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      The Dopaminergic System in Autoimmune Diseases

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          Abstract

          Bidirectional interactions between the immune and the nervous systems are of considerable interest both for deciphering their functioning and for designing novel therapeutic strategies. The past decade has brought a burst of insights into the molecular mechanisms involved in neuroimmune communications mediated by dopamine. Studies of dendritic cells (DCs) revealed that they express the whole machinery to synthesize and store dopamine, which may act in an autocrine manner to stimulate dopamine receptors (DARs). Depending on specific DARs stimulated on DCs and T cells, dopamine may differentially favor CD4 + T cell differentiation into Th1 or Th17 inflammatory cells. Regulatory T cells can also release high amounts of dopamine that acts in an autocrine DAR-mediated manner to inhibit their suppressive activity. These dopaminergic regulations could represent a driving force during autoimmunity. Indeed, dopamine levels are altered in the brain of mouse models of multiple sclerosis (MS) and lupus, and in inflamed tissues of patients with inflammatory bowel diseases or rheumatoid arthritis (RA). The distorted expression of DARs in peripheral lymphocytes of lupus and MS patients also supports the importance of dopaminergic regulations in autoimmunity. Moreover, dopamine analogs had beneficial therapeutic effects in animal models, and in patients with lupus or RA. We propose models that may underlie key roles of dopamine and its receptors in autoimmune diseases.

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          Most cited references102

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          Inflammatory bowel disease: clinical aspects and established and evolving therapies.

          Crohn's disease and ulcerative colitis are two idiopathic inflammatory bowel disorders. In this paper we discuss the current diagnostic approach, their pathology, natural course, and common complications, the assessment of disease activity, extraintestinal manifestations, and medical and surgical management, and provide diagnostic and therapeutic algorithms. We critically review the evidence for established (5-aminosalicylic acid compounds, corticosteroids, immunomodulators, calcineurin inhibitors) and emerging novel therapies--including biological therapies--directed at cytokines (eg, infliximab, adalimumab, certolizumab pegol) and receptors (eg, visilizumab, abatacept) involved in T-cell activation, selective adhesion molecule blockers (eg, natalizumab, MLN-02, alicaforsen), anti-inflammatory cytokines (eg, interleukin 10), modulation of the intestinal flora (eg, antibiotics, prebiotics, probiotics), leucocyte apheresis and many more monoclonal antibodies, small molecules, recombinant growth factors, and MAP kinase inhibitors targeting various inflammatory cells and pathways. Finally, we summarise the practical aspects of standard therapies including dosing, precautions, and side-effects.
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            Increased expression of interleukin 17 in inflammatory bowel disease.

            Interleukin (IL) 17 is a cytokine which exerts strong proinflammatory activities. In this study we evaluated changes in IL-17 expression in the inflamed mucosa and in the serum of patients with inflammatory bowel disease (IBD). Tissue samples were obtained endoscopically or surgically from patients with ulcerative colitis (UC) (n=20), Crohn's disease (CD) (n=20), infectious colitis (n=5), ischaemic colitis (n=8), and normal colorectal tissues (n=15). IL-17 expression was evaluated by a standard immunohistochemical procedure. Serum IL-17 levels were determined by ELISA. IL-17 mRNA expression was analysed by reverse transcriptase-polymerase chain reaction. IL-17 expression was not detected in samples from normal colonic mucosa, infectious colitis, or ischaemic colitis. In the inflamed mucosa of active UC and CD patients, IL-17 expression was clearly detectable in CD3(+) T cells or CD68(+) monocytes/macrophages. The average number of IL-17(+) cells was significantly increased in active UC and CD patients compared with inactive patients. IL-17 mRNA expression was not detected in normal mucosa but was detectable in the mucosa from active UC and CD patients. IL-17 was not detected in the sera from normal individuals, infectious colitis, or ischaemic colitis patients but IL-17 levels were significantly elevated in IBD patients. IL-17 expression in the mucosa and serum was increased in IBD patients. It is likely that IL-17 expression in IBD may be associated with altered immune and inflammatory responses in the intestinal mucosa.
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              T cells in multiple sclerosis and experimental autoimmune encephalomyelitis.

              Multiple sclerosis (MS) is a demyelinating inflammatory disorder of the central nervous system (CNS), which involves autoimmune responses to myelin antigens. Studies in experimental autoimmune encephalomyelitis (EAE), an animal model for MS, have provided convincing evidence that T cells specific for self-antigens mediate pathology in these diseases. Until recently, T helper type 1 (Th1) cells were thought to be the main effector T cells responsible for the autoimmune inflammation. However more recent studies have highlighted an important pathogenic role for CD4(+) T cells that secrete interleukin (IL)-17, termed Th17, but also IL-17-secreting γδ T cells in EAE as well as other autoimmune and chronic inflammatory conditions. This has prompted intensive study of the induction, function and regulation of IL-17-producing T cells in MS and EAE. In this paper, we review the contribution of Th1, Th17, γδ, CD8(+) and regulatory T cells as well as the possible development of new therapeutic approaches for MS based on manipulating these T cell subtypes. © 2010 The Authors. Clinical and Experimental Immunology © 2010 British Society for Immunology.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/98095
                URI : http://frontiersin.org/people/u/137318
                URI : http://frontiersin.org/people/u/25082
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                09 February 2014
                21 March 2014
                2014
                : 5
                : 117
                Affiliations
                [1] 1Laboratory of Neuroimmunology, Fundación Ciencia & Vida , Santiago, Chile
                [2] 2Programa de Biomedicina, Universidad San Sebastián , Santiago, Chile
                [3] 3Universidad Andrés Bello, Facultad de Ciencias Biológicas , Santiago, Chile
                [4] 4INSERM UMR 1132 , Paris, France
                [5] 5University Paris Diderot , Paris, France
                Author notes

                Edited by: Kendall A. Smith, Weill Medical College of Cornell University, USA

                Reviewed by: Kai Fang, University of California Los Angeles, USA; Marco Cosentino, University of Insubria, Italy

                *Correspondence: Moncef Zouali, INSERM U1132, Centre Viggo Petersen, Hôpital Lariboisière, 2, Rue Ambroise Paré, 75475 Paris Cedex 10, France e-mail: moncef.zouali@ 123456wanadoo.fr

                This article was submitted to Inflammation, a section of the journal Frontiers in Immunology.

                Article
                10.3389/fimmu.2014.00117
                3968755
                24711809
                b5d2e819-8841-41ef-9ff6-220864270cb6
                Copyright © 2014 Pacheco, Contreras and Zouali.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 19 December 2013
                : 05 March 2014
                Page count
                Figures: 3, Tables: 1, Equations: 0, References: 126, Pages: 17, Words: 14838
                Categories
                Immunology
                Review Article

                Immunology
                dendritic cell,regulatory t cell,th17,crohn’s disease,multiple sclerosis,ulcerative colitis,systemic lupus erythematosus,rheumatoid arthritis

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