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      ZAP-70 Regulates Autoimmune Arthritis via Alterations in T Cell Activation and Apoptosis

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          Abstract

          T cells play an essential role in the pathogenesis of both human rheumatoid arthritis (RA) and its murine models. A key molecule in T cell activation is ZAP-70, therefore we aimed to investigate the effects of partial ZAP-70 deficiency on the pathogenesis of recombinant human G1(rhG1)-induced arthritis (GIA), a well-established mouse model of RA. Arthritis was induced in BALB/c and ZAP-70 +/− heterozygous mice. Disease progression was monitored using a scoring system and in vivo imaging, antigen-specific proliferation, cytokine and autoantibody production was measured and T cell apoptotic pathways were analyzed. ZAP-70 +/− mice developed a less severe arthritis, as shown by both clinical picture and in vitro parameters (decreased T cell proliferation, cytokine and autoantibody production). The amount of cleaved Caspase-3 increased in arthritic ZAP-70 +/− T cells, with no significant changes in cleaved Caspase-8 and -9 levels; although expression of Bim, Bcl-2 and Cytochrome C showed alterations. Tyrosine phosphorylation was less pronounced in arthritic ZAP-70 +/− T cells and the amount of Cbl-b—a negative regulator of T cell activation—decreased as well. We hypothesize that the less severe disease seen in the partial absence of ZAP-70 might be caused by the decreased T cell activation accompanied by increased apoptosis.

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          Most cited references65

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          Cytochrome C-mediated apoptosis.

          Apoptosis, or programmed cell death, is involved in development, elimination of damaged cells, and maintenance of cell homeostasis. Deregulation of apoptosis may cause diseases, such as cancers, immune diseases, and neurodegenerative disorders. Apoptosis is executed by a subfamily of cysteine proteases known as caspases. In mammalian cells, a major caspase activation pathway is the cytochrome c-initiated pathway. In this pathway, a variety of apoptotic stimuli cause cytochrome c release from mitochondria, which in turn induces a series of biochemical reactions that result in caspase activation and subsequent cell death. In this review, we focus on the recent progress in understanding the biochemical mechanisms and regulation of the pathway, the roles of the pathway in physiology and disease, and their potential therapeutic values.
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            Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice.

            Rheumatoid arthritis (RA), which afflicts about 1% of the world population, is a chronic systemic inflammatory disease of unknown aetiology that primarily affects the synovial membranes of multiple joints. Although CD4(+) T cells seem to be the prime mediators of RA, it remains unclear how arthritogenic CD4(+) T cells are generated and activated. Given that highly self-reactive T-cell clones are deleted during normal T-cell development in the thymus, abnormality in T-cell selection has been suspected as one cause of autoimmune disease. Here we show that a spontaneous point mutation of the gene encoding an SH2 domain of ZAP-70, a key signal transduction molecule in T cells, causes chronic autoimmune arthritis in mice that resembles human RA in many aspects. Altered signal transduction from T-cell antigen receptor through the aberrant ZAP-70 changes the thresholds of T cells to thymic selection, leading to the positive selection of otherwise negatively selected autoimmune T cells. Thymic production of arthritogenic T cells due to a genetically determined selection shift of the T-cell repertoire towards high self-reactivity might also be crucial to the development of disease in a subset of patients with RA.
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              Activation-induced cell death in T cells.

              A properly functioning immune system is dependent on programmed cell death at virtually every stage of lymphocyte development and activity. This review addresses the phenomenon of activation-induced cell death (AICD) in T lymphocytes, in which activation through the T-cell receptor results in apoptosis. AICD can occur in a cell-autonomous manner and is influenced by the nature of the initial T-cell activation events. It plays essential roles in both central and peripheral deletion events involved in tolerance and homeostasis, although it is likely that different forms of AICD proceed via different mechanisms. For example, while AICD in peripheral T cells is often caused by the induction of expression of the death ligand, Fas ligand (CD95 ligand, FasL), it does not appear to be involved in AICD in thymocytes. This and other mechanisms of AICD are discussed. One emerging model that may complement other forms of AICD involves the inducible expression of FasL by nonlymphoid tissues in response to activated T lymphocytes. Induction of nonlymphoid FasL in this manner may serve as a sensing mechanism for immune cell infiltration, which contributes to peripheral deletion.
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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                24 May 2019
                May 2019
                : 8
                : 5
                : 504
                Affiliations
                [1 ]Department of Immunology and Biotechnology, Medical School, University of Pécs, H-7624 Pécs, Hungary; kugyelka.reka@ 123456pte.hu (R.K.); prenek.lilla@ 123456pte.hu (L.P.); olasz.katalin@ 123456pte.hu (K.O.); kohl.zoltan@ 123456pte.hu (Z.K.); berki.timea@ 123456pte.hu (T.B.)
                [2 ]Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, H-7624 Pécs, Hungary; balint.botz@ 123456gmail.com
                [3 ]Department of Radiology, Medical School, University of Pécs, H-7624 Pécs, Hungary
                [4 ]Molecular Pharmacology Research Group, Szentagothai Research Centre, University of Pécs, H-7624 Pécs, Hungary
                [5 ]Department of Molecular Medicine, Rush University Medical Center, Chicago, IL 60612, USA; tibor_glant@ 123456rush.edu
                Author notes
                [* ]Correspondence: boldizsar.ferenc@ 123456pte.hu ; Tel.: +36-72-536-288
                Author information
                https://orcid.org/0000-0001-7831-1018
                Article
                cells-08-00504
                10.3390/cells8050504
                6562615
                31137740
                d996d2fe-fb91-4e0c-a8c4-eff27814e1e4
                © 2019 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
                : 18 March 2019
                : 24 May 2019
                Categories
                Article

                zap-70,t cells,apoptosis,autoimmune arthritis,intrinsic pathway,cbl-b

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