Neuro Endocrinol Lett. 2025 Dec 16;46(6):315-322. Online ahead of print.
ABSTRACT
BACKGROUND: Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that impairs communication. Increasing research indicates that maternal immune activation (MIA) is one of the most important environmental factors that increase the risk of autism spectrum disorder (ASD) in offspring. Maternal immune activation produces elevated cytokine levels that cross the placental barrier and disrupt fetal neurodevelopment, increasing ASD risk. However, the specific causal pathways and mediating mechanisms remain unclear, limiting our understanding.
METHODS: This mediation Mendelian randomization study examined causal pathways linking immune cell traits (exposures) and inflammatory factors (mediators) to ASD risk.The research merged immune data (731 phenotypes + 48 cytokines) and ASD data from a cohort comprising 18,382 cases and 27,969 controls. Various MR approaches were used to reduce potential biases, along with thorough descriptions of statistical procedures and instrumental variable selection.
RESULTS: The study’s findings propose potential causal relationships among cytokines representing inflammatory factors, immune cells, and ASD through mediation Mendelian randomization. Reverse MR was then employed to investigate the possibility of reverse causality. CD8+ T cell %leukocyte (OR = 1.099, 95% CI: 1.039-1.163, p = 0.001), CCR2+ CD62L+ myeloid dendritic cells (OR = 0.933, p = 0.029), and CD45+ immature myeloid-derived suppressor cells (OR = 1.056, p = 0.001) showed evidence of causal association with ASD risk.Furthermore, reduced Artemin levels and elevated FLT3L and 2B4 levels were significantly linked to ASD risk, indicating that abnormalities in immunomodulatory factors may play a crucial role in the pathogenesis of ASD. Additionally, ASD occurrence may result in alterations in Natural Killer cell receptor 2B4 levels.
CONCLUSION: This mediation Mendelian randomization study provides evidence that immune dysfunction is associated with ASD pathophysiology through inflammatory mediators, requiring functional validation before clinical application.Cytokines act as mediators in the pathogenesis of ASD, providing a theoretical basis for understanding its immunoinflammatory pathogenesis and offering insight into treatment.
PMID:41420879
