Spontaneous Mucosal Lymphocyte Cytokine Profiles in Children with Autism and Gastrointestinal Symptoms: Mucosal Immune Activation and Reduced Counter Regulatory Interleukin-10
Abstract
A lymphocytic enterocolitis has been reported in a cohort of children with autistic spectrum disorder (ASD) and gastrointestinal (GI) symptoms. This study tested the hypothesis that dysregulated intestinal mucosal immunity with enhanced pro-inflammatory cytokine production is present in these ASD children. Comparison was made with developmentally normal children with, and without, mucosal inflammation. Duodenal and colonic biopsies were obtained from 21 ASD children, and 65 developmentally normal paediatric controls, of which 38 had signs of histological inflammation. Detection of CD3+ lymphocyte staining for spontaneous intracellular TNFalpha, IL-2, IL-4, IFNgamma, and IL-10, was performed by multicolor flow cytometry. Duodenal and colonic mucosal CD3+ lymphocyte counts were elevated in ASD children compared with noninflamed controls (p<0.03). In the duodenum, the proportion of lamina propria (LP) and epithelial CD3(+)TNFalpha+ cells in ASD children was significantly greater compared with noninflamed controls (p<0.002) but not coeliac disease controls. In addition, LP and epithelial CD3(+)IL-2+ and CD3(+)IFNgamma+, and epithelial CD3(+)IL-4+ cells were more numerous in ASD children than in noninflamed controls (p<0.04). In contrast, CD3(+)IL-10+ cells were fewer in ASD children than in noninflamed controls (p<0.05). In the colon, LP CD3(+)TNFalpha+ and CD3(+)IFNgamma+ were more frequent in ASD children than in noninflamed controls (p<0.01). In contrast with Crohn's disease and non-Crohn's colitis, LP and epithelial CD3(+)IL-10+ cells were fewer in ASD children than in nondisease controls (p<0.01). There was a significantly greater proportion of CD3(+)TNFalpha+ cells in colonic mucosa in those ASD children who had no dietary exclusion compared with those on a gluten and/or casein free diet (p<0.05). There is a consistent profile of CD3+ lymphocyte cytokines in the small and large intestinal mucosa of these ASD children, involving increased pro-inflammatory and decreased regulatory activities. The data provide further evidence of a diffuse mucosal immunopathology in some ASD children and the potential for benefit of dietary and immunomodulatory therapies.
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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 [83]
ASD patients with comorbid GI dysfunction exhibit altered innate immune responses and distinct pro-inflammatory transcriptional profiles compared to ASD patients without GI dysfunction.
“ASD patients with comorbid GI dysfunction specifically exhibit altered innate immune responses and distinct pro-inflammatory transcriptional profiles compared to ASD patients without GI dysfunction [72, 73].”
From Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders (2018) · cites this paper as [72]
Increased pro-inflammatory (TNF-α and IL-6) but decreased regulatory (IL-10) cytokine production in mucosal lamina propria and epithelial lymphocytes was observed in ASD children with GI symptoms compared to typically developing controls matched on GI symptoms.
“Increased pro-inflammatory (TNF-α and IL-6) but decreased regulatory (IL-10) cytokine production in mucosal lamina propria and epithelial lymphocytes was observed in ASD children with GI symptoms compared to typically developing controls matched on GI symptoms [21, 22].”
From Pilot study of probiotic/colostrum supplementation on gut function in children with autism and gastrointestinal symptoms (2019) · cites this paper as [21]
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Self-citation
- Authors
- ASHWOOD, P., ANTHONY, A., TORRENTE, F., & WAKEFIELD, A. J.
- Affiliations
- The Royal Free Hospital (GB)
- Johnson Center for Child Health and Development (US)
- Corresponding author
- ASHWOOD, PAUL
- Venue
- Journal of Clinical Immunology
- Published
- 2004-11
- Volume
- 24
- Issue
- 6
- Pages
- 664-673
- ISSN
- 0271-9142 (ISSN-L)
- 1573-2592
- OpenAlex
- W2135119740
- Cited by
- 212
- References
- 22
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 6 · 2023: 4 · 2022: 5 · 2021: 17 · 2020: 15 · 2019: 9 · 2018: 14 · 2017: 3 · 2016: 4 · 2015: 8 · 2014: 15 · 2013: 9 · 2012: 17
- FWCI
- 4.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Journal of Clinical Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Health Sciences › Medicine › Gastroenterology › Celiac Disease Research and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Keywords
- autism spectrum disorder, gastrointestinal symptoms, intestinal mucosal immunity, inflammatory cytokines, IL-10, TNF-α, interferon-gamma, interleukin-2, IL-4, CD3+ T cells, lamina propria, duodenum, colon, gluten-free diet, casein-free diet, elimination diet
- MeSH terms
- Adolescent, Autistic Disorder, Child, Child, Preschool, Diet, Enterocolitis, Female, Gastrointestinal Diseases, Humans, Immunity, Inflammation, Intestinal Mucosa, Lymphocytes, Male, Prospective Studies, Case-Control Studies, Cytokines, Interleukin-10, CD3 Complex
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