UC DAVIS (US) — Antibodies found only in mothers of children with autism cross the placenta during pregnancy and affect brain development.
The brain changes result in a form of autism known as maternal antibody-related (MAR) autism. The condition could represent as much as 23 percent of all autism cases, researchers say.
During gestation, maternal immunoglobulin-G (IgG) antibodies normally cross the placenta and protect the fetus, conferring the mother’s immunities to the developing child. However, in addition to protective antibodies, autoantibodies that react to fetal proteins can also cross the placenta, essentially attacking fetal tissue.
Published in the journal Translational Psychiatry, the current study is an extension of an earlier study conducted in 2008. It explores the effects of the autism-specific IgG antibodies in rhesus monkeys.
For the study, a group of pregnant female monkeys were exposed to IgG purified from mothers of children with autism that exhibited fetal brain reactivity—the IgG-ASD group; a second group of pregnant female monkeys received IgG antibodies from the mothers of typically developing children. The third group included untreated animals that did not receive antibodies.
To evaluate development in the IgG-ASD offspring, researchers carried out a comprehensive evaluation of behavioral development and periodically conducted longitudinal magnetic resonance imaging (MRI) of the monkeys’ brain development during the first two years of life.
“The offspring of IgG-ASD antibody treated mothers consistently deviated from species-typical behavioral development of young rhesus monkeys,” says Melissa D. Bauman, assistant adjunct professor in the department of psychiatry and behavioral sciences at the University of California, Davis.
More protective moms
Early in development, the monkey mothers treated with IgG-ASD antibodies were much more protective of their offspring. For example, the IgG-ASD treated mothers more frequently approached and contacted their infants and remained in close proximity to them.
The mothers may have detected behavioral abnormalities in their IgG-ASD offspring that were so subtle that they escaped the researchers’ attention, Bauman says.
“The heightened protectiveness of the monkey mothers was observed only when other animals were present, suggesting that the mothers perceived a greater risk to their IgG-ASD treated infants.”
Other alterations in behavior were observed as the animals matured. For example, the offspring of the IgG-ASD antibody-treated animals more frequently approached other infants in their rearing group.
“Even more strikingly, as they grew older, the IgG-ASD offspring increased their approaches to unfamiliar peers,” she says. “Inappropriately approaching a novel animal is highly unusual and potentially dangerous for young rhesus monkeys.”
Less social interaction
Social interactions such as grooming or playing often occur when a young rhesus monkey approaches a peer. Despite the higher frequency of their approaches, the IgG-ASD offspring did not interact socially with peers more often than did the offspring whose mothers did not receive IgG-ASD antibodies.
“In fact, there actually was a trend for the IgG-ASD offspring to receive less grooming from their same-age peers,” she says. “It is possible that there were subtleties in the demeanor of the IgG-ASD offspring that dissuaded their peers from interacting with them.”
These new behavioral findings build upon previous studies exploring the role of maternal antibodies in autism, including a pilot study conducted in non-human primates in 2008. During the past five years, study co-author Judy Van de Water and her colleagues have made substantial progress in characterizing which maternal antibodies are highly specific to autism.
Van de Water recently reported that mouse offspring prenatally exposed to these autism-specific antibodies exhibit altered physical and social development, including anxiety and social behavior.
“The non-human primate study provides an exciting look at the pathologic effect of these autism-specific maternal antibodies,” Van de Water says.
In addition to the behavioral changes, MRI analysis of the brains revealed altered patterns of neurodevelopment in the monkey offspring exposed to the IgG-ASD antibodies. The rate of brain growth was significantly faster in the male, but not female, IgG-ASD offspring, when compared with that of the control offspring. The total brain volume of the male IgG-ASD offspring also was significantly greater than normal.
While it is not clear why prenatal exposure to these antibodies only alters brain volume in the male offspring, a similar trajectory of abnormal brain development has been observed in male children with autism. Recent research from the MIND Institute has reported that boys with autism who were exposed prenatally to the same antibodies have significantly larger brains than boys with autism born to mothers without the IgG-ASD antibodies and typically developing control groups.
“The combination of brain and behavioral changes observed in the nonhuman primate offspring exposed to these autism-specific antibodies suggests that this is a very promising avenue of research.”
In a related study, Van de Water and colleagues identified the specific antibodies that target fetal brain proteins. The findings, published in Translational Psychiatry, are the first to pinpoint a specific risk factor for a significant subset of autism cases, as well as a biomarker for drug development and early diagnosis.
To identify the exact antigens targeted by the mothers’ antibodies, the team conducted the research in Northern California using blood samples from 246 mothers of children with autism and of a control group of 149 mothers of children without autism to examine their reactivity with the candidate antigens.
Seven antigens were significantly more reactive to the blood of mothers of children with autism than to that of the control mothers. The study found that the mothers with antibodies that reacted with any one of these antigens, either individually or in combination with other antigens, were more than three times as likely to have a child with autism spectrum disorder.
Several combinations of antibodies in the blood from mothers of children with autism were not found in the control mothers’ blood.
“It is important to note that women have no control over whether or not they develop these autoantibodies, much like any other autoimmune disorder,” Van de Water says. “And, like other autoimmune disorders, we do not know what the initial trigger is that leads to their production.”
Understanding which proteins and which pathways are implicated in MAR autism can help elucidate the causes of autism and possibly lead to new therapies, such as administering “antibody blockers” to the mother during pregnancy to prevent damage to the developing fetal brain, Van de Water says.
These findings are leading to the development of a MAR diagnostic test for autism, which would be available to the mothers of young children who are showing signs of developmental delay. If the test were positive, the child would be a candidate for early behavioral intervention.
This National Institute of Mental Health and the California National Primate Research Center funded the research led by Bauman. The study led by Van de Water was supported by the National Institute of Environmental Health Sciences, the US Environmental Protection Agency, Autism Speaks, and the UC Davis MIND Institute.
Source: UC Davis