ScienceDaily (July 17, 2012) — Scientists at the California Institute of Technology (Caltech) pioneered the study of the link between irregularities in the immune system and neurodevelopmental disorders such as autism a decade ago. Since then, studies of postmortem brains and of individuals with autism, as well as epidemiological studies, have supported the correlation between alterations in the immune system and autism spectrum disorder.
A constant question that is still unanswered is whether or not changes in the immune system can play a role in the development of the disease or is just a side effect. A new Caltech study implies that changes in an excessive immune system can in fact provide autism-like behaviors in mice, and can be related in some cases to the experiences of a developing fetus.
“We have long suspected that the immune system plays a role in the development of autism spectrum disorder,” says Paul Patterson, the Anne P. and Benjamin F. Biaggini Professor of Biological Sciences at Caltech, who led the work. “In our studies of a mouse model based on an environmental risk factor for autism, we find that the immune system of the mother is a key factor in the eventual abnormal behaviors in the offspring.”
The fist step taken was to create a model mouse that connected the autism-like demeanors together with immune changes. Several studies have found a relationship between a viral infection during the first trimester of pregnancy and the possibility for autism spectrum disorder in the child. The model mouse was injected with a viral imitator that generated the same type of immune response as an actual infection.
“In mice, this single insult to the mother translates into autism-related behavioral abnormalities and neuropathologies in the offspring,” says Elaine Hsiao, a graduate student in Patterson’s lab and lead author of the PNAS paper.
They found that the main behaviors in the baby would display the same symptoms affiliated with ASD-repetitive or sterotyped behaviors, diminished social interactions, and decreased communication. In mice, these behaviors were interpreted as obsessively burying marbles, extreme self grooming, spending time alone voluntarily rather than playing or being social, or expressing themselves differently or not as much as the typical mouse.
The researchers then characterized the immune system of the babies that had been infected and came to the conclusion that they showed numerous immune changes. Some of these correlated with the changes seen in people with autism that includes lowered levels of T cells.
“Remarkably, we saw these immune abnormalities in both young and adult offspring of immune-activated mothers,” Hsiao says. “This tells us that a prenatal challenge can result in long-term consequences for health and development.”
The group was now able to test the model mouse whether or not the baby’s immune problems did in fact contribute to their autism-related behaviors. This test revealed that the researchers were able to correct some of if not many of the behaviors in the babies of immune-activated parent by giving the baby a bone marrow transplant from typical mice. The normal stem-cells in the bone marrow that was transplanted replenished the immune system as well as modified their autism-like behavior.
The researchers emphasize that because the work was conducted in mice, the results cannot be quickly associated to humans, and they certainly do not suggest that bone-marrow transplants should be considered as a treatment for autism. They also have yet to establish whether it was the infusion of stem cells or the bone-marrow transplant procedure itself that altered the behaviors.
Patterson does says however, that the results do suggest that immune imperfections in children could be an important objective for innovative immune manipulations in addressing the behaviors associated with autism spectrum disorder. By correcting these immune problems, he says, it might be possible to improve some of the classic developmental delays seen in autism.
In future studies, the researchers plan to examine the effects of highly targeted anti-inflammatory treatments on mice that show autism-related behaviors and immune changes. They are also interested in considering the gastrointestinal (GI) bacteria, or microbiota, of such mice. Coauthor Sarkis Mazmanian, a professor of biology at Caltech, has shown that gut bacteria are closely tied to the function of the immune system. He and Patterson are researching whether changes to the microbiota of these mice might also effect their autism-related behaviors.