Immune-regulating cells contribute to autism-like traits in mice | Spectrum
Seeing stars: Mice that were exposed to an immune response before birth have high levels of inflammatory molecules in their astrocytes.
Pregnant mice that have been treated to build an immune response have pups that display autism-like behavior and altered immune cells, according to a new study. Injecting immune cells from other mice into adult puppies reverses both properties, the study also shows.
The work can help explain the link between autism and infection or immune disorders during pregnancy.
When pregnant mice are exposed to viral or bacterial compounds, the animals produce immune molecules that affect brain development and lead to autism-like characteristics in their pups, previous research has shown. But actual infections attract the fire of even more immune molecules than these compounds can conjure up.
The new study used the “soluble tachyzoite antigen” of the parasite Toxoplasma gondii, which elicits a broad immune response similar to that in autistic children – making it a good model for understanding the condition, says lead researcher Zikai Zhou , Professor of Neurobiology at the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences and the Shanghai Mental Health Center in China.
It’s “a really cool and comprehensive study,” says Amanda Kentner, an adjunct professor of psychology at the Massachusetts College of Pharmacy and Health Sciences in Boston, who was not involved in the work.
The results also suggest the possibility of a new treatment strategy for altered immune molecules and autism characteristics in people, say Zhou and colleagues.
When the immune system detects a pathogen, pro-inflammatory cells release cytokines that other immune cells recruit to destroy it. Mice exposed to Toxoplasma gondii extracts during pregnancy had abnormally high levels of these pro-inflammatory cells compared to other immune cells – especially those that produce the cytokines interferon-gamma and IL-17 – as did their pups, Zhou and his Colleagues found.
In contrast, their proportion of regulatory T cells that dampen an immune response was atypically low – which led to excessive inflammation overall.
The exposed mice also had unusually high levels of the cytokine IL-6 in their astrocytes, star-shaped brain cells believed to support synapses.
The exposed puppies are also atypical in their behavior, the team found: At the age of 7 and 9 days they vocalize more often and for longer than their non-exposed conspecifics. And they spend less time in open areas of an arena or maze and less time with other mice – suggesting that they are more anxious and less sociable. They also, on average, bury more marbles and build nests in unusual ways – two behaviors traditionally, perhaps controversially, considered to be autism-like traits.
Intravenous injections of regulatory T cells from unexposed control animals – an approach that has been tested in the treatment of autoimmune and neurological diseases – restored the levels of regulatory T cells and pro-inflammatory cells in the exposed puppies as adults. A week after treatment, the animals showed more typical responses when tested for anxiety, social interaction, and repetitive behavior, the researchers found. The use of regulatory T cells from the exposed mothers had an even stronger effect on the behavior of the mice and lowered the IL-17 level more significantly.
“Because these regulatory T cells have already encountered the pathogen … they are primed and can exert a higher immunosuppressive effect,” says Lior Brimberg, assistant professor of neuroimmunology at the Feinstein Institute for Medical Research in Manhasset, New York, who is not involved in the study was involved.
Consistent with this idea, the exposed mothers have a unique subset of regulatory T cells that were not seen in the control mice, the team found when they sequenced RNA from the two groups. These cells express more genes that are associated with improved cellular motility and cell migration. This motility could explain why exposed puppies, when treated with cells from exposed mothers, also had significantly more regulatory T cells crossing the blood-brain barrier.
“This shows the proof of concept that these regulatory T cells are important because they can invade the brain and possibly remodel the inflammatory microenvironment,” says Kentner.
Developing regulatory T cells with similar brain-infiltrating and immunosuppressive properties could be a way to translate the results into treating autism traits that are due to immune changes, says Zhou.
One limitation of the work is that only male puppies were used – although female animals are also affected by maternal immune reactions.
“Autism is also diagnosed in girls and women, and science shouldn’t ignore them,” says Kentner.
The study also didn’t mention the “litter effect” – the fact that littermates have more similarities than non-littermates – which could affect the reproducibility of the work, says Brimberg.
It will be important to see if the results hold up on this and other models of maternal immune activation, she says.
Finding out how long the results of the treatment will last, says Kentner, is also of paramount importance. If they are temporary, “it would affect the feasibility and acceptability of them” [treatment] ever accepted as a clinical intervention, ”she says.