Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many tissue-specific autoimmune diseases are mediated by the induction of autoantigen-specific T cells. These cells are believed to cause tissue damage through the production of cytokines, through direct lysis of cells expressing self-antigens, or through the induction of inflammatory responses. The escape from self-tolerance or anergy is a prerequisite for initiation of an autoimmune process. INS-HA (insulin-hemagglutinin) transgenic mice express the HA of A PR8 34 influenza virus in the pancreatic beta-cells under the rat insulin promotor. TCR-HA (T cell receptor-hemagglutinin) transgenic mice express the TCR specific for the immunodominant epitope HA110-120 from the same virus. Double transgenic (dTg) mice expressing both genes represent an excellent model for understanding the mechanism leading to autoimmune diabetes independently of susceptibility genes. In order to gain information on the breaking down of neonatal self-tolerance we studied the occurrence of insulin dependent diabetes mellitus (IDDM) after birth. Our results showed that newborn mice develop fulminant IDDM characterized by occurrence of insulitis as early as 3 days after birth, followed by hyperglycemia by 7 days, and significant hypoinsulinemia by 28 days. Such "double transgenic" mice expressing wild-type or targeted IL-4R alpha genes were examined for the onset of IDDM. Eight of eleven mice homozygous for the wild-type IL-4R alpha were hyperglycemic by 8 weeks of age, whereas only 1 of 16 mice homozygous for the targeted allele were hyperglycemic at this time. Most IL-4R alpha -/- mice remained normoglycemic to 36 weeks of age. Although only 10% of double transgenic mice homozygous for wild-type IL-4R alpha allele survived to 30 weeks, 80% of mice homozygous for the targeted allele did so. Even as late as 270 days of age, mice homozygous for the targeted allele had no insulitis or only peri-insulitis. Heterozygous mice displayed an intermediate frequency of diabetes. The IL-4R alpha chain acts as the high affinity binding chain and the principal signaling chain for IL-4; it also acts as the signaling chain for IL-13, but in this case the IL-13R alpha 1 chain conveys the bulk of the cytokine specificity. Thus, IL-4R alpha knock-out mice are unresponsive to both IL-4 and IL-13. The finding that the lack of IL-4R alpha chain protects TCR-HA, INS-HA double transgenic mice against diabetes, and death implies that either IL-4 or IL-13 plays a role in the progression of this disease. These studies demonstrate that TCR-HA, INS-HA double transgenic mice may provide a useful model to evaluate new strategies for the prevention of diabetes.
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PMID:Cellular mechanisms involved in experimental insulin-dependent diabetes mellitus. 1216 74

We herein report on two Japanese siblings with autoimmune polyglandular syndrome type 1 (APS-1). The brother, who expressed a characteristic phenotype of APS-1, had developed severe mucocutaneous candidiasis in early infancy and thereafter developed hypoparathyroidism and Addison's disease, along with a severe deterioration of his immunologic function. In contrast, the 44-year-old sister, who showed a noncharacteristic phenotype of APS-1, developed insulin-dependent diabetes with high anti-glutamic acid decarboxylase antibody, mild nail candidiasis, and autoimmune hepatitis with intact immunoreactivity. She had three susceptible human leukocyte antigen (HLA) loci for type 1 autoimmune diabetes. The expression of T cell receptor (TCR)V beta 5.1 increased in both patients, while the brother showed a widely suppressed expression of many TCRV beta families. Both individuals possessed compound heterozygous novel autoimmune regulator (AIRE) gene mutations (L29P and IVS9-1G > C). The same AIRE gene mutations can thus be associated with characteristic and noncharacteristic phenotypes of APS-1, and HLA may possibly influence the phenotype of APS-1.
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PMID:Distinct clinical phenotype and immunoreactivity in Japanese siblings with autoimmune polyglandular syndrome type 1 (APS-1) associated with compound heterozygous novel AIRE gene mutations. 1217 2

Glutamic acid decarboxylase (GAD)65 is an early and important antigen in both human diabetes mellitus and the nonobese diabetic (NOD) mouse. However, the exact role of GAD65-specific T cells in diabetes pathogenesis is unclear. T cell responses to GAD65 occur early in diabetes pathogenesis, yet only one GAD65-specific T cell clone of many identified can transfer diabetes. We have generated transgenic mice on the NOD background expressing a T cell receptor (TCR)-specific for peptide epitope 286-300 (p286) of GAD65. These mice have GAD65-specific CD4(+) T cells, as shown by staining with an I-A(g7)(p286) tetramer reagent. Lymphocytes from these TCR transgenic mice proliferate and make interferon gamma, interleukin (IL)-2, tumor necrosis factor (TNF)-alpha, and IL-10 when stimulated in vitro with GAD65 peptide 286-300, yet these TCR transgenic animals do not spontaneously develop diabetes, and insulitis is virtually undetectable. Furthermore, in vitro activated CD4 T cells from GAD 286 TCR transgenic mice express higher levels of CTL-associated antigen (CTLA)-4 than nontransgenic littermates. CD4(+) T cells, or p286-tetramer(+)CD4(+) Tcells, from GAD65 286-300-specific TCR transgenic mice delay diabetes induced in NOD.scid mice by diabetic NOD spleen cells. This data suggests that GAD65 peptide 286-300-specific T cells have disease protective capacity and are not pathogenic.
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PMID:CD4(+) T cells from glutamic acid decarboxylase (GAD)65-specific T cell receptor transgenic mice are not diabetogenic and can delay diabetes transfer. 1218 40

Pancreatic islets of Langerhans are enveloped by peri-islet Schwann cells (pSC), which express glial fibrillary acidic protein (GFAP) and S100beta. pSC-autoreactive T- and B-cell responses arise in 3- to 4-week-old diabetes-prone non-obese diabetic (NOD) mice, followed by progressive pSC destruction before detectable beta-cell death. Humans with probable prediabetes generate similar autoreactivities, and autoantibodies in islet-cell autoantibody (lCA) -positive sera co-localize to pSC. Moreover, GFAP-specific NOD T-cell lines transferred pathogenic peri-insulitis to NOD/severe combined immunodeficient (NOD/SCID) mice, and immunotherapy with GFAP or S100beta prevented diabetes. pSC survived in rat insulin promoter Iymphocytic choriomeningitis virus (rip-LCMV) glycoprotein/CD8+ T-cell receptor(gp) double-transgenic mice with virus-induced diabetes, suggesting that pSC death is not an obligate consequence of local inflammation and beta-cell destruction. However, pSC were deleted in spontaneously diabetic NOD mice carrying the CD8+/8.3 T-cell receptor transgene, a T cell receptor commonly expressed in earliest islet infiltrates. Autoimmune targeting of pancreatic nervous system tissue elements seems to be an integral, early part of natural type 1 diabetes.
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PMID:Autoimmune islet destruction in spontaneous type 1 diabetes is not beta-cell exclusive. 1256 31

Natural killer T (NKT) cells are a subset of lymphocytes that express receptors characteristic of conventional T cells together with receptors typically found on natural killer cells. A key feature of NKT cells is the expression of a semi-invariant T cell receptor that is specific for glycolipid antigens presented by the unusual major histocompatibility complex class I-like molecule CD1d. While their precise immunological functions remain unknown, NKT cells have been implicated in the regulation of adaptive immune responses, including those directed against autoantigens. These findings raise the possibility that specific stimulation of NKT cells may be exploited for therapeutic purposes. A number of laboratories have tested this hypothesis, utilizing the sea sponge-derived agent alpha-galactosylceramide (alpha-GalCer), a specific agonist of NKT cells. Administration of alpha-GalCer to mice results in potent activation of NKT cells, rapid and robust cytokine production, and activation of a variety of cells of the innate and adaptive immune systems. Most notably, repeated administration of alpha-GalCer to mice favors the generation of conventional T lymphocytes producing T helper (Th) type 2 cytokines such as IL-4 and IL-10. These findings suggest that alpha-GalCer can modulate inflammatory conditions that are mediated by pathogenic Th1 cells. Indeed, recent studies have demonstrated that alpha-GalCer prevents the development of Type 1 diabetes in non-obese diabetic mice and central nervous system inflammation in mouse models of multiple sclerosis. Collectively, these studies provide a solid foundation for the development of NKT cell ligands as pharmacological agents for treatment of autoimmune diseases.
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PMID:Natural killer T cells as targets for therapeutic intervention in autoimmune diseases. 1257 Aug 26

TRAIL, the tumor necrosis factor-related apoptosis-inducing ligand, selectively induces apoptosis of tumor cells, but not most normal cells. Its role in normal, nontransformed tissues is not clear. We report here that mice deficient in TRAIL have a severe defect in thymocyte apoptosis-thus, thymic deletion induced by T cell receptor ligation is severely impaired. TRAIL-deficient mice are also hypersensitive to collagen-induced arthritis and streptozotocin-induced diabetes and develop heightened autoimmune responses. Thus, TRAIL mediates thymocyte apoptosis and is important in the induction of autoimmune diseases.
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PMID:Defective thymocyte apoptosis and accelerated autoimmune diseases in TRAIL-/- mice. 1260 25

Activated insulin-specific CD8(+) T cells (IS-CD8(+) cells) home to the pancreas, destroy beta cells, and cause rapid diabetes upon transfer into diabetes-prone NOD mice. Surprisingly, they also cause diabetes in mouse strains that are free of preexistent inflammation. Thus, we hypothesized that islet-specific homing may be in part dependent on IS-CD8(+) cells' recognition of the cognate major histocompatibility complex (MHC)/peptide complexes presented by pancreatic endothelial cells, which acquire the antigen (insulin) from beta cells. In fact, islet-specific homing was abrogated in mice that lack MHC class I expression, or presentation of the specific peptide, or have impaired insulin secretion. Moreover, we found that IS-CD8(+) cells directly recognized pancreatic endothelial cells in islet organ cultures. Triggering of IS-CD8(+) cells' T cell receptor (TCR) led to activation of integrins expressed by these cells. In addition, chemokines, particularly SLC (CCL21), were also required for IS-CD8(+) cells' adhesion to endothelial monolayers and for successful homing in vivo. Thus, signaling through TCR and chemokine receptors work in concert to assure firm adhesion of T cells to the pancreatic endothelium. The antigen cross-presentation ability of endothelia may therefore contribute to the specificity of homing of activated T lymphocytes to the tissues where antigens are generated by other cell types.
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PMID:Presentation of antigen by endothelial cells and chemoattraction are required for homing of insulin-specific CD8+ T cells. 1261 5

To detect and characterize autoreactive T cells in diabetes-prone NOD mice, we have developed a multimeric MHC reagent with high affinity for the BDC-2.5 T cell receptor, which is reactive against a pancreatic autoantigen. A distinct population of T cells is detected in NOD mice that recognizes the same MHC/peptide target. These T cells are positively selected in the thymus at a surprisingly high frequency and exported to the periphery. They are activated specifically in the pancreatic LNs, demonstrating an autoimmune specificity that recapitulates that of the BDC-2.5 cell. These phenomena are also observed in mouse lines that share with NOD the H-2g7 MHC haplotype but carry diabetes-resistance background genes. Thus, a susceptible haplotype at the MHC seems to be the only element required for the selection and emergence of autoreactive T cells, without requiring other diabetogenic loci from the NOD genome.
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PMID:Susceptible MHC alleles, not background genes, select an autoimmune T cell reactivity. 1297 66

Self-reactivity is potentially so devastating to the organism that a variety of regulatory devices have evolved to control it. One broadly used strategy is that employing the processed T cell receptor (TCR) as a target for TCR-specific regulatory cells. In several autoimmune models, feedback regulation employing both CD4+ and CD8+ T cells of TCR specificity can be shown to occur and to account for remission from the transient disease state, or for its prevention. We will focus here on the experimental autoimmune encephalomyelitis (EAE) model in the B10.PL (H-2u) mouse. In this model, the acetylated 1-9 N-terminal antigenic determinant from myelin basic protein (MBP) induces a transient paralytic disease owing to the activation of self-directed, high-affinity, CD4+ T cells. Although the response is multiclonal, a particularly aggressive member of this repertoire, bearing a Vbeta8.2,Jbeta2.7 receptor, which we have termed a 'driver clone', appears to be largely responsible for the disease process. A CD4+ T cell directed against a TCR determinant in the framework region of the Vbeta chain, and a CD8+ T cell directed against an upstream, distinct framework determinant, both of which are necessary for regulation, bring about a reversal of the disease process. To accomplish this, there must be a Th1 milieu during the induction of regulation, which is provided in part by the CD4+ regulatory cells themselves. To act as a target, the Vbeta8.2 MBP-reactive T cell must be activated, and the Th1 driver clone(s) is down-regulated via apoptotic killing, leaving a group of Th2, MBP-specific clones of weak affinity, which themselves may help in perpetuating long-term regulation. Similar results are also found in the collagen arthritis and NOD diabetes models.
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PMID:Seven surprises in the TCR-centred regulation of immune responsiveness in an autoimmune system. 1460 18

Using BW 5147 T cell hybridomas isolated by fusion with spleen and lymph node cells from NOD female mice, two T cell receptor transgenic NOD mouse lines were produced. Both TCR transgenics respond to their cognate peptide/MHC (GAD65 206-220 and 286-300) and produce IL-2, IFN-gamma, and small amounts of IL-10. Unexpectedly, the transgenic mice do not develop diabetes and have no insulitis. Analysis with a GAD65 286-300/I-A(g7) tetramer reveals that transgenic T cells are negatively selected in the thymus and further negatively selected in the periphery. When crossed to the C(alpha)(-/-) NOD line, CD4 T cells were reduced by 90% in the thymus and periphery. Further, the tetramer positive GAD65 286-300 specific T cells were capable of delaying the onset of diabetes in a standard transfer system. Thus, GAD65 specific TCR transgenic T cells (1) must express a second a chain to survive negative selection, (2) produce IL-2 and IFN-gamma, and (3) have a mildly protective effect on transfer of diabetes with diabetogenic spleen cells.
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PMID:The T cell response to glutamic acid decarboxylase 65 in T cell receptor transgenic NOD mice. 1467 41


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