposure to beta-cell autoantigen through transplantation affect the humoral autoimmune response and whether its modulation correlates with graft outcome. Antibodies to the major autoantigens GAD (GADA) and protein tyrosine phosphatase IA-2 (IA-2A) were measured before and after transplantation in patients with type 1 diabetes who received pancreas and kidney allografts. In the 110 cases studied, pancreas graft survival was not significantly associated with the presence of GADA or IA-2A before transplantation. In the 75 patients with sequential follow-up samples up to 11.2 years after transplantation, autoantibodies were persistently undetectable in 44 cases (59%) and remained at stable detectable levels in 13 cases (17%). Substantial changes in antibody levels were found in 18 cases (24%), of which 13 cases (17%) had declining levels and 5 cases (7%) had marked increments after transplantation. Rising GADA and IA-2A levels in these five patients were predominantly of the IgG1 subclass, with progressive spreading of epitope reactivity. Pancreas graft function was lost 0.7-2.3 years after rising autoantibody levels in four of these five patients, and a significantly lower pancreas graft survival was found in patients with major rises in either GADA or IA-2A levels (P < 0.0001 vs. the remainder) and in patients having persistently high levels of IA-2A (P = 0.002 vs. stable antibody-negative patients). Kidney graft survival was not associated with islet autoantibody status. In conclusion, a minority of patients receiving pancreas allografts under generalized immunosuppression show a stimulation of islet autoantibody reactivity characteristic of that found in preclinical type 1 diabetes, which is almost invariably followed by graft function failure and resumption of insulin therapy.
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PMID:Modulation of humoral islet autoimmunity by pancreas allotransplantation influences allograft outcome in patients with type 1 diabetes. 1086 38

Coxsackievirus infections have been proposed as an environmental trigger for the development of T-cell-mediated autoimmune (type 1) diabetes by either providing a molecular mimic of the candidate pancreatic beta-cell autoantigen GAD or inducing bystander inflammation in the pancreas. In this study in the NOD mouse model, we found that infection with a pancreatrophic coxsackievirus isolate can accelerate type 1 diabetes development through the induction of a bystander activation effect, but only after a critical threshold level of insulitic beta-cell-autoreactive T-cells has accumulated. Thus, coxsackievirus infections do not appear to initiate beta-cell autoreactive immunity but can accelerate the process once it is underway. These findings indicate that the timing of a coxsackievirus infection, rather than its simple presence or absence, may have important etiological implications for the development of T-cell-mediated autoimmune type 1 diabetes in humans.
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PMID:Acceleration of type 1 diabetes by a coxsackievirus infection requires a preexisting critical mass of autoreactive T-cells in pancreatic islets. 1090 77

IA-2, a member of the protein tyrosine phosphatase family, represents a major target autoantigen in type 1 diabetes. To study the regulation of IA-2 gene expression, we used INS-1 insulinoma cells to analyze beta-cell signal transduction pathways as well as the effect of metabolic and hormonal factors involved in the regulation of the insulin secretory pathway. Quantitative competitive reverse transcriptase-polymerase chain reaction revealed that an increase of cellular cAMP mediated by forskolin (10 micromol/l, 24 h) or 3-isobutyl-1-methylxanthine (100 micromol/l, 24 h) induced maximal stimulation of IA-2 mRNA levels (451 +/- 85 and 338 +/- 86% compared with basal conditions; P < 0.001). In contrast, activation of protein kinase C (PKC) by short-term treatment with phorbol 12-myristate 13-acetate (PMA) (1 micromol/l, 6 h) did not alter IA-2 expression, whereas depletion of PKC by prolonged culturing (24 h) exerted a significant inhibition (57 +/- 24%; P < 0.05). cAMP-dependent upregulation was confirmed by the findings that glucagon (10 micromol/l, 24-48 h) increased levels of IA-2 mRNA (190 +/- 35%; P < 0.05), whereas short-term incubation with high glucose concentration showed no effect. However, prolonged incubation in high glucose (21 mmol/l) induced a time- and dose-dependent increase of IA-2 mRNA expression, reaching maximal values after 144 h (285 +/- 68%; P < 0.05). These studies demonstrate that stimuli of insulin secretion that operate by activation of adenylate cyclase generating cAMP significantly increase IA-2 gene expression. In contrast, activation of PKC by high glucose concentration or PMA exerted no effect, suggesting that IA-2 gene expression is not simply coupled to insulin secretion, but may be involved in the fine regulation of beta-cell function. These findings may be important to clarify the function of IA-2 in beta-cells and elucidate mechanisms involved in the induction of autoimmunity to IA-2.
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PMID:Regulation of the diabetes-associated autoantigen IA-2 in INS-1 pancreatic beta-cells. 1090 70


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