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Differential monocyte responses to TLR ligands in children with autism spectrum disorders.

ABSTRACT: Autism spectrum disorders (ASD) are characterized by impairment in social interactions, communication deficits, and restricted repetitive interests and behaviors. Recent evidence has suggested that impairments of innate immunity may play an important role in ASD. To test this hypothesis, we isolated peripheral blood monocytes from 17 children with ASD and 16 age-matched typically developing (TD) controls and stimulated these cell cultures in vitro with distinct toll-like receptors (TLR) ligands: TLR 2 (lipoteichoic acid; LTA), TLR 3 (poly I:C), TLR 4 (lipopolysaccharide; LPS), TLR 5 (flagellin), and TLR 9 (CpG-B). Supernatants were harvested from the cell cultures and pro-inflammatory cytokine responses for IL-1beta, IL-6, IL-8, TNFalpha, MCP-1, and GM-CSF were determined by multiplex Luminex analysis. After in vitro challenge with TLR ligands, differential cytokine responses were observed in monocyte cultures from children with ASD compared with TD control children. In particular, there was a marked increase in pro-inflammatory IL-1beta, IL-6, and TNFalpha responses following TLR 2, and IL-1beta response following TLR 4 stimulation in monocyte cultures from children with ASD (p<0.04). Conversely, following TLR 9 stimulation there was a decrease in IL-1beta, IL-6, GM-CSF, and TNFalpha responses in monocyte cell cultures from children with ASD compared with controls (p<0.05). These data indicate that, monocyte cultures from children with ASD are more responsive to signaling via select TLRs. As monocytes are key regulators of the immune response, dysfunction in the response of these cells could result in long-term immune alterations in children with ASD that may lead to the development of adverse neuroimmune interactions and could play a role in the pathophysiology observed in ASD.

SUBMITTER: Enstrom AM

PROVIDER: S-EPMC3014091 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Differential monocyte responses to TLR ligands in children with autism spectrum disorders.

Enstrom Amanda M AM Onore Charity E CE Van de Water Judy A JA Ashwood Paul P

Brain, behavior, and immunity 20090808 1

Autism spectrum disorders (ASD) are characterized by impairment in social interactions, communication deficits, and restricted repetitive interests and behaviors. Recent evidence has suggested that impairments of innate immunity may play an important role in ASD. To test this hypothesis, we isolated peripheral blood monocytes from 17 children with ASD and 16 age-matched typically developing (TD) controls and stimulated these cell cultures in vitro with distinct toll-like receptors (TLR) ligands: ...[more]

PMID: 19666104

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Project description:ObjectivesMany studies have reported the increased presence of gastrointestinal (GI) symptoms in children with autism spectrum disorders (ASD). Altered microbiome profiles, pro-inflammatory responses and impaired intestinal permeability have been observed in children with ASD and co-morbid GI symptoms, yet few studies have compared these findings to ASD children without GI issues or similarly aged typical developing children. The aim of this study was to determine whether there are biological signatures in terms of immune dysfunction and microbiota composition in children with ASD with GI symptoms.MethodsChildren were enrolled in one of four groups: ASD and GI symptoms of irregular bowel habits (ASDGI), children with ASD but without current or previous GI symptoms (ASDNoGI), typically developing children with GI symptoms (TDGI) and typically developing children without current or previous GI symptoms (TDNoGI). Peripheral blood mononuclear cells (PBMC) were isolated from the blood, stimulated and assessed for cytokine production, while stool samples were analyzed for microbial composition.ResultsFollowing Toll-Like receptor (TLR)-4 stimulation, the ASDGI group produced increased levels of mucosa-relevant cytokines including IL-5, IL-15 and IL-17 compared to ASDNoGI. The production of the regulatory cytokine TGFβ1 was decreased in the ASDGI group compared with both the ASDNoGI and TDNoGI groups. Analysis of the microbiome at the family level revealed differences in microbiome composition between ASD and TD children with GI symptoms; furthermore, a predictive metagenome functional content analysis revealed that pathways were differentially represented between ASD and TD subjects, independently of the presence of GI symptoms. The ASDGI also showed an over-representation of the gene encoding zonulin, a molecule regulating gut permeability, compared to the other groups.ConclusionsOverall our findings suggest that children with ASD who experience GI symptoms have an imbalance in their immune response, possibly influenced by or influencing metagenomic changes, and may have a propensity to impaired gut barrier function which may contribute to their symptoms and clinical outcome.

Project description:Flourishing is an indicator of positive mental health and is important for children's development and well-being. We used variables from the National Survey of Children's Health 2016 as indicators of flourishing (difficulty making friends, is bullied, bullies others, shares ideas with family, argues, finishes tasks, does all homework, shows curiosity, stays calm, and cares about doing well in school) to compare differences in parent perceptions of their children with and without autism spectrum disorder (ASD). We anticipate that these findings will help identify intervention targets to support the well-being of individuals with ASD. Children between 6 and 17 years of age, without intellectual disability, brain injury, cerebral palsy, or Down syndrome were included. Total participants were 34,171 controls (male/female = 17,116/17,155) and 812 with ASD (male/female = 668/144). Factor analysis resulted in three-factor structures (social competence, behavioral control, and school motivation) with good model fit (root mean square error of approximation = 0.08, comparative fit index = 0.92, Tucker-Lewis index = 0.89). The multivariate regression model and propensity score with inverse probability of treatment weighting (PS-IPTW) method revealed that children with ASD had lower scores in the social competence and behavioral control factors compared to the control group (all P < 0.05). However, no significant differences were found in the school motivation factor between the two groups (P > 0.05) in both multivariate regression model and PS-IPTW method. Findings suggest that social competence and behavioral control are indicators of flourishing and are important intervention targets to increase flourishing among children with ASD. Autism Res 2019, 12: 952-966. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Flourishing is an indicator of positive mental health and is important for children's development and well-being. We used variables from The National Survey of Children's Health 2016 to examine differences in parent perceptions of the indicators of flourishing (difficulty making friends, is bullied, bullies others, shares ideas with family, argues, finishes tasks, does all homework, shows curiosity, stays calm, and cares about doing well in school) between children with and without autism spectrum disorders (ASD). We anticipate that this information will help to identify therapeutic targets to support the well-being of individuals with ASD. Children between 6 and 17 years old, without intellectual disability (ID), brain injury (BI), cerebral palsy (CP), or Down syndrome (DS) were included. From the total (N = 50,212), we excluded children under age 6 (n = 14,494), those who once, but do not currently have ASD (n = 81), and those with ID (n = 432), BI (n = 170), CP (n = 35), and DS (n = 17), resulting in 34,983 records used. Total participants, age 6-17 years, were 34,171 controls (male/female = 17,116/17,155) and 812 with ASD (male/female = 668/144). Factor analysis resulted in the identification of three flourishing categories among the indicator variables (social competence, behavioral control, and school motivation). Children with ASD had lower scores in the social competence and behavioral control factors compared to the control group. However, there were no significant differences in the school motivation factor between the two groups. Findings suggest that social competence and behavioral control are indicators of flourishing and are important intervention targets to increase flourishing among children with ASD.

Project description:BackgroundThe development of left and right superior temporal gyrus (STG) 50?ms (M50) and 100?ms (M100) auditory responses in typically developing (TD) children and in children with autism spectrum disorder (ASD) was examined. Reflecting differential development of primary/secondary auditory areas and supporting previous studies, it was hypothesized that whereas left and right M50 STG responses would be observed equally often in younger and older children, left and right M100 STG responses would more often be absent in younger than older children. In ASD, delayed neurodevelopment would be indicated via the observation of a greater proportion of ASD than TD subjects showing missing M100 but not M50 responses in both age groups. Missing M100 responses would be observed primarily in children with ASD with language impairment (ASD?+?LI) (and perhaps concomitantly lower general cognitive abilities).MethodsThirty-five TD controls, 63 ASD without language impairment (ASD?-?LI), and 38 ASD?+?LI were recruited. Binaural tones were presented. The presence or absence of a STG M50 and M100 was scored. Subjects were grouped into younger (6-10?years old) and older groups (11-15?years old).ResultsAlthough M50 responses were observed equally often in older and younger subjects and equally often in TD and ASD, left and right M50 responses were delayed in ASD?-?LI and ASD?+?LI. Group comparisons showed that in younger subjects M100 responses were observed more often in TD than ASD?+?LI (90 versus 66%, p?=?0.04), with no differences between TD and ASD?-?LI (90 versus 76%, p?=?0.14) or between ASD?-?LI and ASD?+?LI (76 versus 66%, p?=?0.53). In older subjects, whereas no differences were observed between TD and ASD?+?LI, responses were observed more often in ASD?-?LI than ASD?+?LI. Findings were similar when splitting the ASD group into lower- and higher-cognitive functioning groups.ConclusionAlthough present in all groups, M50 responses were delayed in ASD. Examining the TD data, findings indicated that by 11?years, a right M100 should be observed in 100% of subjects and a left M100 in 80% of subjects. Thus, by 11?years, lack of a left and especially right M100 offers neurobiological insight into sensory processing that may underlie language or cognitive impairment.

Dataset Information

Differential monocyte responses to TLR ligands in children with autism spectrum disorders.

Publications

Differential monocyte responses to TLR ligands in children with autism spectrum disorders.

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