Immune Endophenotypes in Children With Autism Spectrum Disorder

doi:10.1016/j.biopsych.2015.08.036

Biological Psychiatry

Volume 81, Issue 5, 1 March 2017, Pages 434-441

https://doi.org/10.1016/j.biopsych.2015.08.036 Get rights and content

Abstract

Background

Autism spectrum disorder (ASD) is characterized by social communication deficits and restricted, repetitive patterns of behavior. Varied immunological findings have been reported in children with ASD. To address the question of heterogeneity in immune responses, we sought to examine the diversity of immune profiles within a representative cohort of boys with ASD.

Methods

Peripheral blood mononuclear cells from male children with ASD (n = 50) and from typically developing age-matched male control subjects (n = 16) were stimulated with either lipopolysaccharide or phytohemagglutinin. Cytokine production was assessed after stimulation. The ASD study population was clustered into subgroups based on immune responses and assessed for behavioral outcomes.

Results

Children with ASD who had a proinflammatory profile based on lipopolysaccharide stimulation were more developmentally impaired as assessed by the Mullen Scales of Early Learning. They also had greater impairments in social affect as measured by the Autism Diagnostic Observation Schedule. These children also displayed more frequent sleep disturbances and episodes of aggression. Similarly, children with ASD and a more activated T cell cytokine profile after phytohemagglutinin stimulation were more developmentally impaired as measured by the Mullen Scales of Early Learning.

Conclusions

Children with ASD may be phenotypically characterized based upon their immune profile. Those showing either an innate proinflammatory response or increased T cell activation/skewing display a more impaired behavioral profile than children with noninflamed or non-T cell activated immune profiles. These data suggest that there may be several possible immune subphenotypes within the ASD population that correlate with more severe behavioral impairments.

Section snippets

Subjects

Participants were enrolled through the Autism Phenome Project study conducted at the University of California Davis M.I.N.D. Institute. The study protocols including recruitment and behavioral assessments have been previously described in detail (20, 21). Because of the gender disparities in ASD, we chose to focus on male subjects to eliminate issues of gender differences. In brief, following clinical evaluation for diagnostic confirmation, participants were placed in one of two groups: 1)

Results

We stratified children in this study based on immunological measures using a k-median cluster analysis algorithm. Children with ASD were grouped into two clusters. The first cluster (ASD^high; n = 22) consisted of subjects whose PBMC displayed a proinflammatory response profile based on cytokine production after stimulation with LPS. The second cluster (ASD^low; n = 28) consisted of subjects who displayed a less robust response to LPS (Figure 1A). Children in the ASD^high group displayed

Discussion

We found that when children with ASD were categorized into proinflammatory and noninflammatory groups based on the production of inflammatory-related cytokines by their PBMC stimulated with LPS in culture, those with proinflammatory profiles showed more impaired developmental and behavioral scores, as well as increased problems with sleep and aggression. These children also displayed more impaired social affect and a trend toward increased severity of core autism symptoms. Although the ADOS

Acknowledgments And Disclosures

This study was funded by the National Institute of Health Grants No. RO1MH089626, No. R21HD065269, No. U24 MH081810, and No. PO1ES011269; Autism Speaks Foundation; the Jane Botsford Johnson Foundation; National Alliance for Research on Schizophrenia and Depression; and the Peter Emch Foundation.

We thank the staff of both the University of California Davis M.I.N.D. Institute and the Autism Phenome Project study for their technical support. The commitment of the families who took part in these

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Citation Excerpt :
We observed significantly increased frequencies of CD4+ helper T cells, TH1 (CD4+ IFN-γ+) cells, TH2 (CD4+ IL-4+) cells, TH17 (CD4+ IL-17A+) cells, and elevated CD8+ cytotoxic Tc1 (CD8+ IFN-γ+) frequencies. The increased TH1, TH2, and TH17 frequencies are consistent with those in previous studies (Ahmad et al., 2017; Ashwood et al., 2011a, 2011b; Careaga et al., 2017; Croonenberghs et al., 2002; Goines et al., 2011; Krakowiak et al., 2017; Moaaz et al., 2019; Molloy et al., 2006; Ricci et al., 2013; Rose et al., 2020; Singh, 1996). The increased percentage of CD8+ Tc1 cells is consistent with that reported by Lopez-Cacho et al. (2016).
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Archival ReportImmune Endophenotypes in Children With Autism Spectrum Disorder

Abstract

Background

Methods

Results

Conclusions

Section snippets

Subjects

Results

Discussion

Acknowledgments And Disclosures

Brain Behav Immun

Brain Behav Immun

Neurotoxicol Teratol

Biol Psychiatry

J Neuroimmunol

Biol Psychiatry

Brain Behav Immun

Hum Immunol

J Neuroimmunol

Neurosci Lett

J Neuroimmunol

Biol Psychiatry

Brain Behav Immun

Brain Behav Immun

Brain Behav Immun

Neuroscience

J Neuroimmunol

J Neuroimmunol

J Neuroimmunol

Brain Behav Immun

Psychiatry Res

Brain Behav Immun

Changes in prevalence of parent-reported autism spectrum disorder in school-aged US children: 2007 to 2011–2012

Natl Health Stat Report

Archival Report
Immune Endophenotypes in Children With Autism Spectrum Disorder