Neuroinflammation and Immune Dysregulation in Autism Spectrum Disorder: Integrating Post-mortem, Peripheral, and Prenatal Evidence

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by deficits in social communication and social interaction, alongside restricted and repetitive patterns of behavior. While its etiology remains unknown, genetic and environmental factors contribute substantially to ASD risk, and growing evidence points towards immune dysregulation as a significant contributor to its pathogenesis in some ASD cases or groups. This thesis examines three converging lines of evidence for immune involvement in ASD, including post-mortem findings, peripheral immune alterations, and maternal immune activation, as well as the possible bridges between them. Post-mortem studies consistently report microglial and astroglial activation across multiple brain regions, while peripheral studies reveal a pro-inflammatory cytokine profile and dysregulated innate immune cell function, with several findings correlating with behavioral severity. Evidence from maternal immune activation suggests a prenatal origin for immune dysregulation in a subset of ASD individuals, with mechanistic support from animal models, cytokine studies, and human cellular models, though human causal evidence remains confounded.