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Maternal Antibodies Linked to Autism
Some children with autism are born to mothers carrying antibodies that bind
to proteins involved in brain development.
By Ed Yong | July 9, 2013
WIKIPEDIA, KEN HAMMOND (USDA)
<http://en.wikipedia.org/wiki/File:PregnantWoman.jpg>  In 2008, Judy van de
Water
<http://www.ucdmc.ucdavis.edu/mindinstitute/ourteam/faculty/vandewater.html>
from the University of California, Davis, discovered a group of
autoantibodies-those that trigger immune responses against the body's own
molecules-that are especially common in mothers of children with autism.
Now, her team has identified what these antibodies bind to: six proteins
involved in varied aspects of brain development. By crossing the placenta
and affecting these proteins in a fetus's brain, the maternal antibodies
could increase the risk of developmental problems in some cases of autism,
according to the new research, published today (July 9) in Translational
Psychiatry.
"I cannot laud these authors enough," said Andrew Zimmerman
<http://www.kennedykrieger.org/patient-care/faculty-staff/andrew-zimmerman>
, a neurologist from the Kennedy Krieger Institute, who has also been
studying maternal antibodies but was not involved in this study. "Given
that, at present, only between 15 and 20 percent of children with autism
have known causes-mainly genetic and infectious mechanisms-this will be a
major advance."
Van de Water's team, led by graduate student Dan Braunschweig, is now using
their discovery to develop a test that predicts a child's risk of developing
autism spectrum disorders based on the mother's antibodies. A negative
result on this test would not rule out a risk, "but if it's positive, their
risk is virtually 100 percent," said van de Water. "It would allow mothers
to plan," she added, by enrolling their children in educational programs
that promote social skills from an early age.
The antibody hypothesis would only explain a quarter of autism cases at
most, but van de Water said that it is valuable for affected parents to get
some clues about the biology behind their children's condition. "It provides
some answers," she said. "They couldn't have done anything about this-it's
not like they did anything to cause the antibodies. But as a parent, you
just want to know what happened so you can move forward."
The proteins that the team identified have a wide variety of roles. STIP1
influences the creation of new neurons, for example, while cypin affects the
number of branches they have. CRMP1 and CRMP2 stop neurons from growing and
determine their length. YBX1 is involved in gene transcription, as well as
neural migration during development. Finally, LDH is the most mysterious of
the sextet but is also the most strongly linked to autism. Earlier studies
suggest that it may play a role in metabolism or in responses to viruses or
toxins.
All six are highly expressed in the fetal brain. Of 246 mothers with
children living with autism, 23 percent had antibodies that recognized two
or more of these proteins, compared to just 1 percent of 149 mothers with
normally developing children. The antibodies have more than 99 percent
specificity for autism risk, which means that they have less than a 1 in a
100 chance of finding a false positive.
Meanwhile, the team's colleagues Melissa Bauman
<http://www.ucdmc.ucdavis.edu/psychiatry/ourteam/faculty/bauman.html>  and
David Amaral
<http://www.ucdmc.ucdavis.edu/psychiatry/ourteam/faculty/amaral.html> , also
from UC Davis, injected eight pregnant rhesus monkeys with antibodies
purified from mothers with autistic children. These monkeys were more
protective towards their young during their first 6 months, compared to
those that were injected with antibodies from women with neuro-typical
children. As the young monkeys grew up, they showed unusual social behavior:
compared to typical macaques, they were more likely to approach both
familiar peers and strangers, even when their advances weren't rewarded with
sustained social interactions.
"Moving this to monkeys is a big step," said Paul Patterson
<http://biology.caltech.edu/Members/Patterson> , a neuroimmunologist from
the California Institute of Technology, who was not involved in the work.
"This very careful behavioral study shows that at least some of the
antibodies do have an effect on fetal brain development."
Betty Diamond <http://www.feinsteininstitute.org/faculty/betty-diamond-md/>
, an immunologist at the Feinstein Institute for Medical Research, agrees
the studies represent "an important step forward." However, she noted that
antibodies often bind to many possible targets, and the proteins that the
team identified may not be the relevant ones. She also said that some of the
alleged target proteins are found within cells, "and it is not clear how or
whether the antibodies can penetrate developing neurons."
Zimmerman added, "Much work remains to be done to show how these antibodies
are relevant, how they affect fetal brain development, and what factors lead
some mothers to develop these antibodies."
The team is now working to address these issues, trying to identify the
specific parts of the six proteins that the antibodies stick to, determine
how they affect the developing brain, and understand how they might be used
to predict autism risk. Van de Water and Amaral are consulting for Pediatric
Bioscience, which is creating a predictive test based on the results.
Finally, the researchers also hope to use the new knowledge to help
normalize development in autistic children. "The next step is to come up
with a therapeutic to block the antibodies-not just to pick them up, but to
do something about it," said van der Water. Although the concept of
preventing autism can be controversial, she points out that her panel of
antibodies seem to correlate with the most severe symptoms and language
problems.
Still, she is treading cautiously. "The parents have been surprisingly
supportive," she said. "But the autism field has been fraught with false
alarms, so we want to be really careful."
D. Braunschweig et al., "Autism-specific maternal autoantibodies recognize
critical proteins in developing brain," Translational Psychiatry, 3:e277,
2013. 
M.D. Bauman et al., "Maternal antibodies from mothers of children with
autism alter brain growth and social behaviour development in the rhesus
monkey," Translational Psychiatry, 3:e278, 2013. 


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