A multi-omics approach reveals dysregulated TNF-related signaling pathways in circulating NK and T cell subsets of young children with autism.

Researchers studied immune system differences in young children with autism compared to children without autism. They found that certain immune cells and proteins work differently in children with autism. Importantly, three specific genes were linked to autism symptom severity - when these genes were less active, symptoms were more severe. The study identified specific immune pathways that may be targets for future treatments.

This multimodal study examined immune system dysfunction in young Arab children with autism (ages 2-4) compared to matched controls in Qatar. Researchers integrated transcriptomic, proteomic, and single-cell RNA sequencing data to identify molecular mechanisms underlying immune dysregulation. They found differential expression of 50 immune-related genes in circulating immune cells, with three genes (JAK3, CUL2, CARD11) negatively correlating with autism symptom severity. The study revealed disrupted TNF signaling pathways and elevated levels of specific proteins (TNFSF10/TRAIL, TNFSF11/RANKL, TNFSF12/TWEAK) in plasma.

Single-cell analysis identified B cells, CD4 T cells, and NK cells as contributors to these elevations, with specific pathway disruptions observed in CD8 T cells, CD4 T cells, and NK cells.

Findings suggest TNF signaling pathways and specific immune cell subsets as potential therapeutic targets. The correlation between gene expression and symptom severity may inform biomarker development for monitoring treatment response and disease progression in young children with autism.

Sample size not reported. Study limited to young Arab children (ages 2-4) in Qatar, limiting generalizability across age groups and ethnicities. Cross-sectional design prevents determination of causality between immune dysfunction and autism symptoms.

Peripheral immune dysregulation is frequently reported in autism spectrum disorder (ASD); however, the underlying molecular mechanisms remain unclear. We recruited a well-defined cohort of young Arab children with ASD, aged 2-4 years, along with matched controls in Qatar. Using a multimodal approach, we integrated transcriptomic, proteomic, and single-cell RNA-seq data analyses from this cohort. Targeted transcriptomic profiling identified differential expression of 50 immune-related genes in the circulating PBMCs of children with ASD, three of which (JAK3, CUL2, and CARD11) negatively correlated with ASD symptom severity.

These gene signatures were validated in independent studies using blood and brain tissues from individuals with ASD. Enrichment analysis revealed involvement of these genes in immune function, particularly through TNF signaling pathway. Proteomic analysis highlighted disrupted TNF signaling and upregulated levels of TNFSF10 (TRAIL), TNFSF11 (RANKL), and TNFSF12 (TWEAK) in plasma of individuals with ASD. Single-cell RNA-seq revealed that B cells, CD4 T cells, and NK cells potentially contributed to these upregulations in ASD.

Dysregulated TRAIL, RANKL, and TWEAK signaling pathways were specifically observed in CD8 T cells, CD4 T cells, and NK cells of individuals with ASD. These findings provide new insights into immune dysregulation mechanisms in ASD and highlight potential therapeutic targets.