Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome
Open accessAbstract
Autism spectrum disorders (ASD) are characterized by impairment in social interactions, communication deficits, and restricted repetitive interests and behaviors. A potential role for immune dysfunction has been suggested in ASD. To test this hypothesis, we investigated evidence of differential cytokine release in plasma samples obtained from 2 to 5 year-old children with ASD compared with age-matched typically developing (TD) children and children with developmental disabilities other than autism (DD). Participants were recruited as part of the population based case-control CHARGE (Childhood Autism Risks from Genetics and Environment) study and included: 97 participants with a confirmed diagnosis of ASD using standard assessments (DSM IV criteria and ADOS, ADI-R), 87 confirmed TD controls, and 39 confirmed DD controls. Plasma was isolated and cytokine production was assessed by multiplex Luminex™ analysis. Observations indicate significant increases in plasma levels of a number of cytokines, including IL-1β, IL-6, IL-8 and IL-12p40 in the ASD group compared with TD controls (p<0.04). Moreover, when the ASD group was separated based on the onset of symptoms, it was noted that the increased cytokine levels were predominantly in children who had a regressive form of ASD. In addition, increasing cytokine levels were associated with more impaired communication and aberrant behaviors. In conclusion, using larger number of participants than previous studies, we report significantly shifted cytokine profiles in ASD. These findings suggest that ongoing inflammatory responses may be linked to disturbances in behavior and require confirmation in larger replication studies. The characterization of immunological parameters in ASD has important implications for diagnosis, and should be considered when designing therapeutic strategies to treat core symptoms and behavioral impairments of ASD.
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Elevated plasma cytokine levels (IL-1β, IL-6, IL-12p40, TNFα), altered immunoglobulin levels, elevated complement proteins, and increased chemokine levels (CCL2, CCL5, CCL11) are reported in the plasma of young children with autistic disorder compared with matched typically developing children.
“Elevated plasma cytokine levels (IL-1β, IL-6, IL-12p40 and TNFα) [82–84], altered immunoglobulin levels [85, 86], elevated levels of complement proteins [87], and increased chemokine levels (CCL2, CCL5 and CCL11) [88] are reported in the plasma of young children with AD compared with matched typically developing children.”
From Consensus Paper: Pathological Role of the Cerebellum in Autism (2012) · cites this paper as [82]
Elevations in IL-1β, IL-6, IL-8 and IL-12p40 are specifically associated with a regressive form of ASD and more impaired stereotypical behaviours, and elevations in CCL2, CCL5 and eotaxin are associated with higher aberrant behaviour scores and more impaired development.
“Elevations in IL-1β, IL-6, IL-8, IL-12p40 are specifically associated with a regressive form of ASD and more impaired stereotypical behaviours, and elevations in the chemokines C-C motif chemokine 2 (CCL2), CCL5 and eotaxin are associated with higher aberrant behaviour scores and more impaired development120.”
From Immune mediators in the brain and peripheral tissues in autism spectrum disorder (2015) · cites this paper as [120]
These changes include increases in IL-1β, IL-6, IL-8, IL-12p40 and GM-CSF, and decreases in IL-10 and TGF-β.
“These changes include increases in IL-1β, IL-6, IL-8, IL-12p40 and granulocyte-macrophage colony-stimulating factor (GM-CSF), which are generally considered to be ‘pro-inflammatory’, and decreases in IL-10 and transforming growth factor-β (TGF-β), which are generally considered to be ‘anti-inflammatory’115–120.”
From Immune mediators in the brain and peripheral tissues in autism spectrum disorder (2015) · cites this paper as [120]
Children with ASD have elevated levels of pro-inflammatory cytokines including IL-6, TNF-α, and IFN-γ in different tissues.
“Furthermore, evidence suggests that children with ASD have elevated levels of pro-inflammatory cytokines including, interleukin 6 (IL–6), tumour necrosis factor alpha (TNF–α), and interferon gamma (IFN-γ) in different tissues [3,4,5,6,7].”
From Vitamin D and Autism Spectrum Disorder: A Literature Review (2016) · cites this paper as [4]
Increased cytokines have been reported in association with a regressive autism phenotype with significant communication challenges and aberrant behaviors.
“An increase in inflammatory cytokines has been reported previously in ASD, and increased cytokines have been reported in association with a regressive autism phenotype with significant communication challenges and aberrant behaviors.56, 57”
From Distinct Microbiome-Neuroimmune Signatures Correlate With Functional Abdominal Pain in Children With Autism Spectrum Disorder (2017) · cites this paper as [57]
An increase in inflammatory cytokines has been reported previously in ASD.
“An increase in inflammatory cytokines has been reported previously in ASD, and increased cytokines have been reported in association with a regressive autism phenotype with significant communication challenges and aberrant behaviors.56, 57”
From Distinct Microbiome-Neuroimmune Signatures Correlate With Functional Abdominal Pain in Children With Autism Spectrum Disorder (2017) · cites this paper as [57]
High levels of cytokines such as IL-1B, IL-6, IL-8, and IL-12p40 have been reported in ASD children associated with poor communication and impaired social communication.
“High levels of cytokines (e.g., IL-1B, IL-6, IL-8, and IL-12p40) have been reported in ASD children associated with poor communication and impaired social communication [32,152].”
From Autism, Gastrointestinal Symptoms and Modulation of Gut Microbiota by Nutritional Interventions (2019) · cites this paper as [152]
Levels of the proinflammatory cytokines IL-6 and TNF-α, which lead to activation of the HPA axis, have been shown to be increased in those with ASD.
“Levels of the proinflammatory cytokines IL-6 and tumor necrosis factor-alpha (TNF-α), which lead to activation of the HPA axis (Dunn, 2006), have been shown to be increased in those with ASD (Ashwood et al., 2011; Emanuele et al., 2010; von Känel et al., 2005).”
From Associations between cytokines, endocrine stress response, and gastrointestinal symptoms in autism spectrum disorder (2016) · cites this paper as Ashwood et al., 2011
The modest relationship between upper GI tract symptoms and TNF-α is consistent with previous findings of increased TNF-α associated with GI symptoms in general.
“The modest relationship between upper GI tract symptoms and TNF-α is consistent with previous findings of increased TNF-α associated with GI symptoms in general (Ashwood et al., 2011), but this is limited by the paucity of upper GI tract symptoms in our sample.”
From Associations between cytokines, endocrine stress response, and gastrointestinal symptoms in autism spectrum disorder (2016) · cites this paper as Ashwood et al., 2011
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- Authors
- Ashwood, P., Krakowiak, P., Hertz-Picciotto, I., Hansen, R., Pessah, I., & Van de Water, J.
- Affiliations
- University of California Davis Medical Center (US)
- University of California, Davis (US)
- Corresponding author
- Ashwood, Paul
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2011-01
- Volume
- 25
- Issue
- 1
- Pages
- 40-45
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC2991432
- OpenAlex
- W2152612457
- Cited by
- 940
- References
- 47
- Citations by year
- 2026: 67 · 2025: 75 · 2024: 92 · 2023: 61 · 2022: 77 · 2021: 64 · 2020: 75 · 2019: 65 · 2018: 63 · 2017: 56 · 2016: 57 · 2015: 36 · 2014: 35 · 2013: 48 · 2012: 39
- FWCI
- 21.62
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Environmental Health Sciences (R01ES015359, P01ES011269)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Psychiatry and Mental health › Child Nutrition and Feeding Issues
- Keywords
- autism spectrum disorder, plasma cytokines, immune dysfunction, inflammation, IL-1β, interleukin-6, interleukin-8, interleukin-12p40, regressive autism, communication disorders, aberrant behavior, developmental disabilities, children, CHARGE study
- MeSH terms
- Child Behavior, Child Behavior Disorders, Child Development Disorders, Pervasive, Child, Preschool, Communication, Female, Humans, Male, Neuropsychological Tests, Regression Analysis, Cytokines, Diagnostic and Statistical Manual of Mental Disorders
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