Th1-Th17 immune signature in children with autism spectrum disorder

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by substantial inter-individual variability in clinical presentation and underlying biology. Increasing evidence implicates immune dysregulation in ASD; however, well-defined Th1-Th17 immune signatures in pediatric populations remain incompletely characterized using rigorous analytical approaches.

We conducted a cross-sectional case-control study including 40 children with ASD and 25 neurotypical controls. The plasma concentrations of nine cytokines were quantified using a multiplex immunoassay. Cytokine differences were evaluated using false discovery rate correction, standardized effect size estimation, and generalized linear models adjusted for sex and age of the participants. In parallel, targeted next-generation sequencing of 236 ASD-implicated genes was performed as an exploratory approach to contextualize the immune findings within neurodevelopmental and immune-related pathways.

Children with ASD exhibited a consistent Th1-Th17 immune signature, characterized by significantly higher plasma levels of IL-2, IL-12, and IL-17 than neurotypical controls. These differences remained robust after correction for multiple testing and covariate adjustment, with large standardized effect sizes. No group differences were observed for IL-4, IL-6, IL-10, TNF-α, IFN-γ, or IL-1β, indicating a selective rather than generalized inflammatory profile. Sex-stratified analyses revealed higher IL-2 and IL-17 levels in females with ASD, suggesting a quantitative sex-related modulation of Th1-Th17 immune responses. Exploratory genetic analyses identified rare variants in genes involved in chromatin remodeling, synaptic organization, and immune-related processes, converging on pathways related to transcriptional regulation and immune signaling.

This study provides an exploratory yet analytically robust characterization of the Th1-Th17 immune signature in children with ASD. The consistency and specificity of the immune findings support their biological relevance and underscore the value of integrative immune-informed approaches to understand the biological heterogeneity in pediatric ASD.