UC Davis

A combination of exposure to environmental and biological factors such as stress, age, genetics are well-known contributing elements of neurodevelopmental disorders (NDD) and autism spectrum disorder (ASD). It is only recently that immune molecules such as immune cells and cytokines/chemokines may take pivotal role in ASD progression. Increasing evidence suggest their critical function in mediating neurodevelopment and maintaining brain homeostasis. Aberrant levels of these immune molecules can alter the dynamics of neuro-immune interaction and their function, leading to impairments in neurodevelopment and progress to ASD diagnosis. The aim of this dissertation is to provide further evidence of immune dysregulation in children with ASD, particularly in peripheral cytokines/chemokines levels, and identify potential cytokine/chemokine profiles as predictors of neonatal ASD.The first chapter of this thesis is an introduction and provides background information and the diagnostic methods for ASD. This chapter aims to identify immune molecules, particularly the cytokines/chemokines/growth factors, that are important factors to potentially separate children with ASD from those that are typically developing. The chapter further puts forward the concept that these factors have promise as a tool in augmenting ASD diagnostic methods. The second chapter provides epidemiological evidence of abnormal neonatal cytokine/chemokine levels in children with ASD and developmental delay (DD) compared to those that are typically developing (TD), and further describes the relationship between aberrant cytokine/chemokine levels and their ASD associated behaviors. Some of the novel findings in this chapter includes the identification of two chemokines as early predictors of ASD and DD. These immune profiles in children with ASD and DD can help scrutinize the biological difference between ASD and DD development from TD controls. The third chapter expands upon previously published study by Heuer et al. regarding whether there exists an interaction effect of sex and diagnosis (ASD and DD) in neonatal cytokine/chemokine levels. Unexpected novel findings suggest that 1) at birth, regardless of diagnosis, male and female children are born with different levels of peripheral cytokines/chemokines, and that 2) the inflammatory chemokine, macrophage migration inhibitory factor (MIF), has an interaction effect in females and males depend on the diagnosis. The fourth chapter describes how maternal SARS-CoV-2 (COVID-19) infection during pregnancy impacts the peripheral immune system and neurodevelopmental outcome in newborn offspring. Some of the novel findings include that 1) this is one of the first studies to determine the effect of COVID-19 infection during pregnancy in child immunity and neurodevelopmental outcomes, and that 2) newborn immune response to in utero exposure to COVID-19 is different by sex. The final chapter focuses on a work-in-progress study of the impact of maternal immune and metabolic dysregulation in child neurodevelopmental outcome. Specifically, we are looking at maternal gestational inflammatory conditions and metabolic system during pregnancy adversely impacts child neurodevelopment. Using a longitudinal approach, we aim to characterize existing maternal immune/metabolic dysregulation throughout pregnancy and evaluate whether specific patterns associate with specific neurodevelopmental outcomes in the child. Taken together, the studies included herein provide evidence of dysregulated peripheral immune system in early life of children later diagnosed with NDD and ASD, particularly in the immune signaling molecules, compared to those that are typically developing. These results hint at possible mechanisms regarding the differences in neuro-immune pathology of NDD or ASD compared to healthy neurodevelopment as well as mechanisms of severity for the spectrum of behaviors associated with NDD in the context of neuroimmune dysregulation. Future studies on functional mechanisms of select cytokine/chemokine in brain development will be important to develop new therapeutic interventions.