Amniotic fluid chemokines and autism spectrum disorders: An exploratory study utilizing a Danish Historic Birth Cohort

Department of Epidemiology, Aarhus University School of Public Health, Aarhus, Denmark.
Brain Behavior and Immunity (Impact Factor: 5.89). 09/2011; 26(1):170-6. DOI: 10.1016/j.bbi.2011.09.003
Source: PubMed


Elevated levels of chemokines have been reported in plasma and brain tissue of individuals with Autism Spectrum Disorders (ASD). The aim of this study was to examine chemokine levels in amniotic fluid (AF) samples of individuals diagnosed with ASD and their controls.
A Danish Historic Birth Cohort (HBC) kept at Statens Serum Institute, Copenhagen was utilized. Using data from Danish nation-wide health registers, a case-control study design of 414 cases and 820 controls was adopted. Levels of MCP-1, MIP-1α and RANTES were analyzed using Luminex xMAP technology. Case-control differences were assessed as dichotomized at below the 10th percentile or above the 90th percentile cut-off points derived from the control biomarker distributions (logistic regression) or continuous measures (tobit regression).
AF volume for 331 cases and 698 controls was sufficient for Luminex analysis. Including all individuals in the cohort yielded no significant differences in chemokine levels in cases versus controls. Logistic regression analyses, performed on individuals diagnosed using ICD-10 only, showed increased risk for ASD with elevated MCP-1 (elevated 90th percentile adjusted OR: 2.32 [95% CI: 1.17-4.61]) compared to controls. An increased risk for infantile autism with elevated MCP-1 was also found (adjusted OR: 2.28 [95% CI: 1.16-4.48]). Elevated levels of MCP-1 may decipher an etiologic immunologic dysfunction or play rather an indirect role in the pathophysiology of ASD. Further studies to confirm its role and to identify the potential pathways through which MCP-1 may contribute to the development of ASD are necessary.

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    • "Alterations in chemokine and cytokine levels in other specimen types have been previously reported. In an analysis of chemokine levels in amniotic fluid Abdallah et al. (2012) reported elevated levels of MCP-1 for children who were later diagnosed with autism compared to controls [34]. Whether the chemokines were of maternal or fetal origin is not clear. "
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    ABSTRACT: Biologic markers of infection and inflammation have been associated with Autism Spectrum Disorders (ASD) but prior studies have largely relied on specimens taken after clinical diagnosis. Research on potential biologic markers early in neurodevelopment is required to evaluate possible causal pathways and screening profiles. To investigate levels of cytokines and chemokines in newborn blood specimens as possible early biologic markers for autism. We conducted a population-based case-control study nested within the cohort of infants born from July 2000 to September 2001 to women who participated in the prenatal screening program in Orange County, California, USA. The study population included children ascertained from the California Department of Developmental Services with Autism Spectrum Disorder (ASD, n = 84), or developmental delay but not ASD (DD, n = 49), and general population controls randomly sampled from the birth certificate files and frequency matched to ASD cases on sex, birth month and birth year (GP, n = 159). Cytokine and chemokine concentrations were measured in archived neonatal blood specimens collected for routine newborn screening. Cytokines were not detected in the vast majority of newborn samples regardless of case or control status. However, the chemokine monocyte chemotactic protein-1 (MCP-1) was elevated and the chemokine Regulated upon Activation Normal T-Cell Expressed and Secreted (RANTES) was decreased in ASD cases compared to GP controls. The chemokines macrophage inflammatory protein-1alpha (MIP-1α) and RANTES were decreased in children with DD compared to GP controls. Measurement of immune system function in the first few days of life may aid in the early identification of abnormal neurodevelopment and shed light on the biologic mechanisms underlying normal neurodevelopment.
    Journal of Neuroinflammation 06/2014; 11(1):113. DOI:10.1186/1742-2094-11-113 · 5.41 Impact Factor
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    • "An increased risk for infantile autism with elevated MCP-1 in amniotic fluid was recently reported. Elevated levels of MCP-1 may play an indirect role in the pathophysiology of autism [40]. "
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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.
    Journal of Neuroinflammation 06/2013; 10(1):72. DOI:10.1186/1742-2094-10-72 · 5.41 Impact Factor
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    • "Consistent with this hypothesis, a recent case report found that elevated maternal serum concentrations of IFN-c, and two interleukins (ILs), IL-4 and IL-5, are associated with a 50% increased risk of ASD, while a distinct cytokine profile of increased IL-2, IL-4, and IL-6 is associated with an increased risk of developmental delay without ASD (Goines et al., 2011). The amniotic fluid of mothers of children later diagnosed with ASD also shows increased levels of cytokines, including IL-4, TNF-a and -b (Abdallah et al., in press, 2012). Moreover, there are many reports of altered cytokines in the blood, brain, and CSF of individuals with ASD of various ages (Vargas et al., 2005; Molloy et al., 2006; Chez et al., 2007; Ashwood et al., 2008, 2010, 2011a,b; Manzardo et al., 2011). "
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    ABSTRACT: Autism spectrum disorder (ASD) is a complex disorder that appears to be caused by interactions between genetic changes and environmental insults during early development. A wide range of factors have been linked to the onset of ASD, but recently both genetic associations and environmental factors point to a central role for immune-related genes and immune responses to environmental stimuli. Specifically, many of the proteins encoded by the major histocompatibility complex (MHC) play a vital role in the formation, refinement, maintenance, and plasticity of the brain. Manipulations of levels of MHC molecules have illustrated how disrupted MHC signaling can significantly alter brain connectivity and function. Thus, an emerging hypothesis in our field is that disruptions in MHC expression in the developing brain caused by mutations and/or immune dysregulation may contribute to the altered brain connectivity and function characteristic of ASD. This review provides an overview of the structure and function of the three classes of MHC molecules in the immune system, healthy brain, and their possible involvement in ASD. © 2012 Wiley Periodicals, Inc. Develop Neurobiol, 2012.
    Developmental Neurobiology 10/2012; 72(10):1288-301. DOI:10.1002/dneu.22046 · 3.37 Impact Factor
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