Maternal Allergic Asthma during Gestation Leads to Elevated Inflammatory Cytokines in the Fetal Brain

Background: Maternal infection during gestation is a well-established risk factor for neurodevelopmental disorders in offspring, including autism spectrum disorders (ASD). Most preclinical investigations of these risks have focused on specific responses to bacterial or viral pathogens, however data suggests that the increased risk for ASD is generally associated with maternal immune activation (MIA), specifically increases in pro-inflammatory cytokines during gestation. While MIA animal studies have traditionally focused on one arm of the immune response, allergic responses during gestation characterized by increased T-helper 2(T_H2) cytokines have recently been shown to alter offspring behavior. We hypothesized that MIA associated with asthma and allergies may also elicit changes in offspring immune responses in the brain.

Objectives: Previous MIA investigations specific to a maternal immune response to pathogens have found that MIA increases pro-inflammatory cytokines in the fetal brain compartment. We sought to determine whether activation of the allergic/T_H2 arm of the immune system during gestation would elicit differential immune responses in the fetal brain.

Methods: C57 dams were sensitized by exposures to ovalbumin (OVA) prior to pregnancy, then exposed to either aerosolized OVA or PBS-vehicle repeatedly throughout gestation until embryonic day (E)17.5, at which time fetal brains and maternal sera were collected and processed for cytokine analysis via multiplex technology.

Results: Significant elevations of inflammatory cytokines were present in fetal brains from mothers exposed to aerosolized OVA during gestation compared to vehicle control exposed dams. These cytokines included interleukin (IL)-1alpha, IL-1beta, IL-2, IL-7 and IL-9 (p<0.001). Elevated levels of chemokines were also present, including chemokine (C-X-C motif) ligand (CXCR)-1, chemokine (C-C motif) ligand (CCL)-3 and CCL5 (p<0.01). Fetal brain cytokines positively correlated with gestational maternal sera cytokine levels that are associated with an allergic asthma phenotype.

Conclusions: We demonstrated that the maternal immune responses associated with an allergic T_H2-skewed inflammation during the gestation period in mice lead to significant increases in fetal brain cytokine responses. Our findings provide support that activation of the immune response associated with allergies or asthma during gestation may alter neurobiology and subsequently contribute to the development of neurodevelopmental disorders, including ASD.