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  • Review Article
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Maternal immune activation and neuroinflammation in human neurodevelopmental disorders

Abstract

Maternal health during pregnancy plays a major role in shaping health and disease risks in the offspring. The maternal immune activation hypothesis proposes that inflammatory perturbations in utero can affect fetal neurodevelopment, and evidence from human epidemiological studies supports an association between maternal inflammation during pregnancy and offspring neurodevelopmental disorders (NDDs). Diverse maternal inflammatory factors, including obesity, asthma, autoimmune disease, infection and psychosocial stress, are associated with an increased risk of NDDs in the offspring. In addition to inflammation, epigenetic factors are increasingly recognized to operate at the gene–environment interface during NDD pathogenesis. For example, integrated brain transcriptome and epigenetic analyses of individuals with NDDs demonstrate convergent dysregulated immune pathways. In this Review, we focus on the emerging human evidence for an association between maternal immune activation and childhood NDDs, including autism spectrum disorder, attention-deficit/hyperactivity disorder and Tourette syndrome. We refer to established pathophysiological concepts in animal models, including immune signalling across the placenta, epigenetic ‘priming’ of offspring microglia and postnatal immune–brain crosstalk. The increasing incidence of NDDs has created an urgent need to mitigate the risk and severity of these conditions through both preventive strategies in pregnancy and novel postnatal therapies targeting disease mechanisms.

Key points

  • Human studies are uncovering a role for maternal immune activation (MIA) in the pathogenesis of common neurodevelopmental disorders, such as autism spectrum disorder, attention-deficit/hyperactivity disorder and Tourette syndrome, in the offspring.

  • Prenatal, in utero and postnatal embedding of environmental factors in the epigenetic architecture of both the brain and the peripheral immune system can modulate individual susceptibility to neurodevelopmental disorders.

  • The effects of MIA, mediated by acute and chronic inflammation in pregnancy, are transduced to the fetus through inflammatory cell signalling pathways and epigenetic mechanisms.

  • Pathogen-associated molecular patterns, damage-associated molecular patterns and Toll-like receptors represent a convergent cellular pathway between heterogeneous environmental factors and innate immune activation.

  • In conjunction with individual genetic risk, sex-related factors and second ‘immune’ hits during life, MIA-induced aberrant immune programming results in a loss of immune homeostasis, which is associated with behavioural abnormalities in animal models.

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Fig. 1: Maternal immune activation and offspring development.
Fig. 2: Maternal chronic inflammation and offspring neurodevelopmental disorders.
Fig. 3: Cell signalling pathways linking diverse environmental factors to inflammation and epigenetic programming of DNA.

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Han, V.X., Patel, S., Jones, H.F. et al. Maternal immune activation and neuroinflammation in human neurodevelopmental disorders. Nat Rev Neurol 17, 564–579 (2021). https://doi.org/10.1038/s41582-021-00530-8

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