Epigenetic, ribosomal, and immune dysregulation in PANS

SUMMARY

“Epigenetic, ribosomal, and immune dysregulation in paediatric acute-onset neuropsychiatric syndrome” investigates the biological underpinnings of PANS by examining clinical features, immune function, and blood-based transcriptomic profiles in this cohort of affected children compared with neurotypical controls and children with other neurodevelopmental disorders. Although routine immune testing and cerebrospinal fluid studies were largely normal, children with PANS showed a history of frequent early-life infections, abrupt neuropsychiatric symptom onset, and loss of previously acquired developmental skills. Bulk and single-cell RNA sequencing of peripheral blood revealed a reproducible gene expression signature characterized by upregulation of ribosomal biogenesis, translational machinery, and RNA methylation pathways, alongside downregulation of pathways involved in mitochondrial function, cellular signaling, endocytosis, and innate immune responses. These transcriptional changes were heterogeneous across immune cell types but pointed to global dysregulation of immune and cellular homeostasis rather than classical inflammation. Functional immune assays supported this interpretation, demonstrating reduced cytokine responses following innate immune stimulation. In a subset of patients receiving immune-modulating therapy, longitudinal transcriptomic analyses showed partial normalization of the dysregulated ribosomal, epigenetic, and immune pathways, paralleling short-term clinical improvement. Collectively, the findings suggest that PANS may be best described as a disorder at the intersection of neurodevelopment, immune function, and epigenetic regulation.

LINK TO PAPER: https://www.nature.com/articles/s41380-025-03127-5