Cytokine changes associated with the maternal immune activation (MIA) model of autism: A penalized regression approach

Abstract

Maternal immune activation (MIA) during pregnancy induces a cytokine storm that alters neurodevelopment and behavior in the progeny. In humans, MIA increases the odds of developing neuropsychiatric disorders such as autism spectrum disorder (ASD). In mice, MIA can be induced by injecting the viral mimic polyinosinic:polycytidylic acid (poly(I:C)) to pregnant dams. Although the murine model of MIA has been extensively studied, it is not clear whether MIA results in cytokine changes in the progeny at early postnatal stages. Further, the murine model of MIA suffers from a lack of reproducibility and high inter-individual variability. Multivariable (MV) statistical analysis is widely used in human studies to control for confounders and covariates such as sex, age and exposure to environmental factors. We therefore reasoned that animal studies in general and studies on the MIA model in particular could benefit from MV analyses to account for complex phenotype interactions and high inter-individual variability. Here, we used MV statistical analysis to identify cytokines associated with MIA after adjustment for covariates. Besides confirming the association between previously described variables and MIA, we identified new cytokines that could play a role in behavioural alterations in the progeny during the early postnatal period.

Critical Role of the Maternal Immune System in the Pathogenesis of Autism Spectrum Disorder

“…These findings were also replicated in rhesus monkeys, which are able to perform more human-like behaviours [95]. A recent study used multivariate statistical analysis and identified positive association of MIA with certain ASD-type behaviours and serum cytokine, CXCL10 and IL-5, levels while negative associations with IL-15 and TNF-α levels were observed [96].…”

Pathogenic Infections during Pregnancy and the Consequences for Fetal Brain Development

“…A number of cytokines have been linked to uterine immune activation (UIA) and the severity of disease phenotypes [66] (Figure 1). Several factors influence the cytokine threshold, including the gestational age, pathogen type, and time since the onset of UIA.…”

Contribution of Pro-Inflammatory Molecules Induced by Respiratory Virus Infections to Neurological Disorders

“…However, this association is still controversial in humans due to the study′s limitations [ 125 ]. According to the knowledge about the effects of the maternal immune activation (MIA), which induces systemic increased levels of pro-inflammatory molecules that may be triggered by the infection with influenza virus, can impair the brain development of the fetus [ 42 , 109 ]. However, the Influenza virus has not been detected in the brain of fetuses in an animal model, suggesting that the damage is an indirect effect of the infection [ 72 , 126 ].…”

“…On the other hand, the respiratory infection with Influenza virus in pregnant women can increase maternal immune activation (MIA), which increases the secretion of pro-inflammatory cytokines, such as IL-6, TNF-α and IL-1β. An increase expression of these molecules might indirectly promote brain inflammation of the offspring in the uterus, impairing brain development [ 42 , 109 ]. A possible result of brain inflammation is SCZ and ASD [ 110 ].…”

“…Another neuropsychiatric illness is autism spectrum disorder (ASD), a behavioral alteration mainly in communication and social interaction, besides the stereotyped behavior with restricted interest [ 39 , 40 ]. The etiology of this disease is heterogeneous, but it is thought that maternal pro-inflammatory molecules′ contribution may contribute to the neurodevelopment of the fetus brain [ 41 , 42 , 43 ]. Pro-inflammatory cytokines, such as GM-CSF, IL1-α, IL-6, and IFN-γ increase in the serum during the mid-gestational maternal, correlates with a higher risk of ASD and intellectual disability [ 41 ].…”