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      Re-Examining the Role of TNF in MS Pathogenesis and Therapy

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          Abstract

          Multiple sclerosis (MS) is a common neurological disorder of putative autoimmune origin. Clinical and experimental studies delineate abnormal expression of specific cytokines over the course of the disease. One major cytokine that has been shown to play a pivotal role in MS is tumor necrosis factor (TNF). TNF is a pleiotropic cytokine regulating many physiological and pathological functions of both the immune system and the central nervous system (CNS). Convincing evidence from studies in human and experimental MS have demonstrated the involvement of TNF in various pathological hallmarks of MS, including immune dysregulation, demyelination, synaptopathy and neuroinflammation. However, due to the complexity of TNF signaling, which includes two-ligands (soluble and transmembrane TNF) and two receptors, namely TNF receptor type-1 (TNFR1) and type-2 (TNFR2), and due to its cell- and context-differential expression, targeting the TNF system in MS is an ongoing challenge. This review summarizes the evidence on the pathophysiological role of TNF in MS and in different MS animal models, with a special focus on pharmacological treatment aimed at controlling the dysregulated TNF signaling in this neurological disorder.

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          Dendritic cells and the control of immunity.

          B and T lymphocytes are the mediators of immunity, but their function is under the control of dendritic cells. Dendritic cells in the periphery capture and process antigens, express lymphocyte co-stimulatory molecules, migrate to lymphoid organs and secrete cytokines to initiate immune responses. They not only activate lymphocytes, they also tolerize T cells to antigens that are innate to the body (self-antigens), thereby minimizing autoimmune reactions. Once a neglected cell type, dendritic cells can now be readily obtained in sufficient quantities to allow molecular and cell biological analysis. With knowledge comes the realization that these cells are a powerful tool for manipulating the immune system.
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            Multiple Sclerosis

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              Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self.

              Naturally arising CD25(+)CD4(+) regulatory T cells actively maintain immunological self-tolerance. Deficiency in or dysfunction of these cells can be a cause of autoimmune disease. A reduction in their number or function can also elicit tumor immunity, whereas their antigen-specific population expansion can establish transplantation tolerance. They are therefore a good target for designing ways to induce or abrogate immunological tolerance to self and non-self antigens.
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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                14 October 2020
                October 2020
                : 9
                : 10
                : 2290
                Affiliations
                [1 ]Synaptic Immunopathology Lab, IRCCS San Raffaele Pisana, 00166 Rome, Italy; diego.fresegna@ 123456gmail.com (D.F.); Silvia.Bullitta@ 123456uniroma2.it (S.B.); msllsn00@ 123456uniroma2.it (A.M.); livia.guadalupi@ 123456gmail.com (L.G.); valentina_vanni@ 123456hotmail.it (V.V.); georgia.mandolesi@ 123456uniroma5.it (G.M.); antonellag79@ 123456gmail.com (A.G.)
                [2 ]Synaptic Immunopathology Lab, Department of Systems Medicine, Tor Vergata University, 00133 Rome, Italy; f.rizzo@ 123456med.uniroma2.it (F.R.R.); balletta.sara@ 123456gmail.com (S.B.); krizia.sanna@ 123456live.it (K.S.); ettoredolcetti@ 123456hotmail.it (E.D.); antonio.bruno91@ 123456yahoo.it (A.B.)
                [3 ]Department of Human Sciences and Quality of Life Promotion, University of Rome San Raffaele, 00166 Roma, Italy
                [4 ]Unit of Neurology, IRCCS Neuromed, Pozzilli (Is), 86077 Pozzilli, Italy; f.devito.molbio@ 123456gmail.com (F.D.V.); silviacaioli@ 123456yahoo.it (S.C.); fabio.buttari@ 123456gmail.com (F.B.); m.stampanonibassi@ 123456gmail.com (M.S.B.)
                Author notes
                [* ]Correspondence: centonze@ 123456uniroma2.it ; Tel.: +39-06-7259-6010; Fax: +39-06-7259-6006
                [†]

                Co-first authors.

                Author information
                https://orcid.org/0000-0002-6943-1904
                https://orcid.org/0000-0002-7682-5135
                Article
                cells-09-02290
                10.3390/cells9102290
                7602209
                33066433
                3934cd69-5bb4-45f4-b9d2-325199bb71cb
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 21 September 2020
                : 12 October 2020
                Categories
                Review

                tnfr1,tnfr2,tnf therapy,demyelination,neurodegeneration,synaptic damage,experimental autoimmune encephalomyelitis,cuprizone,theiler’s murine encephalomyelitis virus

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