In utero immune programming of autism spectrum disorder (ASD)

Maladaptation of immune tolerance at the maternal-fetal interface affects balanced maternal-fetal cross-talk and placental health and is associated with adverse pregnancy outcomes. The concept of in utero programming of childhood and adulthood diseases has revolutionized the research on the role of pregnancy in maternal, neonatal, and adult health. However, it is not yet well understood whether dysregulation of uterine immunity contributes to any health consequences during childhood or later in life. Recent observations in mice and humans have strongly supported the notion that uterine immunity during pregnancy determines the health trajectory of the offspring and significantly impacts cognitive function and mental health. Importantly, IL-17a producing Th17 T cells have been projected as the main contributors to heterogeneous pathological and behavioral phenotypes associated with autism spectrum disorder (ASD). However, since normal pregnancy is associated with little or no Th17 cells at the maternal-fetal interface, it is not clear how and when the Th17 T cells are generated and which interventions can ameliorate the ASD-like features in newborns. We propose that infection-associated uterine immune activation within a critical window of development may propel trans-differentiation of Th17 T cells that eventually affect fetal brain development and induce ASD-like behavioral phenotype in the offspring.