Maternal immune systems, autism and the value of prediction

All opinions are my own and do not necessarily reflect those of Novo Nordisk

Following on these two papers (1, 2) published in Translational Psychiatry.

When I wrote about Gene by Environment (GxE) interactions and the possible health of children, I was describing how changes in maternal health might have an effect on child health at the level of what genes are turned on and off.  In that situation, there may be the possibility that actions by potential mothers before conceiving could positively impact child health.  In many other cases, though, the actions for predicted problems can only take place after birth.  Key point: in many cases these interventions are best done early, which is why states have newborn screening programs (although surprisingly the number of tested conditions varies from state to state).  In the context it’s interesting that a couple of recent papers have identified what may be a way to predict the development of autism in children.

The papers describe findings that may, if corroborated, have a large impact on autism prediction and, eventually, possible treatment and prevention for a subset of patients.  First, the team demonstrated through study of non-human primates that these human autoantibodies, when given to pregnant rhesus monkeys, led to significant changes in both maternal and infant monkey behavior.  Mothers in the experimental group showed more protective behavior toward their infants, and those offspring more frequently approached known and unknown monkeys despite not receiving commensurate social responses.  Male offspring also showed measurable increases in brain volume.  Second, the research team discovered that autoantibodies  to combinations of fetal brain proteins are found in a significant fraction of mothers who have Autism Spectrum Disorder (ASD) children, while mothers from the control group rarely have such autoantibodies to so many of these proteins.

While this work describes the presence of autoantibodies, not infectious agents, the experiment does parallel elements of Koch’s postulates for demonstrating causality of a disease causing agent (and thanks, in a strange way, to Peter Duesberg, whose HIV denialism is where I first heard of Koch’s postulates).  The putative disease causing agent in this case is not an infectious agent but an endogenous protein, but it does fit several of Koch’s criteria:

1)  The disease causing agent must be found in the affected organism but not in the healthy.  In this case, autoantibodies to combinations of these neural proteins are found in 23% of mothers of ASD children and 1% of mothers in the control population.

2)  The micro-organism must be isolated from the diseased organism and grown in pure culture.  Not specifically applicable here as the autoantibodies can’t be grown per se, although  the bulk immunogammaglobulins (IgGs), or antibodies, from mothers with autoantibodies were isolated for the rhesus experiment.  Analogous to growing a pure culture, although it would have been even more striking had they purified the specific autoantibodies.

3)  The disease-causing agent should, when introduced into a healthy organism, cause disease.  Here, the introduced IgG caused behavioral changes that are consistent with the pathophysiology of ASD, although extending value judgements on behavioral and psychological traits from humans to non-human primates is dicey at best.

4)  The disease-causing agent should be isolated from the now-affected organism, and shown to be identical to the original agent.  This is a tall order for this system, as the amount of IgG remaining in the offspring after months to years is likely to be nil, given that antibodies break down over time.  Also, the presumed time for activity of the maternal autoantibodies is during prenatal development, which would be the time to analyze for presence of these autoantibodies but well before the monkeys can be evaluated behaviorally.

Still, the evidence here is striking that these researchers have uncovered one possible contributing factor for autism.

So what do we do with this knowledge?  Now we come to territory that has been discussed in all kinds of inflammatory contexts:  what should parents know before a child is born, and what should they do about it?  In cases of suspected severe, debilitating diseases, such as when parents are known carriers for genetic risk genes, prenatal or even embryo testing after in vitro fertilization seem justified to allow a family to make an informed decision.  In cases like ASD, or Down Syndrome, however, where the child is likely to be healthy and capable in many respects, the question of prenatal testing and what to do in the case of a positive becomes harder.

And like a pitcher ducking a line drive hit sharply back up the middle, I’m just going to avoid discussing those decisions (although for the record I think each family should decide for themselves), and instead talk about the value of prediction.  These studies, once validated, open an opportunity for creating tests that an expectant mother can take to see if she is producing these autoantibodies.  As described in the research, 23% of mothers with an ASD child have autoantibodies in specific combinations versus 1% in controls.  This suggests that if autoantibodies for specific combinations of brain proteins are detected and confirmed, expectant parents can prepare for a child who may have ASD.

This isn’t trivial knowledge.  It can be devastating and difficult for parents.  But it’s also amazingly powerful knowledge.  Because we keep learning more and more about what we can do to help kids with ASD learn how to get along and thrive, and early intervention is showing promise as a key part of treatment.  And that has immense value.  And that’s the value of prediction:  allowing steps to be taken early, to do what is possible, to help make these kids’ futures easier and brighter.  I wrote about the Modell Foundation in an earlier post, and they also work on early intervention, in their case for primary immunodeficiencies.  The foundation pushes for newborn screening for immune disorders because the one way to cure some primary immunodeficiencies is a stem cell transplant and that works best when a baby is very young.

For autism, although the problem of false positives will be a real one given that a small percent of mothers of non-ASD kids have these combinations of autoantibodies, having these tests would help many families.

And for the future, knowing about this potential cause leads to some hope that possibly for mothers who test positive, interventions can be designed that will keep the autoantibodies from passing the placental barrier to the fetus, which may help reduce or even prevent ASD symptoms from developing as that child’s grows up.

Advertisements

One thought on “Maternal immune systems, autism and the value of prediction

  1. Pingback: Premature testification is not a laughing matter | Biotech, Baseball, Big Data, Business, Biology...

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s