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Cytokine Profiles in Subjects with Autism Spectrum Disorders

Cytokine Profiles Autism Spectrum Disorders
Cytokine Profiles – Autism Spectrum Disorders

In a study published in the online journal PLoS ONE, a research group from the Hamamatsu University School of Medicine, Hamamatsu, Japan reports the presence of high levels of several pro-inflammatory cytokines in male (≥6 years old) subjects with autism spectrum disorder (ASD).

ASD include autistic disorder, Asperger’s disorder and pervasive developmental disorder.

A dysregulation of the immune system may be implicated in the pathophysiology of ASD. Increased levels of some inflammatory cytokines in peripheral samples such as serum or plasma of patients with ASD were reported, but previous data appear to be inconsistent, most likely due to variations in the experimental designs.

Recent advances in multiplex technologies have enabled measurement of multiple analytes simultaneously.

In the PLoS ONE study, Katsuaki Suzuki and colleagues have used a multiplex assay, and demonstrate that plasma levels of IL-1beta, IL-1RA, IL-5, IL-8, IL-12(p70), IL-13, IL-17 and GRO-α in the high-functioning male subjects with ASD were significantly higher than those of matched control subjects.

The elevated plasma levels of IL-12(p70) substantiate previous data in children with autism and adults with Asperger’s syndrome.

The increased levels of IL-17 reported in this study are also validated by recent research showing that IL-17A levels correlate with the severity of autism. Importantly, it appears that IL-17 interfere with the normal brain development in a mouse model of autism.

Suzuki et al. also discuss that the increased IL-8 and GRO-α plasma levels might have resulted from IL-17 secretion by Th17 cells activated in response to subclinical infections in epithelial or endothelial cells in the subjects with ASD.

The authors suggest that the elevation of these cytokines may indicate an abnormal steady-state immune response in subjects with ASD, and that such a multiplex analysis of cytokines may serve as one of the biological trait markers for the disorder.

SOURCE: PLoS ONE 2011, 6: e20470
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Updates

A 2021 meta-analysis based on 37 cytokines with 289 studies represents one of the most comprehensive review and meta-analysis of the relationship between peripheral cytokines and autism spectrum disorder (ASD) so far. The data from this review and meta-analysis indicates a significant elevation of peripheral blood proinflammatory cytokine levels for IL-6, IL-1β, IL-7, and IL-12p70 in ASD patients compared with controls.

In addition, peripheral blood levels of MIF, eotaxin-1, MCP-1, and IL-8 were also markedly increased in ASD patients compared with controls. MIF, directly or indirectly promotes the production or expression of a large panel of proinflammatory cytokines (such as IL-1β, IL-6, and IL-8) and mediates both acute and chronic inflammatory responses. These findings strengthened the clinical evidence of ASD with an abnormal inflammatory response.

A 2022 systematic review found increased levels of IL-6, IL-17, TNF-α, IL-1β, IFN-γ, RANTES, and IL-8 in the plasma/serum in autism. The reviewed autism studies that investigated cytokine production by in vitro stimulated blood immune cells suggest monocytes, neutrophils, CD4+ T cells, and NK cells as the major cellular sources of these altered cytokines.

In this review, the authors found elevated levels of IL-6, TNF-α, and IL-1β in the plasma/serum of individuals with autism. These cytokines can cross from the peripheral blood into the brain, where they directly affect brain function and behavior. Previous studies have shown that high levels of IL-6, TNF-α, and IL-1β are correlated with the severity of autism symptoms.

In this review the authors also found evidence of increased IL-17 levels in the serum of subjects with autism. The data presented in this review suggest that neutrophils and CD4+ T cells are perhaps the potential sources of IL-17 in the steady state of autism, in addition to IL-17 production by stimulated CD4+ T cells.

As per this review, neutrophils of individuals with autism express the IL-17RC subunit, which is absent in the neutrophils of control subjects. This enables neutrophil to potently respond to IL-17A/IL-17R signaling and release IL-6, leading to increased IL-17 production in autism. Thus, taken together, these results suggest that Th17 cells and neutrophils are potential sources of upregulated IL-17 levels in autism.

Furthermore, the review reports increased levels of RANTES, IL-8, and IFN-γ in the plasma/serum of subjects with autism. However, as per the authors there is still no clear evidence concerning the cellular sources of RANTES and IL-8. And last but not least, the studies presented in this review suggest the prevalence of T helper 1 (Th1) and Th17 phenotypes rather than the Th2 phenotype in autism.

Cover Image: Bio-Plex Multiplex Immunoassays, Multiplex Assays Design: ‘Schematic representation of a immunoassay sandwich-based assay workflow’. Similar to ELISA, a majority of assays are designed according to a capture sandwich immunoassay format. Briefly, the capture antibody-coupled beads are first incubated with antigen standards or samples for a specific time. The plate is then washed to remove unbound materials, followed by incubation with biotinylated detection antibodies. After washing away the unbound biotinylated antibodies, the beads are incubated with a reporter streptavidin-phycoerythrin conjugate (SA-PE). Following removal of excess SA-PE, the beads are passed through the array reader, which measures the fluorescence of the bound SA-PE.