Maternal Immunity in Autism Spectrum Disorders: Questions of Causality, Validity, and Specificity

Autism spectrum disorders (ASD) are complex neurodevelopmental disorders with unknown heterogeneous aetiologies. Epidemiological studies have found an association between maternal infection and development of ASD in the offspring, and clinical findings reveal a state of immune dysregulation in the pre- and postnatal period of affected subjects. Maternal immune activation (MIA) has been proposed to mediate this association by altering fetal neurodevelopment and leading to autism. Although animal models have supported a causal link between MIA and development of ASD, their validity needs to be explored. Moreover, considering that only a small proportion of affected offspring develop autism, and that MIA has been implicated in related diseases such as schizophrenia, a key unsolved question is how disease specificity and phenotypic outcome are determined. Here, we have integrated preclinical and clinical evidence, including the use of animal models for establishing causality, to explore the role of maternal infections in ASD. A proposed priming/multi-hit model may offer insights into the clinical heterogeneity of ASD, its convergence with related disorders, and therapeutic strategies.