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 (ASDs) 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 (DD) without ASD (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 (developmental/cognitive and adaptive composite score<70) (ASD+ID, N=184) and those without (composite score⩾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 granulocyte macrophage colony-stimulating factor, interferon-γ, interleukin-1α (IL-1α) and IL-6, compared with 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 monocyte chemotactic protein-1 compared with 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 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 subphenotypes of ASD.

Figure 1. Mothers of children with ASD and intellectual disability (ASD+ID) had significantly elevated inflammatory T cell and innate immune cell cytokines and chemokines

The alterations of these particular cytokines and chemokines, which are normally downregulated during mid-gestation, suggest a lack of immune regulation that is typically associated with pregnancy. Cell values represent p-values obtained during adjusted logistic regression analyses. Logistic regression models were adjusted for gestational age at time of draw, maternal weight, age, race, ethnicity and country of origin. Highlighted cells represent significant logistic regression findings. Red highlighting denotes an increased risk relative to the comparison group was significantly associated with elevated mid-gestational levels of the indicated cytokines and chemokines. Blue highlighting indicates a reduced risk was significantly associated with elevated mid-gestational levels relative to the comparison group.