Maternal antibodies and ASD risk for the offspring

ASDresearchinitiative asked me to comment on the new papers from UC Davis, so now that I’m back from a grueling trip to E Africa (for lectures and touring), I should get back to work…

In one paper, Melissa Bauman, David Amaral and colleagues report a follow up to their prior work, further showing that when pregnant monkeys are injected with antibodies taken from human mothers of autistic children, the monkey offspring display a couple of abnormal behaviors, including unusual social interactions. Such behaviors are not observed in the offspring of pregnant monkeys  given antibodies taken from human mothers of neurotypical kids. While the behavioral differences between the two sets of monkey offspring are convincing, they do not include some of the cardinal signs of human autism such as stereotyped/repetitive behavior, which was reported in their prior paper on this model. However, the type of antibodies injected in this new experiment is different from the type used in the prior work. The antibodies used in the new work are known to be a subset of the various auto-immune antibodies that recognize antigens in fetal monkey brains.  Overall, these results support the hypothesis that some mothers of autistic children generate antibodies against the fetal brain and that these antibodies cross the placenta and alter fetal brain development. In fact, the investigators showed that the brains of the animals with altered behavior do display some differences from the controls when analyzed by MRI.

In an independent set of experiments that will be published very soon, Melissa, David and I found that activating the pregnant monkey immune system, using the same technique that we used in mice, results in offspring with a series of autism-like behaviors, including repetitive behaviors, a deficit in verbalizations and a highly abnormal type of social interaction. A subsequent paper will also show an autism-like abnormality in eye tracking – not looking at faces as much as controls. Could these two models be related – maternal antibodies and maternal immune activation (MIA)? It is indeed possible that MIA stimulates the production of antibodies. However, I favor a mechanism in which MIA induces the cytokine IL-6, which we find alters placental endocrine function and also directly activates subsets of fetal brain cells.

A second, and related new paper from UC Davis by Judy van de Water and colleagues follows up their prior work on characterizing the antibodies found in the blood of mothers of autistic children. The new paper identifies the proteins to which these antibodies bind in extracts of monkey fetal brain. Interestingly, many of these protein antigens are known to have functions in brain development. However, most of these proteins are thought to reside in the cytoplasm, so it remains to be shown how the maternal antibodies would access them in living cells in the fetal brain. Further animal studies will presumably get at this question. It will also be interesting to find out when these antibodies are generated during pregnancy, and whether they are present in subsequent pregnancies in the same mother that involve neurotypical or autistic offspring. The latter point is important because van de Water et al. propose that the presence of combinations of several of these antibodies could be used as a diagnostic biomarker for an autistic outcome of a pregnancy. In fact, they have formed a company to develop such a diagnostic.

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