Comprehensive multi-omics mapping of immune perturbations in autism spectrum disorder

Abstract

Background: Autism spectrum disorder (ASD) is increasingly recognized as a neurodevelopmental condition with systemic immunological involvement, yet the underlying immune mechanisms remain incompletely defined.

Aims: To delineate the peripheral immune landscape in ASD using integrated multi-omics profiling and to determine how immune and immunometabolic alterations relate to clinical severity.

Materials & Methods: Circulating immune cells from individuals with ASD were profiled using multicolor flow cytometry, single-cell RNA sequencing, and bulk RNA sequencing. Plasma proteomic and metabolomic analyses were performed to identify immune-related and metabolic biomarkers. Immune features were evaluated for associations with clinical severity measures.

Results: Multi-omics profiling revealed marked immune dysregulation in ASD, with significant shifts in immune cell subsets and inflammatory signatures that correlated with clinical severity. T cell abnormalities included reduced frequencies and a skewed Th1/Th2 balance, consistent with a chronic inflammatory milieu. Natural killer (NK) cells showed increased activation but impaired cytotoxic capacity, accompanied by expansion of an atypical NK subset. Myeloid-derived suppressor cells (MDSCs) and hyperinflammatory CD56+ monocytes were elevated. Transcriptomic analyses corroborated broad immune activation, prominently implicating interferon-driven and antiviral signaling pathways. Plasma metabolomics and proteomics further indicated disruptions in purine metabolism and oxidative phosphorylation, alongside increased inflammatory markers, which were significantly associated with symptom severity.

Discussion: These findings support a systemic immunometabolic framework in ASD characterized by concurrent immune activation and altered myeloid/NK cell states, providing mechanistic context for peripheral biomarkers linked to clinical phenotype.

Conclusion: Integrated multi-omics profiling identifies robust peripheral immune and metabolic disturbances in ASD. The dysregulated immune subsets, activated immune pathways, and plasma biomarker signatures highlight potential avenues for biomarker-driven stratification and immune-targeted therapeutic development in ASD.

Keywords

autism spectrum disorder / biomarkers / immune dysregulation / multi-omics analysis

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