Scientists Zero in on Immune Factor that Links Maternal Infection to Autism-like Signs in Mice


by Jim Schnabel

February 24, 2016

Autism spectrum disorders (ASDs) are largely heritable. But for almost thirty years, there has been evidence of a significant environmental cause: a serious infection of the ASD child’s mother during pregnancy. Multiple studies have found that children born to infection-exposed mothers are at least moderately more likely to develop an ASD, compared with other children—and are also moderately more likely to come down with other neurodevelopmental disorders, including schizophrenia.

Now researchers have reported, in the January 29 issue of Science, that they have used a mouse model of maternal infection-related ASD to confirm that the immune protein Interleukin 17A (IL-17A) is a key mediator of this effect—at least in mice.

“Our data suggest that you need to block IL-17A … in maternal sera,” said Jun Huh, a researcher at the University of Massachusetts Medical School who was one of the principal investigators for the study. “You could possibly measure the IL-17A level in susceptible mothers who get infected and treat them with anti-IL-17A” therapies.

From influenza and schizophrenia to MIA mice

The current interest in the possibility that some ASDs originate with maternal infections dates back to epidemiological studies in the late 1980s and early 1990s, which linked pregnant women’s exposures to influenza epidemics to higher rates of schizophrenia in their children.

Following those studies, researchers began to model infections in pregnant mice and analyze the resulting brain and behavior abnormalities in the offspring. By the early 2000s, they were finding hints from such mouse models that maternal infection might be able to explain not only schizophrenia but also ASDs. In 2010, an epidemiological study from Denmark found a relatively strong link between ASDs and maternal infection requiring hospitalization. Other epidemiological studies with similar conclusions have come out more recently. Even twin studies—designed to measure the influence of heredity--have hinted that ASDs are partly due to environmental factors in the womb.

Although the first epidemiological and mouse-model studies focused on influenza virus exposure, later studies implicated viral or bacterial infections more broadly. “We’ve seen this evolve into a hypothesis that’s not about a particular pathogen or infection but just general immune activation,” said Elaine Hsiao, a researcher at UCLA who has worked with such mouse models.

The “maternal immune activation” (MIA) mouse model used in Huh and his colleagues’ new study is almost identical to the model that was described in a 2012 paper from the laboratory of the late Paul Patterson at the California Institute of Technology. Patterson’s group found that after they injected pregnant female mice with an RNA-like, virus-mimicking molecule, called poly (I:C), to stimulate a strong immune reaction, the pups—particularly the males—were born normally but soon exhibited abnormal vocalizations, repetitive/stereotyped behaviors, and decreased sociability. Despite the vast evolutionary gap between the mouse brain and the human brain, these three signs in the young MIA mice strongly resembled the classic signs of ASDs in human children.

That study and others in mice have implicated a pro-inflammatory immune protein, IL-6, as well as IL-17A, whose production is stimulated by IL-6. Human studies also havefound that IL-17A levels are higher in ASD children. IL-17A is a known troublemaker: its over-activity has been linked to autoimmune conditions from psoriasis to multiple sclerosis.

Blocking IL-17A prevents autism-like signs

In the new study, Huh and his colleagues--including first author Gloria Choi, now a researcher at the McGovern Institute for Brain Research at MIT (also Huh’s wife)—did a more conclusive investigation of IL-17A’s role in MIA mice.

First, they injected pregnant mice with poly (I:C) 12.5 days after the start of pregnancy, and observed that, two days later, the mothers’ blood serum and their white blood cells—particularly in the placenta and uterine lining—showed a big jump in the production of IL-17A. The researchers examined some of the (male) fetal mouse brains at this time and found early signs in each of a disruption of the normal layered architecture of the cortex. Six days after their mothers’ injection, these MIA fetal mice had a more clearly evident “patch”—roughly in the same cortical location—where the usual layering and organization of cells had been disrupted. That patch of cortical disorganization persisted as the mice grew up, and the mice also exhibited the behavioral abnormalities seen in previous studies.

However, the researchers could prevent the abnormal cortical development and behaviors by injecting the mother mice, before their poly (I:C) exposures, with antibodies against IL-17A. Normally IL-17A is produced—for the most part—by a subset of T cells called TH17 cells. Drastically reducing IL-17A production by knocking out a key gene in TH17 cells also protected the young mice from cortical and behavioral abnormalities.

Those results point to the possibility that anti-IL-17A antibodies, or drugs aimed at inhibiting the IL-17A-production pathway in TH17 cells, could be used to treat human mothers who have serious infections or even IL-17A-related autoimmune conditions during pregnancy, and thereby reduce the chances that their children will have ASDs.

In fact, a monoclonal antibody that blocks IL-17A activity, secukinumab (Cosentyx), has already been developed by Novartis and was recently FDA-approved for treating three autoimmune conditions: plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis. Other anti-IL-17A antibodies are in clinical trials for similar conditions. The transcription factor RORγt, which appears to be crucial for enabling IL-17A production in TH17 cells, is also a target of drugs being developed for treating autoimmune disorders.

No one has yet tested such drugs in pregnant women—a population for which clinical trials of experimental drugs are particularly risky. Even if the ASD-preventing benefit of blocking IL-17A activity in pregnant women were to be established, that benefit would have to be weighed against the increased risk of certain infections (which IL-17A normally helps combat), any other effects of IL-17A loss, and of course the usual high cost of patented monoclonal antibody treatments.

Could a similar approach be used to treat ASD children?

If ASDs are caused by a short period of abnormal brain development in the womb, it may be possible only to prevent them prenatally—not to treat them after the brain’s maturation is well advanced.

However, a 2012 study first-authored by Hsiao, then a doctoral student in Patterson’s laboratory at Caltech, hinted that there may be some opportunity for treatment. In that study, MIA mice showed immune abnormalities, including increased levels of IL-6 and IL-17A, that persisted after birth. Hsiao tried to correct the immune abnormalities in a drastic way: She wiped out the bone marrow cells of the MIA mice, and thus their immune systems, using ionizing radiation. She then implanted new marrow cells from normal mice to repopulate the MIA mice’s immune systems—and these marrow-recipient mice no longer showed immune abnormalities or ASD-like stereotyped/repetitive and anxiety behaviors.

Unfortunately, in the more recent study, Huh and colleagues found less reason for optimism. Treating pregnant mice with anti-IL-17A antibodies just two days after their exposure to poly(I:C)—rather than before the exposure—resulted in the offspring being only partly protected from brain and behavior abnormalities.

In general, said Hsiao, this is an area that “requires greater exploration.”

Getting at the mechanism: Is IL-17A also a neurodevelopmental protein?

Another big unanswered question here has to do with the mechanism by which IL-17A affects the developing brain. Does it do so simply by promoting a harmful, tissue-damaging inflammatory reaction? Or does it have a more direct effect on brain development—in other words, does IL-17A have an evolved developmental function in the fetal brain?

Huh suspects the latter, which if true might help explain the origins of a host of neurodevelopmental disorders, not just ASDs.

In one set of experiments in their new study, Huh and his colleagues found that as IL-17A levels rose in pregnant mother mice, the expression of IL-17A receptors on the fetal mice brain cells rose in response, clearly having been stimulated to do so by the influx of maternal IL-17A. And whereas injecting IL-17A directly into fetal mouse brains caused the usual ASD-like signs, injecting IL-17A into the brains of fetal mice that lacked IL-17A receptors produced no ASD-like signs. In other words, the neurodevelopmental defects in the MIA mice appeared to be due to abnormal signaling activity at the IL-17A receptors on their developing brain cells.

“We don’t have any proof yet,” said Huh, “but I think there must be a reason why those neurons in fetal brain express that [IL-17A] receptor—obviously they are not there to receive signals when the mother gets infected.”

His hypothesis is that IL-17A receptors have an evolved role in brain development, not just in immunity—so that the presence of IL-17A during maternal inflammation sends the wrong developmental signal at the wrong time to young neurons. “Their proliferation or migration or even apoptosis might be affected,” he said, “and then that could lead to this cortical malformation.”

Huh notes as well that IL-17A is evolutionarily ancient and structurally unique among inflammatory signaling proteins, and bears a notable resemblance to certain neural growth factors.

A neurodevelopmental role for IL-17A could also explain the indications from various experiments that the timing of IL-17A exposure is important. Epidemiological studies have suggested, for example, that maternal infection’s impact on ASD risk may be greatest in the second trimester for humans, corresponding roughly to the stage of brain development at which MIA mouse abnormalities appear.

Huh’s and Choi’s labs are now collaborating to find out more about the chain of events that leads from IL-17A receptor signaling in the fetal brain to the emergence of ASD-like abnormalities.