Coexpression of Fas/FasL and Bax on brain and infiltrating T cells in the central nervous system is closely associated with apoptotic cell death during autoimmune encephalomyelitis

Kohji, Toshihiko; Matsumoto, Yoh

doi:10.1016/s0165-5728(00)00238-1

Cited by 45 publications

(33 citation statements)

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“…The CNS-resident cell population which induces apoptosis of CD4 + T cells in EAE still remains to be identified. We hypothesize that astrocytes, which constitutively express FasL, may play a key role given that FasL-expressing astrocytes are in intimate contact with apoptotic T cells in EAE and can induce apoptosis of activated CD4 + T cells in vitro [21,22]. Consistently, our previous study also demonstrated that increased apoptosis of gp130-deficient astrocytes exacerbated EAE, partially due to an impaired elimination of CD4 + T cells from the CNS [23].…”

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confidence: 75%

Astrocytic Fas ligand expression is required to induce T‐cell apoptosis and recovery from experimental autoimmune encephalomyelitis

et al. 2012

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In T-cell-mediated autoimmune diseases of the CNS, apoptosis of FasKeywords: Autoimmunity r Astrocytes r EAE r FasL Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction EAE is a widely used animal model to study MS, an inflammatory demyelinating disease mediated by accumulation of T lymphocytes and macrophages in the CNS [1,2]. EAE can be induced by either active immunization with myelin Ags including myelin oligodendrocyte glycoprotein (MOG) peptide or passive transfer of myelin-reactive CD4 + T cells, which are both initiators and Correspondence: Prof. Dirk Schlüter e-mail: dirk.schlueter@med.ovgu.de effectors of EAE. Among CD4 + T lymphocytes, GM-CSF-producing CD4 + T cells, IFN-γ-secreting Th1 cells, and IL-17-secreting Th17 cells have been identified as the most important mediators in the immunopathogenesis of EAE [3][4][5][6] and all of them can induce EAE independently, although recent studies point to an essential role of GM-CSF-producing CD4 + T cells, which can induce EAE independent of . Infiltrating T lymphocytes trigger an inflammatory response in the CNS culminating in demyelination and axonal damage clinically resulting in paralysis [8]. Correspondingly, recovery from EAE requires termination of inflammation and the induction of T-cell apoptosis in the CNS [9].www.eji-journal.eu 116Xu Wang et al. Eur. J. Immunol. 2013. 43: 115-124 Fas ligand (FasL; CD95L), a cytotoxic cytokine belonging to the TNF superfamily, acts through Fas, a death receptor of the TNFR superfamily, to induce programed cell death via caspase signaling [10]. Local expression of FasL in immunoprivileged organs including eyes, testis, and placenta is essential for deletion of infiltrating inflammatory cells [11][12][13]. Fas/FasL interaction is of particular importance for homeostasis of the immune system and its dysregulation has been implicated in various autoimmune diseases. Mice carrying autosomal recessive mutations in the Fas (lpr) and FasL (gld) genes develop a spontaneous autoimmune syndrome similar to human systemic lupus erythematosus [14,15]. Fas and FasL are also involved in the pathogenesis of EAE, as EAE is dramatically ameliorated in lpr and gld mice in terms of disease incidence and mean clinical score [16]. Intrathecal infusion of recombinant FasL induces apoptosis of CNS-infiltrating inflammatory cells, including T cells and macrophages, but does not exert cytotoxicity against CNS-resident cells, resulting in mitigated EAE manifestations [17].Elimination of infiltrating T cells in the CNS by Fas/FasLmediated apoptosis is crucial for resolution of EAE [9,18,19], since FasL-deficient gld recipients develop prolonged EAE after adoptive transfer of myelin basic protein-reactive WT Fas + T lymphocytes [20]. The CNS-resident cell population which induces apoptosis of CD4 + T cells in EAE still remains to be identified. We hypothesize that astrocytes, which constitutively express FasL, may play a key role given that FasL-expressing astrocytes a...

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confidence: 75%

Astrocytic Fas ligand expression is required to induce T‐cell apoptosis and recovery from experimental autoimmune encephalomyelitis

et al. 2012

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“…In the EAE model, several studies have proposed that Ag-induced cell death in the CNS contributes to the recovery from the acute phase of the disease (44), and both Fas/ FasL interactions (53)(54)(55) and p53 (56) have been implicated in this process. The observation that the frequency of apoptotic events in the CNS only differed between P2X 7 R Ϫ/Ϫ and WT mice during the early phases of the disease suggests that P2X 7 R-dependent apoptosis may be one of several death-inducing pathways that become activated in the inflamed CNS, forming part of a complex immunoregulatory process that evolves over the course of the disease.…”

Section: Discussionmentioning

confidence: 99%

Exacerbation of Experimental Autoimmune Encephalomyelitis in P2X7R−/− Mice: Evidence for Loss of Apoptotic Activity in Lymphocytes

Chen

Brosnan

2006

The Journal of Immunology

120

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The purinergic receptor P2X7R is a nucleotide-gated ion channel that has been proposed to function as a major regulator of inflammation. In this study we examined the role of this receptor in regulating inflammation in the CNS by determining the effects of the loss of this receptor (P2X7R−/−) on experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. We show here that P2X7R−/− mice developed more severe clinical and pathological expression of EAE than wild type (WT) controls and that spleen and lymph node cells from P2X7R−/− mice proliferated more vigorously to Ag in vitro. Bone marrow (BM) radiation chimeras revealed that enhanced susceptibility to EAE was detected in chimeric mice of WT host engrafted with P2X7R−/− BM cells, indicating that the genotype of the BM cells regulated disease susceptibility. Coculture of P2X7R−/− macrophages with WT lymphocytes and vice versa showed that enhanced proliferative activity resided within the P2X7R−/− lymphocyte population and correlated with reduced levels of IFN-γ and NO and apoptosis of lymphocytes. mRNA and protein for IFN-γ were also significantly reduced in the CNS of P2X7R−/− mice with EAE. FACS analysis of cells isolated from the CNS showed significantly fewer annexin V/propidium iodide-positive lymphocytes in the CNS of P2X7R−/− mice early in the disease, and TUNEL staining of inflamed CNS tissues supported this result. From these data we conclude that enhanced susceptibility of P2X7R−/− mice to EAE reflects a loss of apoptotic activity in lymphocytes, supporting an important role for this receptor in lymphocyte homeostasis.

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“…The apoptotic T cells are phagocytosed by macrophages, microglia, astrocytes and oligodendrocytes (Nguyen and Pender, 1998;Magnus et al, 2002). It should be noted that other inflammatory cells, such as macrophages and microglia (Nguyen et al, 1994(Nguyen et al, , 1997White et al, 1998a;Kohji and Matsumoto, 2000) and B lymphocytes (White et al, 2000), also undergo apoptosis in the CNS in acute EAE. To study T-cell apoptosis in the CNS, it is therefore essential to demonstrate apoptosis of cells expressing T-cell markers rather than simply to demonstrate apoptosis in an unlabelled inflammatory cell infiltrate.…”

Section: Role Of Lymphocyte Apoptosis In the Cnsmentioning

confidence: 99%

“…An alternative experimental approach analyzing the expression of CD95 and CD95L by T cells in the CNS has indicated that the CD95 pathway is involved in T-cell apoptosis in the CNS during recovery from EAE in the rat (White et al, 1998b). T cells, particularly Vβ8.2 + T cells (representing the encephalitogenic MBP-specific T cells), express CD95 and CD95L in the CNS of rats with acute EAE (White et al, 1998b;Kohji and Matsumoto, 2000). During spontaneous recovery from acute EAE induced by immunization with MBP, Vβ8.2 + T cells expressing CD95 or CD95L are much more vulnerable to apoptosis in the CNS than Vβ8.2 + T cells not expressing these proteins (White et al, 1998b).…”

Section: Activation-induced Apoptosismentioning

confidence: 99%

“…In Lewis rats with EAE, apoptotic inflammatory cells associate with astrocytes (Kohji et al, 1998), and astrocytes express CD95L, leading to the suggestion that CD95L-expressing astrocytes induce T-cell apoptosis in the CNS by ligating T-cell CD95 (Kohji and Matsumoto, 2000). Astrocytes expressing CD95L can induce apoptosis in target cells in vitro (Bechmann et al, 1999;Choi et al, 1999).…”

Section: T-cell Apoptosis Induced By Ligation Of T-cell Cd95 By Cd95lmentioning

confidence: 99%

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Treating autoimmune demyelination by augmenting lymphocyte apoptosis in the central nervous system

Pender

2007

Journal of Neuroimmunology

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The elimination of autoreactive T cells from the central nervous system (CNS) by apoptosis plays an important role in switching off autoimmune attack. B-cell apoptosis in the CNS probably also has a key role in downregulating autoimmunity. Augmenting lymphocyte apoptosis in the CNS is a potential strategy for treating autoimmune CNS diseases such as multiple sclerosis. These strategies involve modulation of the physiological pro-apoptotic and anti-apoptotic pathways that control lymphocyte fate in the CNS. In the case of T cells, apoptosis can be augmented by enhancing activation-induced T-cell apoptosis through the CD95 (Fas) pathway and by inhibiting costimulation-induced antiapoptotic pathways mediated through BCL-2 and BCL-X L .

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Coexpression of Fas/FasL and Bax on brain and infiltrating T cells in the central nervous system is closely associated with apoptotic cell death during autoimmune encephalomyelitis

Cited by 45 publications

References 14 publications

Astrocytic Fas ligand expression is required to induce T‐cell apoptosis and recovery from experimental autoimmune encephalomyelitis

Astrocytic Fas ligand expression is required to induce T‐cell apoptosis and recovery from experimental autoimmune encephalomyelitis

Exacerbation of Experimental Autoimmune Encephalomyelitis in P2X7R−/− Mice: Evidence for Loss of Apoptotic Activity in Lymphocytes

Treating autoimmune demyelination by augmenting lymphocyte apoptosis in the central nervous system

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