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      Inflammation and Neuro-Immune Dysregulations in Autism Spectrum Disorders

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          Abstract

          Autism Spectrum Disorder (ASD) is characterized by persistent deficits in social communication and interaction and restricted-repetitive patterns of behavior, interests, or activities. Strong inflammation states are associated with ASD. This inflammatory condition is often linked to immune system dysfunction. Several cell types are enrolled to trigger and sustain these processes. Neuro-inflammation and neuro-immune abnormalities have now been established in ASD as key factors in its development and maintenance. In this review, we will explore inflammatory conditions, dysfunctions in neuro-immune cross-talk, and immune system treatments in ASD management.

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          Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism.

          In the neurodevelopmental disorder autism, several neuroimmune abnormalities have been reported. However, it is unknown whether microglial somal volume or density are altered in the cortex and whether any alteration is associated with age or other potential covariates. Microglia in sections from the dorsolateral prefrontal cortex of nonmacrencephalic male cases with autism (n = 13) and control cases (n = 9) were visualized via ionized calcium binding adapter molecule 1 immunohistochemistry. In addition to a neuropathological assessment, microglial cell density was stereologically estimated via optical fractionator and average somal volume was quantified via isotropic nucleator. Microglia appeared markedly activated in 5 of 13 cases with autism, including 2 of 3 under age 6, and marginally activated in an additional 4 of 13 cases. Morphological alterations included somal enlargement, process retraction and thickening, and extension of filopodia from processes. Average microglial somal volume was significantly increased in white matter (p = .013), with a trend in gray matter (p = .098). Microglial cell density was increased in gray matter (p = .002). Seizure history did not influence any activation measure. The activation profile described represents a neuropathological alteration in a sizeable fraction of cases with autism. Given its early presence, microglial activation may play a central role in the pathogenesis of autism in a substantial proportion of patients. Alternatively, activation may represent a response of the innate neuroimmune system to synaptic, neuronal, or neuronal network disturbances, or reflect genetic and/or environmental abnormalities impacting multiple cellular populations. Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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            The role of immune dysfunction in the pathophysiology of autism.

            Autism spectrum disorders (ASD) are a complex group of neurodevelopmental disorders encompassing impairments in communication, social interactions and restricted stereotypical behaviors. Although a link between altered immune responses and ASD was first recognized nearly 40 years ago, only recently has new evidence started to shed light on the complex multifaceted relationship between immune dysfunction and behavior in ASD. Neurobiological research in ASD has highlighted pathways involved in neural development, synapse plasticity, structural brain abnormalities, cognition and behavior. At the same time, several lines of evidence point to altered immune dysfunction in ASD that directly impacts some or all these neurological processes. Extensive alterations in immune function have now been described in both children and adults with ASD, including ongoing inflammation in brain specimens, elevated pro-inflammatory cytokine profiles in the CSF and blood, increased presence of brain-specific auto-antibodies and altered immune cell function. Furthermore, these dysfunctional immune responses are associated with increased impairments in behaviors characteristic of core features of ASD, in particular, deficits in social interactions and communication. This accumulating evidence suggests that immune processes play a key role in the pathophysiology of ASD. This review will discuss the current state of our knowledge of immune dysfunction in ASD, how these findings may impact on underlying neuro-immune mechanisms and implicate potential areas where the manipulation of the immune response could have an impact on behavior and immunity in ASD. Copyright © 2011 Elsevier Inc. All rights reserved.
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              The Role of the Immune System in Autism Spectrum Disorder.

              Autism is a neurodevelopmental disorder characterized by deficits in communication and social skills as well as repetitive and stereotypical behaviors. While much effort has focused on the identification of genes associated with autism, research emerging within the past two decades suggests that immune dysfunction is a viable risk factor contributing to the neurodevelopmental deficits observed in autism spectrum disorders (ASD). Further, it is the heterogeneity within this disorder that has brought to light much of the current thinking regarding the subphenotypes within ASD and how the immune system is associated with these distinctions. This review will focus on the two main axes of immune involvement in ASD, namely dysfunction in the prenatal and postnatal periods. During gestation, prenatal insults including maternal infection and subsequent immunological activation may increase the risk of autism in the child. Similarly, the presence of maternally derived anti-brain autoantibodies found in ~20% of mothers whose children are at risk for developing autism has defined an additional subphenotype of ASD. The postnatal environment, on the other hand, is characterized by related but distinct profiles of immune dysregulation, inflammation, and endogenous autoantibodies that all persist within the affected individual. Further definition of the role of immune dysregulation in ASD thus necessitates a deeper understanding of the interaction between both maternal and child immune systems, and the role they have in diagnosis and treatment.
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                Author and article information

                Journal
                Pharmaceuticals (Basel)
                Pharmaceuticals (Basel)
                pharmaceuticals
                Pharmaceuticals
                MDPI
                1424-8247
                04 June 2018
                June 2018
                : 11
                : 2
                : 56
                Affiliations
                [1 ]Department of Experimental Medicine, University of Campania, 80138 Naples, Italy
                [2 ]Italian Group for Study Autism—GISA, 25018 Brescia, Italy; brigida.annalisa@ 123456gmail.com
                [3 ]Centre for Autism—La Forza del Silenzio, 81036 Caserta, Italy
                [4 ]Department of Cellular and Integrative Physiology, School of Medicine, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA; stevendri0629@ 123456gmail.com
                [5 ]Biomedical Centre for Autism Research and Treatment, 70124 Bari, Italy; info@ 123456antonucci.eu
                Author notes
                [* ]Correspondence: dariosin@ 123456uab.edu ; Tel.: +39-081-566-5880
                Article
                pharmaceuticals-11-00056
                10.3390/ph11020056
                6027314
                29867038
                4e670922-a073-4dcb-bb7c-91b88ea0a94f
                © 2018 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
                : 02 May 2018
                : 01 June 2018
                Categories
                Review

                autism,monocytes,macrophages,inflammation,neuro-immune system

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