Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation

Abstract

Immune abnormalities have been described in some individuals with autism spectrum disorders (ASD) as well as their family members. However, few studies have directly investigated the role of prenatal cytokine and chemokine profiles on neurodevelopmental outcomes in humans. In the current study, we characterized mid-gestational serum profiles of 22 cytokines and chemokines in mothers of children with ASD (N=415), developmental delay without ASD (DD) (N=188), and general population (GP) controls (N=428) using a bead-based multiplex technology. The ASD group was further divided into those with intellectual disabilities (DQ<70) (ASD+ID, N=184) and those without (DQ≥70) (ASD-noID, N=201). Levels of cytokines and chemokines were compared between groups using multivariate logistic regression analyses, adjusting for maternal age, ethnicity, birth country, and weight, as well as infant gender, birth year, and birth month. Mothers of children with ASD+ID had significantly elevated mid-gestational levels of numerous cytokines and chemokines, such as GM-CSF, IFN-γ, IL-1α, and IL-6, compared to mothers of children with either ASD-noID, those with DD, or GP controls. Conversely, mothers of children with either ASD-noID or with DD had significantly lower levels of the chemokines IL-8 and MCP-1 compared to mothers of GP controls. This observed immunologic distinction between mothers of children with ASD+ID from mothers of children with ASD-noID or DD suggests that the intellectual disability (ID) associated with ASD might be etiologically distinct from DD without ASD. These findings contribute to the ongoing efforts toward identification of early biological markers specific to sub-phenotypes of ASD.

Maternal Immune Activation and Autism Spectrum Disorder: From Rodents to Nonhuman and Human Primates

“…A subsequent study found that maternal infections diagnosed in a hospital setting, presumably associated with more severe infections, were associated with an increased risk of ASD, while infections diagnosed in outpatient settings were not associated ASD (23). Quantification of cytokines, chemokines and other inflammatory markers obtained from archived maternal sera (24, 25) and amniotic fluid (26, 27) lends further support to the link between maternal infection and increased ASD risk, though studies have yielded mixed results (28, 29). Although there is a clear need for additional epidemiological studies, the current data suggest that, at least for a subset of women, exposure to infection during pregnancy may increase the risk of ASD or other CNS disorders (30, 31).…”

The Role of the Immune System in Autism Spectrum Disorder

“…Most recently, studies have demonstrated that elevated mid-gestational levels of inflammatory cytokines and chemokines are more highly associated with the ASD subphentoype that presents with intellectual disability (ID), compared with ASD without ID, developmental delay (DD) without ASD, and typically developing controls (Jones et al, 2016). These included higher levels of GM-CSF, TNF-α, IFN-γ, IL-1α, IL-1β, IL-4, and IL-6.…”

Developmental Neurotoxicity of Traffic-Related Air Pollution: Focus on Autism

“…Perhaps the strongest association between an environmental factor and ASD has been found with maternal infection [94]. Studies in humans and in various animal species have indeed evidenced that maternal immune activation (MIA), due to viral or bacterial infection, increases neuroinflammation in the placenta and in the fetal brain, leading to offspring that display ASD-like behaviors [95–98]. As discussed in a further section, several effects seen in MIA are also found upon developmental exposure to air pollution.…”