Pregnancy in mammalian females represents an unique challenge to their immune system. Essentially, from immune system's "point of view" growing fetus is a semi-allogeneic transplant that should be seen as a "foreign" and be rejected. But fetus, in general, is tolerated by maternal immune system. Such tolerance implies that maternal immune system takes some specific steps to avoid its attack on fetus. On the other hand, maternal immune system cannot let guard down completely because at least mother needs some level of defense.
Such conflicting "defense programs" operating in pregnant females occasionally damages fetus. For example, viral infection of women during pregnancy [and maternal immune response to it] could increase frequency of autism spectrum disorder (ASD) in the offspring.
In this regard, new study in Science is of interest. In this paper the authors showed that injection of poly(I:C) to mimic viral infection produced ASD-like phenotypes in offspring via action of IL-17A.
First, the authors showed that poly(I:C) injection increased serum IL-17a in pregnant dams in a IL-6 dependent manner (this IL-17a induction was specific to placenta- and decidua [uterus]-associated mononuclear cells).
Second, poly(I:C) injection in pregnant dams produced abnormalities in layered structure of the developing fetal cortex that could be reversed by pre-treatment with IL-17a blocking antibody.
Similarly, poly(I:C)-induced malformation of the fetal brain was prevented in offspring from RORĪ³t-KO mothers that lacked CD4 T cell-specific IL-17a expression.
The authors showed prophylactic pre-treatment with IL-17a blocking antibody of poly(I:C)-injected mothers could reverse ASD-like behavioral abnormalities in offspring such as increase in pup ultrasonic vocalization (USV) responses or repetitive/perseverative behaviors.
Finally, the authors found that therapeutic application of IL-17a blocking antibody after poly(I:C) injection could partially [but not fully] correct some of the ASD-like features in offspring.
In summary, these results suggest that in "susceptible" mothers immune response to virus infection could impair offspring's brain development via direct effect of maternal cytokine IL-17a on fetal neurons. Here the "susceptibility" in mothers could be defined as a tendency for hyperactive IL-6/IL-17 axis. In general, this finding is surprising since IL-17a isn't ordinarily associated with viral infection. But, IL-6/IL-17 axis is well accepted concept.
Of note, there is FDA approved IL-17a antibody, Novartis Cosentyx (secukinumab) that could be used in a scenario described in this paper.
David Usharauli
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