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Insights into Immune Changes & Autism

Researchers produce autism behaviors in mice by mimicking infection during pregnancy; reverse symptoms by resetting offspring’s immune system

Over the last decade, studies have suggested links between autism and immune-system abnormalities. What remained unanswered was whether immune changes played a role in causing autism or resulted from it.

Results from a mouse study published this summer provide new insights into how challenges to the immune system may contribute to the development of autism spectrum disorder (ASD).

The researchers mimicked a maternal infection during pregnancy in mice. Doing so produced both an overactive immune system and autism-like behaviors in the offspring. Further, the investigators reversed some of the behaviors by “resetting” the offspring’s immune systems with a bone-marrow transplant.

"We have long suspected that the immune system plays a role in the development of autism spectrum disorder," said senior researcher Paul Patterson, Ph.D., of the California Institute of Technology. "In our studies of this mouse model, we found that the mother’s immune system is a key factor in the eventual abnormal behaviors in the offspring."

The team’s report appeared in the Proceedings of the National Academy of Science. It was supported by an Autism Speaks Weatherstone Predoctoral Fellowship for lead researcher Elaine Hsiao.

The investigators injected pregnant mice with a molecule that mimicked viral infection by triggering a similar type of inflammation. "This single insult to the mother translated into autism-related behavioral abnormalities in the offspring," Hsiao explained. These abnormalities included all three of autism’s core symptoms: repetitive behaviors, impaired communication and reduced sociability. The mice compulsively buried marbles and self-groomed, avoided new mice and exhibited reduced and abnormal vocalizations. 

The mice also had a number of immune abnormalities similar to those seen in some people with autism. These included decreased levels of key immune-calming cells called regulatory T cells. Taken together, the immune abnormalities reflected an immune system in overdrive, Hsiao said.

"We saw these abnormalities in both young and adult offspring of immune-activated mothers," she added. "This tells us that a prenatal challenge can result in long-term consequences for health and development."

In addition, the team directly tested whether the immune problems contributed to the mice’s autism-like behaviors. They gave the affected offspring bone-marrow transplants from normal mice. In effect, this reset their immune systems to normal. It also reduced their autism-like behaviors.

“Researchers have studied immune changes in pregnant mothers or in offspring, but have rarely linked the two findings together,” commented Alycia Halladay, Ph.D., Autism Speaks senior director of environmental and clinical sciences. “This study is an important contribution to understanding the link between gestational immune dysfunction and outcomes.”

Such results in mice can't be directly applied to humans, experts agreed. Nor would a bone marrow transplant be an appropriate treatment for autism. Rather, it was a useful research tool for studying immune system changes in an animal model.

That said, normalizing immune irregularities could be an important target for future treatments, Dr. Patterson said. “By correcting immune problems through safe and proven methods, it might be possible to relieve some of autism’s classic developmental delays.”

Hsiao is continuing her research on the molecular basis of autism at Caltech, with the aim of developing novel therapeutics for the disorder.

Hsiao EY, McBride SW, Chow J, Mazmanian SK, Patterson PH. Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proceedings of the National Academy of Sciences.2012; 109(30).

Next: Discovery of Pre-symptom Marker of Autism

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