The Role of Fas in Autoimmune Diabetes

Chervonsky, Alexander V.; Wang, Yi; Wong, F. Susan; Visintin, Irene; Flavell, Richard A.; Janeway, Charles A.; Matis, Louis A.

doi:10.1016/s0092-8674(00)80178-6

Cited by 468 publications

(367 citation statements)

References 43 publications

(21 reference statements)

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“…We first assessed how well InsHA-derived K d HA-specific CTL performed in mediating lysis through the Fas/FasL pathway, as other investigators have observed that destruction of Fas ϩ ␤ cells solely through this pathway can initiate autoimmune diabetes in mouse models (41,62). However, InsHA-derived K d HA-specific CTL were proficient in lysing targets when the perforin pathway was inhibited.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of CD8+ T Lymphocytes That Persist After Peripheral Tolerance to a Self Antigen Expressed in the Pancreas

Nugent

Morgan

Biggs

et al. 2000

The Journal of Immunology

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As a result of expression of the influenza hemagglutinin (HA) in the pancreatic islets, the repertoire of HA-specific CD8+ T lymphocytes in InsHA transgenic mice (D2 mice expressing the HA transgene under control of the rat insulin promoter) is comprised of cells that are less responsive to cognate Ag than are HA-specific CD8+ T lymphocytes from conventional mice. Previous studies of tolerance induction involving TCR transgenic T lymphocytes suggested that a variety of different mechanisms can reduce avidity for Ag, including altered cell surface expression of molecules involved in Ag recognition and a deficiency in signaling through the TCR complex. To determine which, if any, of these mechanisms pertain to CD8+ T lymphocytes within a conventional repertoire, HA-specific CD8+ T lymphocytes from B10.D2 mice and B10.D2 InsHA transgenic mice were compared with respect to expression of cell surface molecules, TCR gene utilization, binding of tetrameric KdHA complexes, lytic mechanisms, and diabetogenic potential. No evidence was found for reduced expression of TCR or CD8 by InsHA-derived CTL, nor was there evidence for a defect in triggering lytic activity. However, avidity differences between CD8+ clones correlated with their ability to bind KdHA tetramers. These results argue that most of the KdHA-specific T lymphocytes in InsHA mice are not intrinsically different from KdHA-specific T lymphocytes isolated from conventional animals. They simply express TCRs that are less avid in their binding to KdHA.

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Section: Discussionmentioning

confidence: 99%

“…Fas/FasL-mediated lysis has been found to be an important potentiator of islet destruction (41,42). In addition, some CTL specific for self are unable to lyse targets via the perforin pathway, but are proficient in Fas/FasL-mediated lysis (43,44).…”

Section: Comparison Of the Lytic Mechanism Employed By Ha-specific Ctmentioning

confidence: 99%

Characterization of CD8+ T Lymphocytes That Persist After Peripheral Tolerance to a Self Antigen Expressed in the Pancreas

Nugent

Morgan

Biggs

et al. 2000

The Journal of Immunology

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“…Whenagonistic anti-Fas antibody or the recombinant FasL was administered into mice, mice were killed by acute liver failure (1 1), suggesting an involvement of the Fas-induced apoptosis in CTL-mediated tissue distraction. In fact, we and others could show that CTL-mediated autoimmune diseases such as hepatitis, thyrodidis and insulitis are caused by overfunction of the Fas-mediated apoptosis (12)(13)(14). In addition, stroma cells of the eye and testis constitutively express FasL (15,16), which is believed to kill the inflammatory cells infiltrating into these tissues (Fig.…”

Section: Fas and Fas Ligand And Fas-mediated Apoptosismentioning

confidence: 91%

Fas-induced Apoptosis.

Nagata

1998

Intern. Med.

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“…Recently, FasL/Fas interaction has received attention as an explanation for autoimmune beta-cell destruction in Type I diabetes [24,25]. However, little is known about which are the most important pathways mediating beta-cell damage in Type I diabetes.…”

Section: Multiple Factors Influenced the Susceptibility Of Normal Islmentioning

confidence: 99%

“…However, little is known about the roles played by the TRAIL death pathway on beta-cell destruction in Type I diabetes. Recently, pancreatic beta-cell "fratricide" through apoptosis mediated by the "ligand/receptor pair" FasL/Fas has been advanced as an explanation for beta-cell destruction in Type I diabetes, although conflicting experimental results have been given [24,25]. TRAIL and its two death signalling receptors, R1 and R2, are closely related to FasL and Fas, respectively [8,13], suggesting similar mechanisms of death signalling.…”

mentioning

confidence: 99%

TNF-Related Apoptosis-Inducing Ligand Death Pathway-Mediated Human Beta-Cell Destruction

Metzger

Wang

et al. 2002

Diabetologia

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Aims/hypothesis. The aim of this study is to investigate whether apoptosis in human beta cells can be related to the induction of the tumor necrosis factorrelated apoptosis-inducing ligand (TRAIL) pathway. Methods. We examined the expression of TRAIL and TRAIL receptors in two human pancreatic beta-cell lines and in human primary islet cells using RT-PCR assays and flow cytometric analyses and tested TRAIL-mediated beta-cell destruction in 51 Cr release cytotoxicity assays, Annexin-V and APO-DIREC assays.Results. Most of the human beta cells express TRAIL receptors-R1, -R2, -R3, -R4 and/or TRAIL. TRAIL induced much stronger cytotoxicity and apoptosis to beta-cell lines CM and HP62 than did FasL, TNF-α, LTα1β2, LTα2β1, LIGHT, and IFN-γ. The cytotoxicity and apoptosis induced by TRAIL to beta-cell lines CM were inhibited competitively by soluble TRAIL receptors, R1, R2, R3 or R4. Treatment of these beta cells with antibodies against TRAIL receptors was able to block the cytotoxicity of TRAIL to these cells. Beta-cell antigen-specific CTL (CD4 + and CD8 + ) clones express TRAIL, suggesting that these cells are potential sources of TRAIL-inducing betacell destruction. Normal primary islet cells from most donors are resistant to the cytotoxicity mediated by TRAIL. However, treatment with an inhibitor of protein synthesis (cycloheximide) or with an enzyme (PI-PLC) that can remove TRAIL-R3 from the isletcell membrane was able to increase the susceptibility of TRAIL-resistant primary islet cells to the TRAIL death pathway. Conclusion/interpretation. The TRAIL death pathway is present and can function in human islet beta cells, but unidentified inhibitors of the TRAIL death pathway are present in normal islet cells. [Diabetologia (2002[Diabetologia ( ) 45:1678[Diabetologia ( -1688

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The Role of Fas in Autoimmune Diabetes

Cited by 468 publications

References 43 publications

Characterization of CD8+ T Lymphocytes That Persist After Peripheral Tolerance to a Self Antigen Expressed in the Pancreas

Characterization of CD8+ T Lymphocytes That Persist After Peripheral Tolerance to a Self Antigen Expressed in the Pancreas

Fas-induced Apoptosis.

TNF-Related Apoptosis-Inducing Ligand Death Pathway-Mediated Human Beta-Cell Destruction

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