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      Elevated serum levels of macrophage-derived chemokine and thymus and activation-regulated chemokine in autistic children

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          Abstract

          Background

          In some autistic children, there is an imbalance of T helper (Th)1/Th2 lymphocytes toward Th2, which may be responsible for the induction of the production of autoantibodies in these children. Th2 lymphocytes express CCR4 receptors. CCR4 ligands include macrophage-derived chemokine (MDC) and thymus and activation-regulated chemokine (TARC). They direct trafficking and recruitment of Th2 cells. We are the first to measure serum levels of CCR4 ligands in relation to the degree of the severity of autism.

          Methods

          Serum concentrations of MDC and TARC were measured, by quantitative sandwich enzyme immunoassay technique, in 56 autistic children and 32 healthy matched children.

          Results

          Autistic children had significantly higher serum levels of MDC and TARC than healthy controls ( P <0.001 and P <0.001, respectively). Children with severe autism had significantly higher serum levels of MDC and TARC than patients with mild to moderate autism ( P <0.001 and P = 0.01, respectively). In addition, there were significant positive correlations between CARS and serum levels of both MDC ( P <0.001) and TARC ( P <0.001) in children with autism. There were significant positive correlations between serum levels of MDC and TARC in autistic children ( P <0.001).

          Conclusions

          Serum levels of CCR4 ligands were elevated in autistic children and they were significantly correlated to the degree of the severity of autism. However, further research is warranted to determine the pathogenic role of CCR4 ligands in autism and to shed light on the therapeutic role of CCR4-ligand antagonism in autistic children.

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          Most cited references41

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          Chemokines: a new classification system and their role in immunity.

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            The T cell-directed CC chemokine TARC is a highly specific biological ligand for CC chemokine receptor 4.

            Thymus and activation-regulated chemokine (TARC) is a recently identified CC chemokine that is expressed constitutively in thymus and transiently in stimulated peripheral blood mononuclear cells. TARC functions as a selective chemoattractant for T cells that express a class of receptors binding TARC with high affinity and specificity. To identify the receptor for TARC, we produced TARC as a fusion protein with secreted alkaline phosphatase (SEAP) and used it for specific binding. By stably transfecting five orphan receptors and five known CC chemokine receptors (CCR1 to -5) into K562 cells, we found that TARC-SEAP bound selectively to cells expressing CCR4. TARC-SEAP also bound to K562 cells stably expressing CCR4 with a high affinity (Kd = 0.5 nM). Only TARC and not five other CC chemokines (MCP-1 (monocyte chemoattractant protein-1), RANTES (regulated upon activation, normal T cells expressed and secreted), MIP-1alpha (macrophage inflammatory protein-1alpha), MIP-1beta, and LARC (liver and activation-regulated chemokine)) competed with TARC-SEAP for binding to CCR4. TARC but not RANTES or MIP-1alpha induced migration and calcium mobilization in 293/EBNA-1 cells stably expressing CCR4. K562 cells stably expressing CCR4 also responded to TARC in a calcium mobilization assay. Northern blot analysis revealed that CCR4 mRNA was expressed strongly in human T cell lines and peripheral blood T cells but not in B cells, natural killer cells, monocytes, or granulocytes. Taken together, TARC is a specific functional ligand for CCR4, and CCR4 is the specific receptor for TARC selectively expressed on T cells.
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              Th17 cell, the new player of neuroinflammatory process in multiple sclerosis.

              Multiple sclerosis (MS) is an autoimmune disease characterized by recurrent episodes of demyelination and axonal lesion mediated by CD4(+) T cells with a proinflammatory Th1 and Th17 phenotype, macrophages, and soluble inflammatory mediators. Identification of Th17 cells led to breaking the dichotomy of Th1/Th2 axis in immunopathogenesis of autoimmune diseases such as MS, and its experimental model, experimental autoimmune encephalomyelitis (EAE). Th17 cells are characterized by expression of retinoic acid-related orphan receptor (ROR)γt and signal transducer and activator of transcription 3 (STAT3) factors. Th17-produced cytokine profile including interleukin (IL)-17, IL-6, IL-21, IL-22, IL-23 and tumour necrosis factor (TNF)-α, which have proinflammatory functions, suggests it as an important factor in immunopathogenesis of MS, because the main feature of MS pathophysiology is the neuroinflammatory reaction. The blood brain barrier (BBB) disruption is an early and central event in MS pathogenesis. Autoreactive Th17 cells can migrate through the BBB by the production of cytokines such as IL-17 and IL-22, which disrupt tight junction proteins in the central nervous system (CNS) endothelial cells. Consistent with this observation and regarding the wide range production of proinflammatory cytokines and chemokines by Th17 cells, it is expected that Th17 cell to be as a potent pathogenic factor in disease immunopathophysiology. Th17-mediated inflammation is characterized by neutrophil recruitment into the CNS and neurons killing. However, the majority of our knowledge about the role of Th17 in MS pathogenesis is resulted in investigation into EAE animal models. In this review, we intend to focus on the newest information regarding the precise role of Th17 cells in immunopathogenesis of MS, and its animal model, EAE. © 2011 The Authors. Scandinavian Journal of Immunology © 2011 Blackwell Publishing Ltd.
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                Author and article information

                Journal
                J Neuroinflammation
                J Neuroinflammation
                Journal of Neuroinflammation
                BioMed Central
                1742-2094
                2013
                19 June 2013
                : 10
                : 72
                Affiliations
                [1 ]Autism Research and Treatment Center, AL-Amodi Autism Research Chair, Department of Physiology, Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia
                [2 ]Department of Pediatrics, Faculty of Medicine, Ain Shams University, 9 Ahmed El-Samman Street off Makram Ebaid, Nasr City, Cairo 11511, Egypt
                Article
                1742-2094-10-72
                10.1186/1742-2094-10-72
                3704803
                23782855
                3ca00c5f-bad9-44e0-ae43-7c6d1005bc50
                Copyright ©2013 AL-Ayadhi and Mostafa; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 12 March 2013
                : 21 May 2013
                Categories
                Research

                Neurosciences
                autism,autoimmunity,childhood autism rating scale,ccr4 ligands,macrophage-derived chemokine,thymus and activation-regulated chemokine

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