The Role of Maternal Immune Activation in the Pathogenesis of Autism: A Review of the Evidence, Proposed Mechanisms and Implications for Treatment

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disease that is characterized by a deficit in social interactions and communication, as well as repetitive and restrictive behaviors. Increasing lines of evidence suggest an important role for immune dysregulation and/or inflammation in the development of ASD. Recently, a relationship between inflammation, oxidative stress, and mitochondrial dysfunction has been reported in the brain tissue of individuals with ASD. Some recent studies have also reported oxidative stress and mitochondrial abnormalities in animal models of maternal immune activation (MIA). This review is focused on the hypothesis that MIA induces microglial activation, oxidative stress, and mitochondrial dysfunction, a deleterious trio in the brain that can lead to neuroinflammation and neurodevelopmental pathologies in offspring. Infection during pregnancy activates the mother's immune system to release proinflammatory cytokines, such as IL-6, TNF-α, and others. Furthermore, these cytokines can directly cross the placenta and enter the fetal circulation, or activate resident immune cells, resulting in an increased production of proinflammatory cytokines, including IL-6. Proinflammatory cytokines that cross the blood-brain barrier (BBB) may initiate a neuroinflammation cascade, starting with the activation of the microglia. Inflammatory processes induce oxidative stress and mitochondrial dysfunction that, in turn, may exacerbate oxidative stress in a self-perpetuating vicious cycle that can lead to downstream abnormalities in brain development and behavior.

Keywords: autism; cytokines; inflammation; maternal immune activation (MIA); therapeutic strategy.

Figure 1

Immunological changes in the placenta and fetal brain in response to systemic inflammation during pregnancy resulting in neuronal development dysfunction in offspring. Infection during pregnancy activates the mother’s immune system, which releases proinflammatory cytokines, such as IL-6, Il-1β, TNF-α, and others. The elevated level of IL-6 leads to the activation of maternal TH17 cells. As a consequence, IL-17A is released and, together with IL-6 and TNF-α, may reach the placenta, where they additionally activate resident immune cells, resulting in an increased production of proinflammatory cytokines, including IL-6. Moreover, activated maternal TH17 cells also transmigrate through the placenta and enhance cytokine production, which affects placenta function and causes damage. This allows the cytokines to pass through to the developing fetus and enhance the production of fetus-derived cytokines. Then, proinflammatory cytokines cross the BBB and initiate a neuroinflammation cascade. This leads to the abnormal development of neurons, as well as alterations in synaptic transmission, which may further lead to the development of ASD in subsequent stages of growth.