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)

The non-obese diabetic (NOD) mouse strain provides a remarkable model for investigating the mechanisms of autoimmunity. Independent genetic analyses of this model have previously shown that chromosome 1-linked loci were involved in the control of periinsulitis and sialitis on the one hand and of insulitis and diabetes on the other hand. In the present work, analysis of a [NOD x (NOD x C57BL/6)F1] backcross progeny allowed us to clearly dissociate two genetic regions: one was associated with periinsulitis and mapped to the middle region of chromosome 1, in the vicinity of the Bcl-2 gene; the other was associated with insulitis and mapped to the proximal part of the chromosome. Three intermediate markers D1Mit18, D1Mit5 and D1Mit19 covering at least 25 centiMorgans between these two regions, were associated with neither periinsulitis nor insulitis. The role of the Bcl-2-linked region in the immune anomalies of NOD mice was further investigated in a (NOD x C57BL/6)F2 cross where the Bcl-2nod haplotype was linked to elevated serum levels of IgG (p < 0.0005). The middle region of chromosome 1 is, therefore, involved in the control of three phenotypes, including periinsulitis, sialitis and hyperIgG, pointing to Bcl-2 as a good candidate for a cause of the NOD mouse disease. Consistent with the anti-apoptotic function of the Bcl-2 gene product, activated T lymphocytes from NOD mice showed a markedly increased resistance to induction of apoptosis following deprivation of interleukin-2 when compared to those from non-autoimmune strains. After the recent observation of the Fas gene alterations in the lpr and lprcg mutations, these findings indicate that deregulation of lymphoid cell apoptosis may be a general pathogenetic mechanism in autoimmune diseases.
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PMID:Genetic analysis of immune dysfunction in non-obese diabetic (NOD) mice: mapping of a susceptibility locus close to the Bcl-2 gene correlates with increased resistance of NOD T cells to apoptosis induction. 829 87

Allogeneic transplantation of islets of Langerhans was facilitated by the cotransplantation of syngeneic myoblasts genetically engineered to express the Fas ligand (FasL). Composite grafting of allogeneic islets with syngeneic myoblasts expressing FasL protected the islet graft from immune rejection and maintained normoglycemia for more than 80 days in mice with streptozotocin-induced diabetes. Graft survival was not prolonged with composite grafts of unmodified myoblasts or Fas-expressing myoblasts. Islet allografts transplanted separately from FasL-expressing myoblasts into the contralateral kidney were rejected, as were similarly transplanted third-party thyroid allografts. Thus, the FasL signal provided site- and immune-specific protection of islet allografts.
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PMID:Prevention of islet allograft rejection with engineered myoblasts expressing FasL in mice. 941 54

Studies with perforin-deficient mice have demonstrated that two independent mechanisms account for T cell-mediated cytotoxicity: A main pathway is mediated by the secretion of the pore-forming protein perforin by the cytotoxic T cell, whereas an alternative nonsecretory pathway relies on the interaction of the Fas ligand that is upregulated during T cell activation with the apoptosis-inducing Fas molecule on the target cell. NK cells use the former pathway exclusively. The protective role of the perforin-dependent pathway has been shown for infection with the noncytopathic lymphocytic choriomeningitis virus, for infection with Listeria monocytogenes, and for the elimination of tumor cells by T cells and NK cells. In contrast, perforin-dependent cytotoxicity is not involved in protection against the cytopathic vaccinia virus and vesicular stomatitis virus. LCMV-induced immunopathology and autoimmune diabetes have been found to require perforin-expression. A contribution of perforin-dependent cytotoxicity to the rejection of MHC class I-disparate heart grafts has also been observed. Its absence is efficiently compensated in rejection of fully allogeneic organ or skin grafts. So far, evidence for a role of Fas-dependent cytotoxicity as a T cell effector mechanism in vivo is lacking. Current data suggest that the main function of Fas may be in regulation of the immune response and apparently less at the level of an effector mechanism in host defense. Further analysis is necessary, however, to settle this point finally.
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PMID:Molecular mechanisms of lymphocyte-mediated cytotoxicity and their role in immunological protection and pathogenesis in vivo. 871 13

Triggering of CD95 (Fas/APO-1) cell surface receptors regulates the elimination of autoreactive T and B lymphocytes through a mechanism of cell suicide called apoptosis. Three different mutations involving CD95 or its ligand are responsible for induction of autoimmunity in susceptible mouse strains. To determine whether a defect involving the CD95 receptor is associated with human insulin-dependent diabetes mellitus (IDDM), we have studied the expression of CD95 on peripheral blood mononuclear cells from IDDM patients at different stages of the disease. Three-colour flow cytometry and mean fluorescence analysis showed that T and B lymphocytes from newly diagnosed IDDM and patients with long-standing disease, and subjects at high risk of developing the disease were highly defective in CD95 expression (p < 0.001), whereas monocytes from all the groups studied expressed normal amounts of CD95 molecules on their cell surface. T-cell subset analysis showed that the impairment of CD95 expression in IDDM patients and high-risk subjects involved both CD3+ CD4+ (p < 0.001) and CD3+ CD8+ cells (p range: < 0.01-0.001), suggesting that this alteration concerns both helper and cytotoxic T cells. Moreover, after activation in vitro with anti-CD3 monoclonal antibody, T cells from newly diagnosed IDDM patients maintained a reduced CD95 expression during the entire cell culture period (24-72 h) in comparison to the control population (p < 0.001). In conclusion, we found a reduced expression of the apoptosis-inducing CD95 receptor on T and B lymphocytes of individuals with clinical and preclinical IDDM. We hypothesize that this defective expression may impair the capacity of autoreactive lymphocytes to undergo CD95-mediated apoptosis, contributing to the lack of control on beta-cell specific B- and T-cell clones.
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PMID:Defective expression of the apoptosis-inducing CD95 (Fas/APO-1) molecule on T and B cells in IDDM. 878 19

This study was conducted to investigate the possible involvement of Fas in beta-cell death in insulitis of Type 1 (insulin-dependent) diabetes mellitus. Although primary cultured Balb/c mouse islet cells did not express Fas mRNA, 4-12 hours of treatment with 10(2)-10(3) U/l of mouse interleukin-1 alpha (IL-1 alpha) induced the expression of Fas mRNA. Surface Fas expression was detected by immunofluorescence flow cytometry using a non-cytolytic anti-Fas monoclonal antibody after 6 or 12 h of incubation with 10(3) U/l of IL-1 alpha. Primary islet cells were resistant to an agonistic anti-Fas monoclonal antibody. However, 12 h pretreatment with IL-1 alpha sensitized islet cells to its cytolytic effect. Significant cell death was observed 24 h after the addition of anti-Fas, and progressively increased until 72 h, when specific 51Cr release was 72 +/- 6%. Agarose gel electrophoresis of DNA extracted from cells exposed to IL-1 alpha and agonistic anti-Fas showed internucleosomal DNA fragmentation, a hallmark of apoptotic cell death. Since the Fas antibody showed no cross-reactive activity of tumour necrosis factor (TNF), the cytotoxic effect was not mediated by TNF receptors. A protein synthesis inhibitor cycloheximide augmented Fas-mediated islet cell death. The Fas-mediated killing of islet cells was not L-arginine-dependent, or blocked by N(G)-monomethyl-L-arginine. beta-TC1 cells also expressed Fas mRNA when exposed to IL-1 alpha or IL-1 alpha plus interferon-gamma. These observations suggest that Fas-mediated apoptosis may be a mechanism of islet cell death in autoimmune insulitis.
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PMID:Mouse islet cell lysis mediated by interleukin-1-induced Fas. 893 96

Fas-associated death domain protein (FADD)/MORT1 is a 23-kDa cytoplasmic protein containing a C-terminal death domain that interacts with the intracellular death domain of the Fas transmembrane receptor. Cross-linking of Fas mediates apoptosis in a variety of cells, primarily peripheral T lymphocytes, for which this pathway plays a major role in mature lymphocyte homeostasis. We report the characterization of the human FADD gene, which spans approximately 3.6 kb and contains two exons (286 and 341 bp) separated by a 2.0-kb intron. FADD was mapped to chromosome 11q13.3 by the independent techniques of PCR screening of somatic cell hybrid mapping panels and fluorescence in situ hybridization. In addition FADD was shown by fluorescence in situ hybridization to be amplified along with other 11q13.3 genes previously studied in the breast cancer cell line MDA-MB-134-VI, raising the possibility that overexpression of mutant FADD could contribute to poor prognosis and increased invasiveness of tumors. Its known role in apoptosis has made FADD a candidate susceptibility gene for autoimmune lymphoproliferative syndrome. Now that it has been colocalized in 11q13.3 with IDDM4, a diabetes susceptibility locus, alterations in FADD should also be considered as potential contributors to insulin-dependent familial diabetes. Elucidation of the map position and gene structure of FADD will make possible linkage and mutation analysis to study the role of this gene in human diseases.
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PMID:Genomic structure and mapping of human FADD, an intracellular mediator of lymphocyte apoptosis. 895 95

Immunologically privileged sites express Fas ligand (FasL), which protects them from attack by activated T cells that express Fas and die upon contact with FasL. In an attempt to protect nonobese diabetic mice (NOD) from autoimmune diabetes, we made FasL transgenic NOD mice using the beta cell-specific rat insulin-1 promoter. Surprisingly, these transgenic mice showed heightened sensitivity to diabetogenic T cells, which was due to self-destruction of beta cells upon T cell-mediated induction of Fas. Fas-negative NOD(lpr/lpr) animals were resistant to diabetogenic T cells and to spontaneous diabetes. Thus, induction of Fas expression on beta cells and their subsequent destruction constitutes the main pathogenic mechanism in autoimmune diabetes.
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PMID:The role of Fas in autoimmune diabetes. 909 10

Immunoglobulins from patients with diabetic neuropathy are toxic to neuroblastoma cells. The cell death has characteristics of apoptosis: condensed chromatin, shrunken cytoplasm, elevation of [Ca2+]i and DNA fragmentation. N1E-115 cell membranes contain Fas, a regulator of apoptosis that recently has been shown to be involved in pancreatic beta-cell destruction leading to diabetes. Fas-specific antibodies bind to the surface of N1E-115 cells and induce apoptosis. Serum from patients with diabetic neuropathy block Fas-antibody binding. We conclude that sera from patients with diabetic neuropathy contain an activator of Fas-regulated apoptosis that may contribute to the pathogenesis of diabetic neuropathy.
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PMID:The apoptotic death of neuroblastoma cells caused by serum from patients with insulin-dependent diabetes and neuropathy may be Fas-mediated. 918 45

Fas ligand is believed to mediate immune privilege in a variety of tissues, including the eye, testis, and a subset of tumors. We tested whether expression of Fas ligand on pancreatic islets either following adenoviral or germline gene transfer could confer immune privilege after transplantation. Islets were infected with an adenoviral vector containing the murine Fas ligand cDNA (AdFasL), and were transplanted into allogenic diabetic hosts. Paradoxically, AdFasL-infected islets underwent accelerated neutrophilic rejection. The rejection was T cell and B cell independent and required Fas protein expression by host cells, but not on islets. Similarly, transgenic mice expressing Fas ligand in pancreatic beta cells developed massive neutrophilic infiltrates and diabetes at a young age. Thus, Fas ligand expression on pancreatic islets results in neutrophilic infiltration and islet destruction. These results have important implications for the development of Fas ligand-based immunotherapies.
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PMID:Fas ligand expression in islets of Langerhans does not confer immune privilege and instead targets them for rapid destruction. 921 96

Insulin-dependent diabetes mellitus (IDDM) is assumed to be a T cell-mediated autoimmune disease. To investigate the role of Fas-mediated cytotoxicity in pancreatic beta cell destruction, we established nonobese diabetic (NOD)-lymphoproliferation (lpr)/lpr mice lacking Fas. Out of three genotypes, female NOD-+/+ and NOD-+/lpr developed spontaneous diabetes by the age of 10 mo with the incidence of 68 and 62%, respectively. In contrast, NOD-lpr/lpr did not develop diabetes or insulitis. To further explore the role of Fas, adoptive transfer experiments were performed. When splenocytes were transferred from diabetic NOD, male NOD-+/+ and NOD-+/lpr developed diabetes with the incidence of 89 and 83%, respectively, whereas NOD-lpr/lpr did not show glycosuria by 12 wk after transfer. Severe mononuclear cell infiltration was revealed in islets of NOD-+/+ and NOD-+/lpr, whereas islet morphology remained intact in NOD-lpr/lpr. These results suggest that Fas-mediated cytotoxicity is required to initiate beta cell autoimmunity in NOD mice. Fas-Fas ligand system might be critical for autoimmune beta cell destruction leading to IDDM.
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PMID:Requirement of Fas for the development of autoimmune diabetes in nonobese diabetic mice. 925 59


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