Cytokines and effector T cell subsets causing autoimmune CNS disease

Petermann, Franziska; Korn, Thomas

doi:10.1016/j.febslet.2011.03.064

Cited by 115 publications

(94 citation statements)

References 227 publications

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“…Of major interest in this study is the suppressed release of T cell effector cytokines: IFN-g and IL-17. These cytokines represent the markers of Th1 and Th17 cells, which have been considered the major driving force of inflammation and autoimmunity in MS (24). EP and DMF provoked a drop in macrophage release/ production of cytokines (IL-6 and TNF) and reactive species (NO and ROS), which promote neuroinflammatory and neurodegenerative events in MS. For example, it has been shown that IL-6 potentiates the resistance of effector T cells to regulatory T cells in MS (34), and that soluble TNF actively contributes to demyelination and axonal degeneration in EAE neuroinflammation (35).…”

Section: Discussionmentioning

confidence: 99%

“…This model has been proved useful in studying pathological mechanisms of MS. Also, some of the MS therapies, including Copaxone and natalizumab, emerged from EAE studies (23). Th phenotypes that produce IFN-g or IL-17, that is, Th1 and Th17 cells, are considered to be the major pathogenic population in MS and EAE (24). Their interactions with APCs, such as dendritic cells and macrophages, both within the CNS and in lymphoid organs, are essential for initiation and propagation of autoimmune response directed against the CNS (25).…”

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confidence: 99%

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A Comparative Analysis of Multiple Sclerosis–Relevant Anti-Inflammatory Properties of Ethyl Pyruvate and Dimethyl Fumarate

Miljković

Blaževski

Petković

et al. 2015

The Journal of Immunology

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Dimethyl fumarate (DMF), a new drug for multiple sclerosis (MS) treatment, acts against neuroinflammation via mechanisms that are triggered by adduct formation with thiol redox switches. Ethyl pyruvate (EP), an off-the-shelf agent, appears to be a redox analog of DMF, but its immunomodulatory properties have not been put into the context of MS therapy. In this article, we examined and compared the effects of EP and DMF on MS-relevant activity/functions of T cells, macrophages, microglia, and astrocytes. EP efficiently suppressed the release of MS signature cytokines, IFN-γ and IL-17, from human PBMCs. Furthermore, the production of these cytokines was notably decreased in encephalitogenic T cells after in vivo application of EP to rats. Production of two other proinflammatory cytokines, IL-6 and TNF, and NO was suppressed by EP in macrophages and microglia. Reactive oxygen species production in macrophages, microglia activation, and the development of Ag-presenting phenotype in microglia and macrophages were constrained by EP. The release of IL-6 was reduced in astrocytes. Finally, EP inhibited the activation of transcription factor NF-κB in microglia and astrocytes. Most of these effects were also found for DMF, implying that EP and DMF share common targets and mechanisms of action. Importantly, EP had in vivo impact on experimental autoimmune encephalomyelitis, an animal model of MS. Treatment with EP resulted in delay and shortening of the first relapse, and lower clinical scores, whereas the second attack was annihilated. Further studies on the possibility to use EP as an MS therapeutic are warranted.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

A Comparative Analysis of Multiple Sclerosis–Relevant Anti-Inflammatory Properties of Ethyl Pyruvate and Dimethyl Fumarate

Miljković

Blaževski

Petković

et al. 2015

The Journal of Immunology

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“…MS is thought to occur in genetically predisposed individuals under certain environmental conditions, leading to the development of CNS Agspecific Th1 and Th17 cells (2), which can then be reactivated by their cognate Ag in the CNS and cause autoimmune disease (3). This development of CNS autoimmunity can be modeled in susceptible mouse strains by immunizing them with CNS Ags, for example, myelin peptides, resulting in myelin-specific Th1 and Th17 responses and experimental autoimmune encephalomyelitis (EAE) (4).…”

Section: Ultiple Sclerosis (Ms)mentioning

confidence: 99%

Neutrophils Amplify Autoimmune Central Nervous System Infiltrates by Maturing Local APCs

Steinbach

Piedavent

Bauer

et al. 2013

The Journal of Immunology

111

130

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Multiple sclerosis is considered to be initiated by a deregulated, myelin-specific T cell response. However, the formation of inflammatory CNS lesions and the contribution of different leukocyte subsets in setting up these lesions are still incompletely understood. In this study, we show that, in the mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis, neutrophil granulocytes are important contributors in preparing CNS inflammation. Preclinical single-dose Ab-mediated depletion of neutrophils delayed the onset and continuous depletion attenuated the development of experimental autoimmune encephalomyelitis, whereas the generation of a myelin-specific T cell response remained unaffected. Neutrophil-related enzymes such as myeloperoxidase and neutrophil elastase did not contribute in mounting CNS inflammation, as analyzed by using respective knockout mice and inhibitors. CNS-infiltrating neutrophils secreted proinflammatory molecules and matured bone marrow–derived dendritic cells in vitro, which in turn enhanced their ability to restimulate myelin-specific T cells. This was mirrored in vivo, in which depletion of neutrophils specifically impaired maturation of microglia and macrophages into professional APCs, resulting in a diminished amplification of early CNS inflammation. Therefore, inside the CNS neutrophils provide local cofactors that are required for the maturation of myeloid cells into professional APCs representing an essential step for the local restimulation of myelin-specific T cells and the development of autoimmune disease.

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“…At day 15 p.i., IFN-γ, TNF, GM-CSF, IL-27, and iNOS but not IL17 mRNA was increased in GFAP-Cre FasL fl/fl mice as compared with that in FasL fl/fl mice. IFN-γ, TNF, and GM-CSF have been reported to contribute to disease progression and demyelination in EAE [7,28]. GM-CSF and IFN-γ are mainly produced by encephalitogenic T cells.…”

Section: Discussionmentioning

confidence: 99%

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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Cytokines and effector T cell subsets causing autoimmune CNS disease

Cited by 115 publications

References 227 publications

A Comparative Analysis of Multiple Sclerosis–Relevant Anti-Inflammatory Properties of Ethyl Pyruvate and Dimethyl Fumarate

A Comparative Analysis of Multiple Sclerosis–Relevant Anti-Inflammatory Properties of Ethyl Pyruvate and Dimethyl Fumarate

Neutrophils Amplify Autoimmune Central Nervous System Infiltrates by Maturing Local APCs

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

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