Virally Induced Inflammation Triggers Fratricide of Fas-Ligand–Expressing β-Cells (original) (raw)
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Virally Induced Inflammation Triggers Fratricide of Fas-Ligand-Expressing -Cells
Diabetes, 2004
Tissue-specific expression of Fas-ligand (Fas-L) can provide immune privilege by inducing apoptosis of "invading" lymphocytes expressing Fas. However, accelerated diabetes has been reported in transgenic mice expressing Fas-L in islets (RIP-Fas-L) as a result of Fas-dependent fratricide of -cells after transfer of diabetogenic clones. Here we studied whether Fas-L could protect islets from autoaggressive CD8 lympho-
Diabetes, 1999
Similarly, polymerase chain reaction analysis of islet grafts revealed that Fas mRNA expression was significantly lower in islet grafts from normoglycemic compared with diabetic mice. Also, mRNA levels of interleukin (IL)-1 , tumor necrosis factor (TNF)-, and interferon (IFN)-w e r e s i g n i ficantly lower in islet grafts from normoglycemic mice. Finally, Fas was induced on NOD islet cells by incubation with IL-1 , IFN-, and the combination of IL-1 , TNF-, and IFN-. These findings support the concept that cytokine-induced Fas receptor expression on islet -cells is a mechanism for their destruction by FasL-expressing CD4 + and CD8 + T-cells and, possibly, by FasL-expressing -cells themselves. D i a b e t e s 48:21-28, 1999 a l b e r t a . c a .
Journal of Biomedical Science, 2001
Fas (CD95) and Fas ligand (FasL/CD95L) are involved in programmed cell death and the regulation of host immune responses. FasL has been shown to provide immune privilege, thus prolonging the survival of unmatched grafts in a variety of tissues, such as eyes and testis. In murine FasL (mFasL) transgenic mice, FasL provoked granulocyte infiltration and insulitis in the pancreas. We intended to study whether the expression of human FasL, instead of mFasL, on mouse !3 islet cells could avoid granulocyte infiltration, and whether islet cells transgenic for FasL could be used in islet transplantation. We produced transgenic mice in which the human FasL transgene was driven by rat insulin promoter and was expressed exclusively in the pancreas islet cells in ICR mice. In contrast to mFasL transgenic mice, histochemical staining showed that the pancreas was intact in human FasL transgenic ICR mice. However, when human FasL transgenic islet cells were transplanted into allogeneic mice with streptozotocin-induced diabetes, human FasL appeared not to prolong graft survival.
Significant Role for Fas in the Pathogenesis of Autoimmune Diabetes
The Journal of Immunology, 2000
Programmed cell death represents an important pathogenic mechanism in various autoimmune diseases. Type I diabetes mellitus (IDDM) is a T cell-dependent autoimmune disease resulting in selective destruction of the β cells of the islets of Langerhans. β cell apoptosis has been associated with IDDM onset in both animal models and newly diagnosed diabetic patients. Several apoptotic pathways have been implicated in β cell destruction, including Fas, perforin, and TNF-α. Evidence for Fas-mediated lysis of β cells in the pathogenesis of IDDM in nonobese diabetic (NOD) mice includes: 1) Fas-deficient NOD mice bearing the lpr mutation (NOD-lpr/lpr) fail to develop IDDM; 2) transgenic expression of Fas ligand (FasL) on β cells in NOD mice may result in accelerated IDDM; and 3) irradiated NOD-lpr/lpr mice are resistant to adoptive transfer of diabetes by cells from NOD mice. However, the interpretation of these results is complicated by the abnormal immune phenotype of NOD-lpr/lpr mice. Here...
The Role of Fas Ligand in Beta Cell Destruction in Autoimmune Diabetes of NOD Mice
Annals of the New York Academy of Sciences, 2006
Fas ligand (FasL), a type 2 membrane protein belonging to the TNF family, plays an important role in the induction of cell death. Ligation of Fas receptors by FasL results in apoptosis of the Fas-expressing cell. Autoimmune diabetes results from β β β β cell destruction by islet-reactive T cells, a process that involves β β β β cell apoptosis. This raises the question of whether the FasL-Fas pathway plays a major role in β β β β cell death. To address this issue it is important to know whether β β β β cells express Fas and/or FasL and, if so, whether induction of these molecules leads to β β β β cell death. In fact, both Fas and FasL have been demonstrated to be expressed by β β β β cells in response to cytokine stimulation, although there remains an argument in the literature as to whether β β β β cells truly express FasL. This is largely because FasL expression has only been demonstrable by immunohistochemistry and not by flow cytometry. Transgenic NOD mice with β β β β cells expressing a FasL transgene develop an accelerated form of diabetes. We show here that β β β β cells from FasL transgenic NOD mice are more susceptible to cytokine-induced apoptosis than wild-type β β β β cells, consistent with the hypothesis that if β β β β cells express FasL then Fas-FasL interaction on the β β β β cell surface is able to mediate β β β β cell self-death in the absence of T cells. Interventions that block the Fas-FasL pathway may be useful, therefore, in the prevention or treatment of type 1 diabetes.
Global profiling of coxsackievirus- and cytokine-induced gene expression in human pancreatic islets
Diabetologia, 2005
Aims/hypothesis: It is thought that enterovirus infections initiate or facilitate the pathogenetic processes leading to type 1 diabetes. Exposure of cultured human islets to cytolytic enterovirus strains kills beta cells after a protracted period, suggesting a role for secondary virusinduced factors such as cytokines. Methods: To clarify the molecular mechanisms involved in virus-induced beta cell destruction, we analysed the global pattern of gene expression in human islets. After 48 h, RNA was extracted from three independent human islet preparations infected with coxsackievirus B5 or exposed to interleukin 1β (50 U/ml) plus interferon γ (1,000 U/ml), and gene expression profiles were analysed using Affymetrix HG-U133A gene chips, which enable simultaneous analysis of 22,000 probe sets. Results: As many as 13,077 genes were detected in control human islets, and 945 and 1293 single genes were found to be modified by exposure to viral infection and the indicated cytokines, respectively. Four hundred and eighty-four genes were similarly modified by the cytokines and viral infection. Conclusions/ interpretation: The large number of modified genes observed emphasises the complex responses of human islet cells to agents potentially involved in insulitis. Notably, both cytokines and viral infection significantly (p<0.02) increased the expression of several chemokines, the cytokine IL-15 and the intercellular adhesion molecule ICAM-1, which might contribute to the homing and activation of mononuclear cells in the islets during infection and/or an early autoimmune response. The present results provide novel insights into the molecular mechanisms involved in viral-and cytokine-induced human beta cell dysfunction and death.