The impact of inflammation

Risk of autism linked to mother’s immune system dysfunction during pregnancy

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SACRAMENTO, Calif.—Aimed at one day unlocking the mystery to a miracle therapy and cure for autism, researchers with the UC Davis MIND Institute have found that pregnant women with higher levels of inflammatory cytokines and chemokines, proteins that control communication between cells of the immune system, may be at a greater risk of having a child with autism combined with intellectual disability (previously known as mental retardation) than having autism alone. This is the first time a clinical study has teased out the difference between diagnosing lower-functioning (autism with intellectual disability) and higher-functioning (autism alone) forms of autism.
The research also suggests a potential immune profile for the differentiation of autism combined with intellectual disability, distinct from either autism or developmental disability alone. This opens the door to an early and more precise diagnosis that will point a clearer path for parents, especially in terms of education, therapy and their children’s options for independent living.
Currently diagnosed in one of 68 infants, autism is characterized by difficulty communicating and interacting with others, repetitive behaviors with limited interests or activities and symptoms that hurt the individual’s ability to function socially.
And it all begins with the mother.
“Inflammation during the second trimester in the mothers of children with autism who also have intellectual disability was significantly greater than in mothers of children with autism but without intellectual disability in our study,” says Judy Van de Water, professor of internal medicine in the Division of Rheumatology, Allergy and Clinical Immunology and a researcher affiliated with the MIND Institute.
“However, equally significant was that profiles of mothers whose children go on to be diagnosed with autism and intellectual disability differed markedly from those whose children have intellectual disability without autism, as well as from the typically developing general population,” Van de Water continues. “Their profiles are distinct from all of the other groups that we studied, based on their cytokine and chemokine profiles. This finding suggests an avenue to explore that could potentially identify possible markers to separate sub-phenotypes in the autism population.”
The large, diverse, population-based study was conducted using blood serum samples obtained from the California Department of Public Health of mothers in the Kaiser Permanente Early Markers for Autism Study—184 whose children developed autism and intellectual disability; 201 who had children with autism without intellectual disability; 188 whose children had developmental disability alone and 428 general population control participants.
The study was designed to evaluate biomarkers for autism. Women were eligible for participation if they delivered their infants between July 2000 and September 2003. The participants were largely from Orange, San Diego or Imperial counties.
The researchers examined the mothers’ mid-gestational blood serum levels of 22 different cytokines and chemokines, including GM-CSF, IL-1Alpha, IL-6 and IFN-Gamma.
Ironically, “this study was just part of a large epidemiological study to better understand the risk factors leading to the birth of children on the autism spectrum,” Van de Water told DDNews.
“As this study progressed, we noted differences within the autism group in terms of maternal cytokine and chemokine levels,” she adds. “That led to the differentiation between autism with intellectual disability—and autism without intellectual disability—based on maternal inflammation during pregnancy.”
According to Van de Water, the lack of immune regulation in the mother is manifested by elevated inflammatory cytokines, when typically the cytokines are down-regulated during pregnancy. However, the mother’s system dysfunction only affects the fetus.
“We have no idea as to why this regulation is disturbed, but it is likely due to genetic susceptibility,” she says, adding that “research suggests that schizophrenia might also stem from maternal immune activation (lower regulation) during pregnancy.”
While these findings “have opened the door to possibilities in drug discovery and future clinical trials, it is premature to speculate about possible drugs or treatments based upon this study,” Van de Water cautions. “However, we hope that it paves the way for future studies and the development of potential biomarkers or therapeutics.”
The study was published in Molecular Psychiatry under the title “Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation.”
“The fact that we see this increase in inflammatory markers with the autism/intellectual disability group compared with all of the other reference groups is striking, because the ones we’re seeing that are affected are usually down-regulated during the second trimester of pregnancy,” stated Karen L. Jones, the study’s first author and a postdoctoral fellow in the Division of Rheumatology, Allergy and Clinical Immunology. “This really is suggesting that there is a lack of the immune regulation in these moms that is typically associated with a healthy pregnancy.”
The authors postulate that alterations in the gestational immune environment among mothers of children with autism and intellectual disability may lead to alterations in the neurodevelopmental trajectory of the developing fetus, which may subsequently result in the altered behavioral phenotype characteristic of children with autism and intellectual disability.
They noted that maternal immune activation represents one of several pathways that can result in differences in maternal cytokines, including environmental toxicants. Mid-gestational maternal cytokine and chemokine levels also may interact with other potential risk factors, such as parental genetics.
“It is particularly exciting that this work does start to tease apart a potential source of differences in autism—with and without intellectual disability—as well as from intellectual disability without autism,” Jones says.
Leonard Abbeduto, director of the MIND Institute, says the study is “incredibly valuable because it helps us understand more about the sources of variability within autism spectrum disorder, providing important insights into the different neurobiological mechanisms underlying important subtypes of the disorder.”
“At the same time, the study reinforces the importance of the maternal immune system in a host of child outcomes," Abbeduto says. "Most importantly, this study brings us closer to knowing how to prevent adverse developmental outcomes.”

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