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

Type 1 diabetes has been associated with an increased frequency of activated T cells and T-cell hyperactivity to non-specific and disease-specific stimuli including the islet autoantigen glutamic acid decarboxylase 65 (GAD). To address whether T-cell hyperactivity is genetic or acquired we measured whole blood cytokines in vitro in response to GAD or tetanus in 18 identical twin pairs, nine discordant for type 1 diabetes. In addition, the activity of 2', 5' oligoadenylate synthetase (OAS) in blood mononuclear cells was measured as a marker of viral infection. Interleukin-2 (IL-2) basally and IL-2 and interferon-gamma (IFN-gamma) in response to GAD, were detected more frequently and at higher levels in diabetic compared to non-diabetic twins. IL-10 was not different between groups. OAS activity was increased in diabetic compared to non-diabetic twins and showed a correlation with basal IL-2 and GAD-stimulated IFN-gamma and IL-10. These findings suggest that T-cell hyperactivity in type 1 diabetes is an acquired trait and could reflect persisting virus expression.
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PMID:Evidence from twins for acquired cellular immune hyperactivity in type 1 diabetes. 1215 22

Enhanced cellular immune response to bovine beta-casein has been reported in patients with type 1 diabetes. In this study we aimed to establish beta-casein-specific T cell lines from newly diagnosed type 1 diabetic patients and to characterise these cell lines in terms of phenotype and epitope specificity. Furthermore, since sequence homologies exist between beta-casein and putative beta-cell autoantigens, reactivity to the latter was also investigated. T cell lines were generated from the peripheral blood of nine recent onset type 1 diabetic patients with different HLA-DQ and -DR genotypes, after stimulation with antigen pulsed autologous irradiated antigen presenting cells (APCs) and recombinant human interleukin-2 (rhIL-2). T cell line reactivity was evaluated in response to bovine beta-casein, to 18 overlapping peptides encompassing the whole sequence of beta-casein and to beta-cell antigens, including the human insulinoma cell line, CM, and a peptide from the beta-cell glucose transporter, GLUT-2. T cell lines specific to beta-casein could not be isolated from HLA-matched and -unmatched control subjects. beta-Casein T cell lines reacted to different sequences of the protein, however a higher frequency of T cell reactivity was observed towards the C-terminal portion (peptides B05-14, and B05-17 in 5/9 and 4/9 T cell lines respectively). Furthermore, we found that 1 out of 9 beta-casein-specific T cell lines reacted also to the homologous peptide from GLUT-2, and that 3 out of 4 of tested cell lines reacted also to extracts of the human insulinoma cell line, CM. We conclude that T cell lines specific to bovine beta-casein can be isolated from the peripheral blood of patients with type 1 diabetes; these cell lines react with multiple and different sequences of the protein particularly towards the C-terminal portion. In addition, reactivity of beta-casein T cell lines to human insulinoma extracts and GLUT-2 peptide was detected, suggesting that the potential cross-reactivity with beta-cell antigens deserves further investigation.
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PMID:Establishment of T cell lines to bovine beta-casein and beta-casein-derived epitopes in patients with type 1 diabetes. 1252 58

We describe in detail the labelling of interleukin-2 with I ( I-IL2), its biochemical characterization, the binding assay and its use for the detection of tissues infiltrated with mononuclear cells. Human recombinant IL2 was labelled using an enzymatic method and its biochemical characterization was performed using high performance liquid chromatography (HPLC) analysis of cyanogen bromide-cleaved protein. biological and binding assays were performed on CTLL-2 cell line and on activated peripheral blood lymphocytes. studies were performed 1 h after administration of 2-3 mCi of I-IL2 in 10 newly diagnosed type 1 diabetes patients, five pre-diabetic patients, 10 Hashimoto's thyroiditis patients, 10 coeliac disease patients and 10 normal volunteers. I-IL2 scintigraphy allowed the detection and quantification of activated mononuclear cells in several affected tissues. In detail, I-IL2 accumulation was detected in the thyroid of all patients affected by Hashimoto's thyroiditis, in the bowel of all coeliac disease patients and in the pancreas of all pre-type 1 diabetic patients. By contrast, in newly diagnosed type 1 diabetics, I-IL2 scan was positive in five of the 10 studied patients. I-IL2 scintigraphy may be useful for studying autoimmune phenomena and in diagnostic protocols to evaluate the presence of other tissue involvement in patients with an organ-specific autoimmune disease.
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PMID:123I-Interleukin-2: biochemical characterization and in vivo use for imaging autoimmune diseases. 1261 72

Type 1 diabetes is an autoimmune disease wherein autoreactive T-cells promote the specific destruction of pancreatic islet beta-cells. Evidence for a crucial role for Fas/FasL interactions in this destruction has been highly controversial because of the pleiotropic effects of Fas deficiency on the lymphoid and other systems. Fas-deficient mice are protected from spontaneous development of diabetes not because Fas has a role in the destruction of beta-cells, but rather because insulitis is abrogated. Fas may somehow be involved in the series of events provoking insulitis; for example, it may play a role in the physiological wave of beta-cell death believed to result in the export of pancreatic antigens to the pancreatic lymph nodes and, thereby, to circulating, naive, diabetogenic T-cells for the first time. To explore the implication of Fas in these events, we crossed the lpr mutation into the BDC2.5 model of type 1 diabetes to make it easier to monitor direct effects on the pathogenic specificity. We demonstrated that BDC2.5/NOD(lpr/lpr) mice have qualitatively and quantitatively less aggressive insulitis than do BDC2.5/NOD mice. In vitro proliferation assays showed that BDC2.5/NOD(lpr/lpr) splenocytes proliferated less vigorously than those from control mice in the presence of islet extracts, which reflects their inability to produce interleukin-2, resulting in weaker pathogenicity.
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PMID:Fas deficiency prevents type 1 diabetes by inducing hyporesponsiveness in islet beta-cell-reactive T-cells. 1550 59

Altered peptide ligands derived from T cell-reactive self antigens have been shown to be protective therapeutic agents in animal models of autoimmunity. In this study we identified several altered peptide ligands derived from the type 1 diabetes-associated autoantigen human glutamic acid decarboxylase 65 (hGAD65) epitope that were capable of antagonizing a subset of a panel of human CD4(+) GAD65 (555-567)-responsive T cell clones derived from a diabetic individual. While no altered peptide ligand was able to antagonize all six clones in the T cell panel, a single-substituted peptide of isoleucine to methionine at position 561, which resides at the TCR contact p5 position, was able to antagonize five out of the six hGAD65-responsive clones. In a mixed T cell culture system we observed that altered peptide ligand-mediated antagonism is inhibited in a dose-dependent manner by the presence of non-antagonizable hGAD65 (555-567)-responsive T cells. From an analysis of the cytokines present in the mixed T cell cultures, interleukin-2 was sufficient to inhibit altered peptide ligand-induced antagonism. The inhibition of altered peptide ligand-mediated antagonism of self-antigen-responsive T cells by non-antagonizable T cells has implications in altered peptide ligand therapy where T cell antagonism is the goal.
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PMID:Inhibition of altered peptide ligand-mediated antagonism of human GAD65-responsive CD4+ T cells by non-antagonizable T cells. 1554 75

As part of an ongoing search for genes associated with type 1 diabetes (T1D), a common autoimmune disease, we tested the biological candidate gene IL2RA (CD25), which encodes a subunit (IL-2R alpha) of the high-affinity interleukin-2 (IL-2) receptor complex. We employed a tag single-nucleotide polymorphism (tag SNP) approach in large T1D sample collections consisting of 7,457 cases and controls and 725 multiplex families. Tag SNPs were analyzed using a multilocus test to provide a regional test for association. We found strong statistical evidence in the case-control collection (P=6.5x10(-8)) for a T1D locus in the CD25 region of chromosome 10p15 and replicated the association in the family collection (P=7.3x10(-3); combined P=1.3x10(-10)). These results illustrate the utility of tag SNPs in a chromosome-regional test of disease association and justify future fine mapping of the causal variant in the region.
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PMID:Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. 1577 95

A SNP in the gene PTPN22 is associated with type 1 diabetes, rheumatoid arthritis, lupus, Graves thyroiditis, Addison disease and other autoimmune disorders. T cells from carriers of the predisposing allele produce less interleukin-2 upon TCR stimulation, and the encoded phosphatase has higher catalytic activity and is a more potent negative regulator of T lymphocyte activation. We conclude that the autoimmune-predisposing allele is a gain-of-function mutant.
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PMID:Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. 1631 59

Interleukin-2 (IL-2) plays an established role in T-cell regulation through binding to the high-affinity IL-2 receptor (IL-2R). The alpha-chain encoded by the IL2RA (CD25) gene is a substantial component of the high-affinity receptor molecule highly expressed by activated T lymphocytes. Recently, a strong evidence was obtained for the involvement of IL-2RA in conferring susceptibility to type 1 diabetes (T1D). Significant association with T1D was also found in the region on chromosome 4q27 containing the IL2 gene and homologous to the susceptibility locus idd3 in non-obese diabetic (NOD) mice, an animal model for human T1D. Here we focus on the discussion of these new findings suggesting for a crucial role of IL-2/IL-2RA-mediated regulatory mechanisms in preventing T1D. The non-redundant role of IL-2 and its receptor in etiology of T1D could be particularly attributable to the regulation of CD4+ CD25+ regulatory T cells, whose function is critical in maintaining immune homeostasis.
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PMID:The crucial role of IL-2/IL-2RA-mediated immune regulation in the pathogenesis of type 1 diabetes, an evidence coming from genetic and animal model studies. 1841 24

The dynamics of CD4(+) effector T cells (Teff cells) and CD4(+)Foxp3(+) regulatory T cells (Treg cells) during diabetes progression in nonobese diabetic mice was investigated to determine whether an imbalance of Treg cells and Teff cells contributes to the development of type 1 diabetes. Our results demonstrated a progressive decrease in the Treg cell:Teff cell ratio in inflamed islets but not in pancreatic lymph nodes. Intra-islet Treg cells expressed reduced amounts of CD25 and Bcl-2, suggesting that their decline was due to increased apoptosis. Additionally, administration of low-dose interleukin-2 (IL-2) promoted Treg cell survival and protected mice from developing diabetes. Together, these results suggest intra-islet Treg cell dysfunction secondary to defective IL-2 production is a root cause of the progressive breakdown of self-tolerance and the development of diabetes in nonobese diabetic mice.
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PMID:Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. 1895 59


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