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      Increased midgestational IFN-γ, IL-4 and IL-5 in women bearing a child with autism: A case-control study

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          Abstract

          Background

          Immune anomalies have been documented in individuals with autism spectrum disorders (ASDs) and their family members. It is unknown whether the maternal immune profile during pregnancy is associated with the risk of bearing a child with ASD or other neurodevelopmental disorders.

          Methods

          Using Luminex technology, levels of 17 cytokines and chemokines were measured in banked serum collected from women at 15 to 19 weeks of gestation who gave birth to a child ultimately diagnosed with (1) ASD ( n = 84), (2) a developmental delay (DD) but not autism ( n = 49) or (3) no known developmental disability (general population (GP); n = 159). ASD and DD risk associated with maternal cytokine and chemokine levels was estimated by using multivariable logistic regression analysis.

          Results

          Elevated concentrations of IFN-γ, IL-4 and IL-5 in midgestation maternal serum were significantly associated with a 50% increased risk of ASD, regardless of ASD onset type and the presence of intellectual disability. By contrast, elevated concentrations of IL-2, IL-4 and IL-6 were significantly associated with an increased risk of DD without autism.

          Conclusion

          The profile of elevated serum IFN-γ, IL-4 and IL-5 was more common in women who gave birth to a child subsequently diagnosed with ASD. An alternative profile of increased IL-2, IL-4 and IL-6 was more common for women who gave birth to a child subsequently diagnosed with DD without autism. Further investigation is needed to characterize the relationship between these divergent maternal immunological phenotypes and to evaluate their effect on neurodevelopment.

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          Most cited references61

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          Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon?

          Pregnant females are susceptible to intracellular pathogens and are biased towards humoral rather than cell-mediated immunity. Since TH1 cytokines compromise pregnancy and TH2 cytokines are produced at the maternal-fetal interface, we hypothesize that these TH2 cytokines inhibit TH1 responses, improving fetal survival but impairing responses against some pathogens.
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            Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders.

            Exposure to prenatal infection has been suggested to cause deficiencies in fetal neurodevelopment. In this study we included all children born in Denmark from 1980, through 2005. Diagnoses of autism spectrum disorders (ASDs) and maternal infection were obtained through nationwide registers. Data was analyzed using Cox proportional hazards regression. No association was found between any maternal infection and diagnosis of ASDs in the child when looking at the total period of pregnancy: adjusted hazard ratio = 1.14 (CI: 0.96-1.34). However, admission to hospital due to maternal viral infection in the first trimester and maternal bacterial infection in the second trimester were found to be associated with diagnosis of ASDs in the offspring, adjusted hazard ratio = 2.98 (CI: 1.29-7.15) and adjusted hazard ratio = 1.42 (CI: 1.08-1.87), respectively. Our results support prior hypotheses concerning early prenatal viral infection increasing the risk of ASDs.
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              Maternal immune activation alters fetal brain development through interleukin-6.

              Schizophrenia and autism are thought to result from the interaction between a susceptibility genotype and environmental risk factors. The offspring of women who experience infection while pregnant have an increased risk for these disorders. Maternal immune activation (MIA) in pregnant rodents produces offspring with abnormalities in behavior, histology, and gene expression that are reminiscent of schizophrenia and autism, making MIA a useful model of the disorders. However, the mechanism by which MIA causes long-term behavioral deficits in the offspring is unknown. Here we show that the cytokine interleukin-6 (IL-6) is critical for mediating the behavioral and transcriptional changes in the offspring. A single maternal injection of IL-6 on day 12.5 of mouse pregnancy causes prepulse inhibition (PPI) and latent inhibition (LI) deficits in the adult offspring. Moreover, coadministration of an anti-IL-6 antibody in the poly(I:C) model of MIA prevents the PPI, LI, and exploratory and social deficits caused by poly(I:C) and normalizes the associated changes in gene expression in the brains of adult offspring. Finally, MIA in IL-6 knock-out mice does not result in several of the behavioral changes seen in the offspring of wild-type mice after MIA. The identification of IL-6 as a key intermediary should aid in the molecular dissection of the pathways whereby MIA alters fetal brain development, which can shed new light on the pathophysiological mechanisms that predispose to schizophrenia and autism.
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                Author and article information

                Journal
                Mol Autism
                Molecular Autism
                BioMed Central
                2040-2392
                2011
                2 August 2011
                : 2
                : 13
                Affiliations
                [1 ]Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, 451 Health Sciences Dr. Suite 6510, Davis, CA 95616, USA
                [2 ]M.I.N.D. Institute, 2825 50th Street, University of California at Davis, Sacramento, CA 95817, USA
                [3 ]Division of Research, Kaiser Permanente, 2000 Broadway, Oakland, CA 94612, USA
                [4 ]Environmental Health Investigations Branch, California Department of Public Health, Richmond, CA 94804, USA
                [5 ]Department of Pediatrics, 2521 Stockton Boulevard, Suite 4100. Sacramento, CA 95817, USA
                [6 ]Genetic Disease Screening Program, California Department of Public Health, Richmond, CA 94804, USA
                [7 ]Department of Medical Microbiology and Immunology, One Shields Ave, University of California at Davis, Davis, CA 95616, USA
                Article
                2040-2392-2-13
                10.1186/2040-2392-2-13
                3170586
                21810230
                8341feef-f8df-45a1-ae3f-07f4bc648e02
                Copyright ©2011 Goines et al; 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
                : 1 February 2011
                : 2 August 2011
                Categories
                Research

                Neurosciences
                Neurosciences

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