"Antibrain" antibodies that slip through the placenta from mother to fetus during pregnancy may account for roughly a quarter of autism cases, a new study suggests. Some scientists say the work could lead to a blood test that accurately predicts whether a mother will bear a child with this immune-triggered form of the disorder—a claim that's raising eyebrows among skeptics.
Autism spectrum disorder (ASD), a range of communication and social deficits estimated to affect 1 in 88 children, is now largely thought to be a neurodevelopmental malady that begins in the womb. For years, many researchers have brushed aside the idea that an out-of-whack immune response could contribute to this, preferring to focus on genetic factors that could derail typical brain development, says immunologist Judy Van de Water. Over the past decade, however, she and her colleagues at the University of California (UC), Davis, as well as several other research groups, have been slowly building a case for the role of an immune disorder in a subset of autism cases. "We just didn't quit," she says.
In 2008, Van de Water found that roughly a quarter of 61 women with autistic children carried in their blood an unusual group of antibodies—large, Y-shaped proteins with sticky ends that normally bind to and destroy foreign or potentially harmful microbes. Some of these, called autoantibodies, occasionally go rogue and attack the body's healthy cells, causing autoimmune diseases such as lupus and rheumatoid arthritis. The higher the level of autoantibodies in the mother's blood, the more severe the child's autistic symptoms, Van de Water observed. She hypothesized that these autoantibodies were attacking proteins necessary for fetal brain development.
Further studies showed that the autoantibodies do, indeed, bind to proteins contained in fetal brain tissue and that they could penetrate the fetal blood-brain barrier, a network of tightly packed blood vessels that is permeable to only certain substances. When injected into pregnant mice, the antibodies produced deficits such as impaired motor development and increased anxiety in the offspring, suggesting that they were interfering with brain development. It wasn't clear, however, which precise brain proteins the antibodies attacked and if they would have similar effects on the behavior of an animal more closely related to humans.
Two new studies by Van de Water and colleagues attempt to answer those questions. Both are published this week in Translational Psychiatry. In the first, the researchers identify six of the proteins to which the antibodies bind. All are abundant in the developing fetal brain, and "each works at some stage in the development of a neuron," Van de Water says. (This developmental specificity may partly explain why the autoantibodies don't attack a mother's own brain; the blood-brain barrier also matures to become less permeable to antibodies.) For example, cypin, one protein targeted by the autoantibodies, plays a key role in how neurons in the hippocampus, a brain area associated with memory and learning, branch out and connect to neighboring cells. Another called CRMP1 shepherds the growth and proper migration of neurons to their proper places in the brain.
In a parallel study, Van de Water's colleagues Melissa Bauman and David Amaral injected eight pregnant rhesus monkeys with antibodies extracted from the blood of mothers who have a child with autism. The researchers noted several behavioral abnormalities in the first 2 years of the young animals' lives. First, the monkey mothers that received the autoantibodies showed heightened protectiveness over their infants—a possible sign that they sensed something wrong in their young that the researchers couldn't detect. In addition, as these infants grew up, "there was a disconnect between approaching others and being approached" by their peers, Bauman says. In normal rhesus monkeys, these exchanges follow a tit-for-tat pattern, with roughly equal and reciprocal approaches. The animals whose fetal brains had been exposed to the antibodies, however, approached their peers far more often than they were approached, Bauman says—a sign that there was something socially "off" about them. Most striking was the young monkeys' behavior around strange animals, she says: They directly approached unknown animals far more often than their peers, which could be dangerous.
Bauman emphasizes that although these behaviors provide a closer match to the social deficits seen in human autism than can be observed in mice, autism is a uniquely human disorder. The odd behaviors are significant because they signal a departure from normal monkey behavior, she says.
The brains of the male monkeys whose mothers had received autoantibody injections also grew larger than those of females or controls, a pattern that mirrors abnormal brain development in human autism, Van de Water says.
"The fact that you can take these antibodies and squirt them into animals and replicate autistic behaviors is really powerful," says Kevin Becker, a geneticist and immunologist at the National Institute on Aging in Bethesda, Maryland. However, he notes that the small number of animals in the study means that although the results are "suggestive," "you don't want to write home to mom about it."
In an expanded analysis of blood samples from 246 mothers whose children have an autism spectrum disorder, Van de Water's team found that 23% had autoantibodies that recognized one or more of the six fetal brain proteins, compared with only 1% of 149 mothers who have typically developing children. Based on these results, she and her colleagues have calculated that the presence of a specific combination of these antibodies indicate a 99% likelihood of having a child with autism, Van de Water says. She and her colleagues at UC Davis are now collaborating with the company Pediatric Bioscience to develop a diagnostic test for prospective mothers that they say will be ready for use in about 18 months.
Other scientists are skeptical. Based on his own calculations using numbers provided in the study, "it looks to me like only 16.5% of the time will a positive value actually predict autism," if one takes into account the low prevalence of autism in the general population, says George Anderson, a neuroscientist at Yale University. "I'm amazed that they're going ahead at this point and trying to commercialize a test—this needs to be replicated several times."
Betty Diamond, a physician and immunologist at the Feinstein Institute for Medical Research in Manhasset, New York, agrees that "there's more work to be done," before such a diagnostic test is ready for prime time. "If you're using this to determine the likelihood that someone is going to have a child with ASD," which might influence the decision to have a baby or not, she says, "you want a very, very strong degree of certainty." However, she says, "this is a very exciting approach, because if this indeed contributes to some proportion of cases of ASD then there is a way to identify risk pregnancies and also a way to think about prevention" with drugs such as antibody blockers, or to begin early interventions, such as behavioral therapy, that have been shown to improve how autistic children fare long-term.