Altered gene expression and function of peripheral blood natural killer cells in children with autism

Department of Medical Microbiology and Immunology, University of California at Davis, USA.
Brain Behavior and Immunity (Impact Factor: 5.89). 08/2008; 23(1):124-33. DOI: 10.1016/j.bbi.2008.08.001
Source: PubMed


Immune related abnormalities have repeatedly been reported in autism spectrum disorders (ASD), including evidence of immune dysregulation and autoimmune phenomena. NK cells may play an important role in neurodevelopmental disorders such as ASD. Here we performed a gene expression screen and cellular functional analysis on peripheral blood obtained from 52 children with ASD and 27 typically developing control children enrolled in the case-control CHARGE study. RNA expression of NK cell receptors and effector molecules were significantly upregulated in ASD. Flow cytometric analysis of NK cells demonstrated increased production of perforin, granzyme B, and interferon gamma (IFNgamma) under resting conditions in children with ASD (p<0.01). Following NK cell stimulation in the presence of K562 target cells, the cytotoxicity of NK cells was significantly reduced in ASD compared with controls (p<0.02). Furthermore, under similar stimulation conditions the presence of perforin, granzyme B, and IFNgamma in NK cells from ASD children was significantly lower compared with controls (p<0.001). These findings suggest possible dysfunction of NK cells in children with ASD. Abnormalities in NK cells may represent a susceptibility factor in ASD and may predispose to the development of autoimmunity and/or adverse neuroimmune interactions during critical periods of development.

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    • "In addition, there is an increased prevalence of immune-mediated disorders in family members of children with ASD (Ashwood et al., 2006; Careaga et al., 2010; Comi et al., 1999; Croen et al., 2005; Lyall et al., 2013; Money et al., 1971). However, there are conflicting reports among the research findings regarding the prevalence of clinically relevant immune-mediated conditions and whether they are an accurate or only indicate immune dysregulation in ASD (Enstrom et al., 2009; Lyall et al., 2013; Menage et al., 1992; Renzoni et al., 1995). For instance, reported levels of IgE antibodies, which play a key role in the allergic immune response, are not consistently different between ASD and typically developing (TD) controls (Bakkaloglu et al., 2008; Goines et al., 2011a; Heuer et al., 2008) and makes for a poor biomarker for immune dysregulation in ASD. "
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    ABSTRACT: Inflammation and asthma have both been reported in some children with autism spectrum disorder (ASD). To further assess this connection, peripheral immune cells isolated from young children with ASD and typically developing (TD) controls and the production of cytokines IL-17, -13, and -4 assessed following ex vivo mitogen stimulation. Notably, IL-17 production was significantly higher following stimulation in ASD children compared to controls. Moreover, IL-17 was increased in ASD children with co-morbid asthma compared to controls with the same condition. In conclusion, children with ASD exhibited a differential response to T cell stimulation with elevated IL-17 production compared to controls. Copyright © 2015. Published by Elsevier B.V.
    Journal of neuroimmunology 09/2015; 286:33-41. DOI:10.1016/j.jneuroim.2015.07.003 · 2.47 Impact Factor
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    • "Research on gene expression in autism has previously focused on identifying specific or a limited group of genes related to disease. (Enstrom et al., 2009, Hu t al., 2006). The idea that alterations at the global level of gene expression regulation might be important in mediating the risk for autism, as well as a novel tool for prognostic biomarker discovery has been largely underexplored. "
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    ABSTRACT: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder having both genetic and epigenetic etiological elements. Currently it is unclear how many genes have been associated with ASD and how strong the evidence is. MiRNAs are a widespread class of small non-coding RNAs that have the ability to silence gene expression through sequence complementarity to their targets. Owing to the dynamic nature of the whole blood transcriptome, understanding miRNAs gene expression profiling in autism is a promising tool for discovery of disease-related genes and biological pathways. The aim of this study was to identify miRNAs expression changes in children with ASD compared to general population controls. In the present study, to demonstrate the relevance of miRNAs expression changes in the autistic patients we examined miR let-7b-3p and let-7d-3p gene expression, applying custum made LC Science miRNA expression profiling. The involved miRNAs expression changes may contribute to define the etiology, genetics, and clinical phenotype. Further molecular analysis on miRNA gene expression changes will give a more detailed picture about the miRNA associated mechanism and processes common to ASD.
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    • "This supports the presence of neuroinflammatory conditions in the brain of ASD patients. Peripheral immune abnormalities in autistic individuals have also been reported , including differential monocyte responses to in vitro stimulation (Jyonouchi et al., 2005; Molloy et al., 2006), dysfunctional natural killer (NK) cells (Enstrom et al., 2009; Vojdani et al., 2008) and altered serum levels of immunoglobulins (Croonenberghs et al., 2002; Heuer et al., 2008; Lucarelli et al., 1995), cytokines (Ashwood et al., 2011a; Manzardo et al., 2012; Singh, 1996) and chemokines (Ashwood et al., 2011b). Immune disturbances have also been observed in the gastrointestinal tract of ASD patients. "
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    ABSTRACT: Autism spectrum disorder (ASD) is a cluster of neurodevelopmental disorders characterized by impairments in communication, social interest and stereotypical behaviour. Dysfunction of the intestinal tract is reported in patients with ASD and implicated in the development and severity of ASD symptoms. However, more research is required to investigate the association of intestinal problems with ASD and the potential underlying mechanisms. The purpose of this study was to investigate comorbid symptoms of intestinal inflammation in a murine model of ASD induced by prenatal exposure to valproic acid (VPA). Pregnant BALB/c females were treated subcutaneously with 600 mg/kg VPA or phosphate buffered saline on gestational day 11. Offspring were housed with their mother until weaning on postnatal day 21 (P21). All pups were exposed to a social behaviour test on P28. Inflammatory correlates and activity of the serotonergic system were measured in brain and intestinal tissue. Here we demonstrate, in addition to reduced social behaviour and increased expression of neuroinflammatory markers in the brain, that VPA in utero- exposed male offspring showed epithelial cell loss and neutrophil infiltration in the intestinal tract. Furthermore, reduced levels of serotonin were not only observed the prefrontal cortex and amygdala of VPA in utero- exposed males, but also in the small intestine. Overall, we demonstrate that gender-specific inflammatory conditions are present in the small intestines of VPA in utero- exposed mice and are accompanied by a disturbed serotonergic system in the brain as well as in the intestinal tract.
    Brain Behavior and Immunity 12/2013; 37. DOI:10.1016/j.bbi.2013.12.004 · 5.89 Impact Factor
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