UC DAVIS (US) — Pregnant women with a particular gene variation are more likely to produce antibodies that may injure the brains of developing fetuses—increasing the risk their children will develop autism.
The research is the first to demonstrate a genetic mechanism at play in the development of autism, raising the possibility of a genetic test for women at risk, according to the study published online in the journal Translational Psychiatry.
“Our study gives strong support for the idea that, in at least some cases, autism results from maternal immunity gone overboard,” says Judy Van de Water, professor of internal medicine at the University of California, Davis, who is affiliated with the MIND Institute. “This is the first time that a genetic factor known to be important in autism and its effects have been demonstrated.”
For the study, Van de Water and colleagues examined the action of the MET gene, which has a known association with autism, among 200 mothers of children with autism and 150 mothers of typically developing children enrolled in the Northern California-based Childhood Autism Risks from Genetics and the Environment (CHARGE) Study.
All of the study participants were between 2 and 5 years of age at the time of study enrollment, lived with one biological parent, and spoke either English or Spanish.
The researchers found that the C-allele of the MET gene is more common in mothers with several immunologic abnormalities that might contribute to the development of autism. Analysis of the MET C-allele is a method of determining susceptibility for immune dysregulation in the mothers.
One abnormality they attributed to the MET C-allele is the presence of antibodies against fetal brain proteins in the blood of the mothers. These brain-attacking antibodies occur in some mothers with an autistic child, but are not found in mothers of typically developing children. It is believed that these antibodies somehow injure the developing brain of the fetus, and in some instances may cause autism.
Researchers do not yet know when or how the antibodies are formed, or precisely what happens to the brain tissue exposed to them, but based on a collaborative paper with Loren Martin at Azuza Pacific University, they appear to have pathologic significance, or a functional effect on brain development, changing the way the brain develops.
Van de Water and her group are still working on the precise effect of these maternal antibodies on the developing brain.
MET protein levels were also found to be reduced in cells from mothers with one C-allele and one normal allele, and were even lower in those with two C-alleles. Lower MET protein on the cell surface may increase susceptibility to a more intense and prolonged immune response when the cells are activated, like exposure to a bacteria or virus. This, in turn, could make these individuals more prone to forming antibodies against “self” proteins, such as those found in the fetal brain.
The investigators evaluated the functional polymorphism in the study participants’ immunological cytokines, molecules that tell other cells what to do. The cytokine IL-10, an important anti-inflammatory marker, was reduced in women with the MET C-allele.
IL-10 is a well-studied immunosuppressive molecule that is important for preventing autoimmunity. A reduction in IL-10 would increase the chances that an inflammatory response would continue unchecked, Van de Water says.
“The convergence of these two distinct associations with autism risk—that of maternal antibodies to fetal brain proteins and the MET C-allele—provides the first link between an autism susceptibility gene and its effects.”
“The presence of maternal antibodies to fetal blood proteins is one of the best markers known for autism, accounting for about 12 percent of cases. In contrast, genetic factors previously identified in children with autism account for only 2 or 3 percent of cases,” says Daniel B. Campbell, assistant professor of psychiatry and the behavioral sciences at the University of Southern California, co-principal investigator of the study.
“Now we not only have a marker, but we are starting to understand the actual mechanisms of what causes autism. These findings can greatly enhance our understanding of the origins of some cases of autism and may directly lead to screening tests and treatments to prevent it.”
Why women with the C-allele form antibodies against fetal brain proteins is another important area of interest, according to Van de Water, because it suggests a hyper-responsive immune system. Proteins associated with the MET gene function as key blockers of immune activity.
“Our study has found that a kind of safety switch that regulates the immune system and prevents it from targeting the brain of the developing fetus is defective in some mothers of children who later develop autism.”
The relationship between autism and aberrations in the immune system, once a radical notion in the scientific community, is now becoming a well-accepted and very fruitful focus of research, Van de Water says. “While it is not known how the antibody response against fetal brain proteins arise, it may be possible to one day treat susceptible women to reduce the likelihood of having an autistic child.”
The research was funded by the National Institutes of Environmental Health Sciences, the United States Environmental Protection Agency and the Autism Speaks Foundation.
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