Association of a MET genetic variant with autism-associated maternal autoantibodies to fetal brain proteins and cytokine expression
Open accessAbstract
The contribution of peripheral immunity to autism spectrum disorders (ASDs) risk is debated and poorly understood. Some mothers of children with ASD have autoantibodies that react to fetal brain proteins, raising the possibility that a subset of ASD cases may be associated with a maternal antibody response during gestation. The mechanism by which the maternal immune system breaks tolerance has not been addressed. We hypothesized that the mechanism may involve decreased expression of the MET receptor tyrosine kinase, an ASD risk gene that also serves as a key negative regulator of immune responsiveness. In a sample of 365 mothers, including 202 mothers of children with ASD, the functional MET promoter variant rs1858830 C allele was strongly associated with the presence of an ASD-specific 37+73-kDa band pattern of maternal autoantibodies to fetal brain proteins (P=0.003). To determine the mechanism of this genetic association, we measured MET protein and cytokine production in freshly prepared peripheral blood mononuclear cells from 76 mothers of ASD and typically developing children. The MET rs1858830 C allele was significantly associated with MET protein expression (P=0.025). Moreover, decreased expression of the regulatory cytokine IL-10 was associated with both the MET gene C allele (P=0.001) and reduced MET protein levels (P=0.002). These results indicate genetic distinction among mothers who produce ASD-associated antibodies to fetal brain proteins, and suggest a potential mechanism for how a genetically determined decrease in MET protein production may lead to a reduction in immune regulation.
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The MET variant appears connected to an increase in 37/73 kDa maternal autoantibodies and a decrease in maternal IL-10.
“This MET variant also appears connected to both an increase in 37/73 kDa maternal autoantibodies and a decrease in maternal IL-10, suggesting another mechanism through which MET may associate with ASD as a susceptibility factor (Heuer et al, 2011).”
From The Role of the Immune System in Autism Spectrum Disorder (2017) · cites this paper as Heuer et al, 2011
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Self-citation
- Authors
- Heuer, L., Braunschweig, D., Ashwood, P., Van de Water, J., & Campbell, D. B.
- Affiliations
- University of California, Davis (US)
- University of Southern California (US)
- Corresponding author
- Campbell, D B
- ORCID
- Venue
- Translational Psychiatry
- Published
- 2011-10-18
- Volume
- 1
- Issue
- 10
- Pages
- e48-e48
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC3309488
- OpenAlex
- W2089112861
- Cited by
- 62
- References
- 58
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 2 · 2019: 4 · 2018: 5 · 2017: 4 · 2016: 7 · 2015: 5 · 2014: 4 · 2013: 8 · 2012: 8
- FWCI
- 3.25
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (unspecified)
- Locations
- Translational Psychiatry (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Autism Speaks (R01-ES015359, AS4907)
- U.S. Environmental Protection Agency (R-829388)
- National Institute of Environmental Health Sciences (1 P01-ES11269, 1 P01 ES11269-01, ES015359, R01ES015359, P01ES011269, R829388)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Keywords
- autism spectrum disorder, maternal autoantibodies, MET receptor tyrosine kinase, maternal-fetal immune tolerance, IL-10, cytokine expression, peripheral immunity, genetic susceptibility
- MeSH terms
- Adult, Autistic Disorder, Autoantibodies, Brain, Child, Preschool, Female, Fetal Proteins, Humans, Immune Tolerance, Male, Maternal-Fetal Exchange, Nerve Tissue Proteins, Pregnancy, Down-Regulation, Interleukin-10, Proto-Oncogene Proteins c-met
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