New studies in pregnant mice using antibodies against fetal
brains made by the mothers of
autistic children show that immune cells can cross the
placenta and trigger neurobehavioral changes
similar to autism in the mouse pups.
A report on the research from investigators at the
Johns Hopkins
Children's Center published
online in the Journal of Neuroimmunology expands on a
2008 report from the same team showing that
mothers of autistic children tested positive for fetal brain
antibodies. Antibodies are proteins the
body naturally makes to attack foreign tissues, viruses or
bacteria. Because a growing fetus is not
"rejected" by the mother's immune system even though some of
its DNA is "foreign" (from the
father), scientists have long suspected that some
combination of maternal and fetal biological
protection is at work. The new research from Johns Hopkins,
however, suggests that the protective
system is not perfect and that antibodies are not only made
but are recirculated back to the fetus
through the placenta, possibly triggering inflammation in
the brain and leading to a cascade of
neurological changes resulting in neurodevelopmental
disorders, such as autism.
Despite this new evidence, the researchers warn against
over-interpreting the results, saying
that prenatal exposure to maternal antibodies is likely only
one of several factors implicated in autism.
"Autism is a complex disorder, and it would be naive to
assume there's a single mechanism that
can cause it," said Harvey Singer, director of Pediatric
Neurology at Hopkins Children's. "It's most
likely the cumulative result of several factors, including
genes, metabolism and environment. We
believe we have identified one of these factors."
For the new study, Singer and colleagues injected
antibodies from mothers of autistic children
into pregnant mice and used several standard neurobehavioral
tests to identify neurobehavioral
changes in the pups. As control groups, they used offspring
of mice injected with antibodies from
mothers of nonautistic children and the offspring of mice
who received no injections.
"Comparing mice to humans is tricky, and we should be
cautious anytime we do so, but our
findings strongly suggest that the behaviors we observed in
the offspring of mice injected with fetal
brain antibodies from human mothers did behave in a manner
that mimics some behaviors seen in
people with autism," Singer said.
Following the mice throughout adolescence (four to six
weeks) and adulthood (four to six
months), the Johns Hopkins team measured novelty-seeking (or
willingness to explore unfamiliar open
spaces), response to loud noise, sociability and anxietylike
behavior.
Overall, mice exposed prenatally to antibodies from
mothers of autistic children behaved more
anxiously, spent less time in open spaces when placed in an
elevated maze and were overall more
hyperactive, fretting back and forth between open and closed
spaces in the maze and in an open field
environment, both behaviors that in humans would equal
abnormal activity.
Again, compared to control mice, the mice exposed to
antibodies from mothers of autistic
children also were more easily startled by loud noises and
were less social, choosing to spend more
time visiting an empty cage rather than one with a live
mouse in it.
The differences between groups were less pronounced in
the adolescent mice, but as the mice
aged, researchers observed an increase in autismlike
symptoms, a finding consistent with
neurodevelopmental disorders in humans, who tend to develop
new or more pronounced symptoms over
time, investigators point out.
Comparing brain tissues from all groups of mice,
researchers observed markedly more activation
of microglia — immune cells in the central nervous
system activated during inflammation — in the brain
tissues of the group injected prenatally with antibodies
from mothers of autistic children.
In further studies, the Johns Hopkins scientists hope
to identify which specific brain proteins
the antibodies affect and to correlate changes in brain
anatomy and function to changes in behavior.
Ultimately, researchers hope to develop ways to detect
and analyze culprit antibodies in
pregnant women and prevent them from binding to fetal brain
proteins.
The causes of autism — a disorder manifesting
itself with a range of brain problems, impaired
social interactions, communication disorders and repetitive
behaviors — remain unknown for an
estimated 90 percent of children diagnosed with it. Genetic,
metabolic and environmental factors have
been implicated in various studies of autism, which affects
an estimated one in 150 U.S. children,
according to the Centers for Disease Control and
Prevention.
The study was funded by the Hussman Foundation.
Co-authors are Mikhail Pletnikov, Christina
Morris, Colin Gause and Matthew Pollard, all of Johns
Hopkins; and Andrew W. Zimmerman, of the
Center for Autism and Related Disorders at the Kennedy Krieger
Institute.