Maternal immune activity during pregnancy and offspring neurodeveloment

Gilman, Stephen

Abstract

Associations of maternal immune activity with offspring neurodevelopmental phenotypes reinforce the importance of immune molecules such as cytokines for normal neurodevelopment given their involvement in neural migration and synaptic plasticity processes which are tightly regulation. Therefore, extremely high and low levels of cytokines could be detrimental to the developing brain. During pregnancy, adverse events in the mother such as infection and pregnancy complications that result in immune responses have been linked with neuropsychiatric disorders in the offspring. In addition, prenatal stressors have also been shown to drive immune responses during pregnancy with resulting adverse consequences for offspring. Pro-inflammatory cytokines, or an imbalance between pro- and anti-inflammatory cytokines, are suggested as one of the underlying mechanisms that explain the association between these events that cause immune responses and childrens risk of neuropsychiatric disorders, as these cytokines can pass through the placenta and the blood brain barrier and lead to aberrant neural growth and plasticity. Perturbations in the mothers immune activity during pregnancy might therefore have broad consequences for the offsprings neurodevelopment ranging from neurological abnormalities to deficits in executive function. Participants in the current study will be approximately 1,000 mother-child pairs enrolled in the Collaborative Perinatal Project (CPP) between 1959 and 1966. The CPP was designed to examine the relationships between perinatal events and neurological defects of the offspring in a total of 55,908 women across 12 hospitals. Offspring were followed through age 7, with approximately 70% retention for the duration of the study. Maternal serum was extracted from blood collected serially during pregnancy from the date of study registration through delivery and stored in the National Institutes of Health repositories at minus 20 degrees Celsius. We will obtain CPP prenatal serum samples from the NIH repository and conduct assays for concentrations of the following immune markers using Q-PlexTM Human Cytokine HS Screen (15 plex), a fully quantitative ELISA-based chemiluminescent assay allowing the concurrent measure of 15 biomarkers: IL-1, IL-1, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, IL-15, IL-17, IL-23, IFN-, TNF-, and TNF-. The multiplex technology will allow measurement of these markers in just 50l of serum. The following markers will also be measured separately by ELISA: IL-8, hsCRP, MIP1-alpha, GM-CSF, BDNF, and IL-1R1 antagonist. Previous work using CPP samples demonstrated the long-term stability of many of these cytokines, with replicated associations with neuropsychiatric outcomes in offspring. These concentrations will then be linked with a broad range of offsprings' neurocognitive outcomes. Accomplishments in FY17: This proposal was developed in the current fiscal year. The CPP samples were identified. Laboratory methods were finalized for conducting the assays.