Cytokine Profiles – Mothers Autistic Children
A study by Paula E Goines et al., published in Molecular Autism, indicates that divergent cytokine profiles are expressed in serum samples taken during the second trimester of pregnancy from i) mothers bearing a child with autism spectrum disorder (ASD); ii) a child with a developmental delay (DD) other than ASD; or iii) a child from the general population with no known developmental deficiencies (GP).
Approximately 1 in 100 children is diagnosed with an ASD, and there are no clear biological markers for children with autism spectrum disorder.
Of note, maternal cytokines may affect the fetal compartment directly, as IL-6 has been shown to cross the human placenta (unlike many other cytokines), or indirectly through stimulation of placental cells, which may alter the placental environment and thereby impact the fetus.
Mothers of children with ASD have been reported to have a higher incidence of allergic and autoimmune diseases compared to mothers of typically developing children. However, it is not known whether the maternal immune profile during pregnancy is associated with the risk of bearing a child with ASD or other neurodevelopmental disorders.
In the Molecular Autism study, Paula E Goines and colleagues from the University of California at Davis, USA, conducted a case-control study using archived maternal blood samples collected during the period from 15 to 19 weeks of gestation to investigate the potential association between serum cytokine profiles and the risk of bearing a child subsequently diagnosed with a neurodevelopmental disorder.
The authors of this study found increased serum levels of IL-4, IL-5 and IFN-γ in mothers bearing a child with ASD. In contrast, mothers bearing a child with developmental delay (DD) but not ASD demonstrated increased levels of the cytokines IL-2, IL-4, IL-6, GM-CSF and MIP-α. Thus, mothers bearing children with autism had cytokine profiles that may be consistent with an allergy and/or asthma immune phenotype, while mothers bearing children with DD but not autism demonstrated a more inflammatory phenotype.
The authors conclude that different maternal immune profiles during pregnancy may be linked to divergent neurodevelopmental outcomes in the child.
SOURCE: Mol Autism 2011, 2: 13 [Epub ahead of print]
Updates
A 2017 study by Karen L. Jones et al., published in Molecular Psychiatry assessed mid-gestational serum profiles of 22 cytokines and chemokines in mothers of children with ASD, developmental delay (DD) without ASD (N=188), and general population (GP) controls 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) and those without (ASD-noID, N=201).
This study indicates that significantly higher maternal levels of pro-inflammatory cytokines and chemokines during gestation are distinctly associated with an increased risk of having a child with ASD+ID. Further, this immunologic distinction between mothers of children with ASD+ID and those with ASD-noID or DD suggests that the intellectual disability associated with ASD might be etiologically distinct from DD without ASD.
Thus, mothers of children with ASD+ID had significantly elevated mid-gestational levels of numerous cytokines and chemokines, such as granulocyte–macrophage colony-stimulating factor (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 monocyte chemoattractant protein-1 (MCP-1) compared to mothers of GP controls.
The above-discussed study by Paula E Goines et al. is the only other study utilizing mid-gestational maternal serum samples, we previously found that higher levels of IFN-γ, IL-4, and IL-5 were significantly associated with increased risk of ASD, regardless of ID status, relative to GP controls. The present study contrasts with this finding, as increases in risk of ASD were only seen when taking ID status into account.
A 2021 study by S. Casey et al., published in the Journal of Autism and Developmental Disorders examined the mid-gestational cytokine profiles in mothers of children with a subsequent ASD diagnosis examined at two mid-gestation time points (15 and 20 weeks).
The authors discuss that midgestation is an important neurodevelopmental period. Some of the key processes occurring during this period include the development of the hippocampus, cortical plate, the longitudinal fissure, sulci and gyri, cerebellum, superior and inferior colliculi, primary visual, motor and sensory cortices, the cerebrospinal tract, as well as spinal cord myelination, as well as neurogenesis.
The authors identified IL-17A as a potential cytokine biomarker whose expression is significantly reduced in mid-gestation (20 weeks) in pregnancies resulting in a child with ASD after adjusting for folate intake at 15 weeks.
Another 2021 study by Michael Carter et al., published in Scientific Reports examined the mid-gestational serum cytokine profiles of the mothers of autistic children. The nested sub-cohort within a large mother–child birth cohort was identified based on a confirmed multi-disciplinary diagnosis of autism before the age 10 years. From a cohort of 2137 children, 25 had confirmed autism before 10 years and stored maternal serum from mid-gestation.
The authors found that concentrations of IL-4 were significantly altered between groups. In fact, downregulated IL-4 levels in the mothers of children with ASD. The other analytes did not differ significantly using either multiplex or ultra-sensitive assays.
Interestingly, and importantly, the investigators discuss that cytokines should be analysed contemporaneously, acute phase reactants such as IL-1β and IL-6 have demonstrated greater than 50% degradation within 3 years even in − 80 °C. IL-4 is stable only for 3 years, while IL-17A, IFN-γ, and TNF-α, all suffer more than 50% degradation within 4 years at ultra-low temperature storage.
A 2022 review by Janna McLellan et al. discuss several clinical studies demonstrating altered cytokine levels in mothers and neonatal blood samples that are strongly associated with ASD. The authors of this review outline an important feature of several cytokines associated with ASD – their ability to induce the blood-brain barrier (BBB) to become more permissive. Thus, the cytokine IL-17, which has been implicated in several neurodevelopmental disorders, including ASD, has been shown to promote inflammation and disrupting the BBB postnatally. In addition, FN-γ, which is involved in neuronal differentiation and synaptic formation, was shown to be higher in mothers of children with ASD during the second trimester, potentially suggesting disrupted synaptic connectivity.
