Intravenous immunoglobulin has epigenetic, ribosomal, and immune effects in Paediatric Acute-Onset Neuropsychiatric Syndrome

Paediatric acute-onset neuropsychiatric syndrome (PANS) is characterised by infection provoked abrupt and dramatic onset of obsessive compulsive disorder (OCD) or eating restriction, along with neurodevelopmental regression. Although the aetiology of PANS remains uncertain, due to a prevailing neuroimmune hypothesis some children receive the immune modulator intravenous immunoglobulin (IVIg). Using single-cell RNA sequencing of peripheral immune cells, we examined gene expression in five children with PANS (mean age 10.2 years, range 5 to 17, 60% male) who were receiving open label IVIg. Maternal autoimmunity (n=3) and familial neurodevelopmental/neuropsychiatric disorders (n=5) were present. The index PANS event occurred age 1.8 to 13 years, characterised by abrupt eating restriction (n=5), developmental regression (n=4), and OCD (n=3). Single-cell RNA sequencing (144,470 cells) was performed in five patients pre- and post-IVIg, and four controls (mean age 13.5 years, range 11 to16, 50% male). In PANS pre IVIg compared to neurotypical controls, there were downregulated immune pathways (defense response, innate immunity, secretory granules) in most cell types. However, NK cells exhibited upregulated immune pathways (response to corticosteroid), supporting a baseline immune dysregulation. In PANS pre IVIg compared to controls, ribosomal pathways were upregulated in neutrophils and CD8 T cells, but downregulated in NK cells. Post IVIg, the previously downregulated immune pathways were upregulated in most cell types, and the baseline ribosomal pathway abnormalities were reversed. Additionally, histone modification pathways (histone methyltransferase, chromatin) were downregulated in neutrophils and NK cells post-IVIg. We propose PANS is an epigenetic immune-brain disorder with cellular epigenetic, ribosomal, and immune dysregulation. Therefore, epigenetic and immune modulating therapies, such as IVIg, may have a critical role in treating this disabling disorder.