Sex-associated and disease state-dependent monocyte polarization and CNS-trafficking phenotypes in pediatric acute-onset neuropsychiatric syndrome (PANS)

Pediatric acute-onset neuropsychiatric syndrome (PANS) is characterized by the sudden onset of obsessive-compulsive symptoms alongside a constellation of neuropsychiatric and somatic features. Disease progression typically includes flare and recovery states, with some patients exhibiting a persistent disease course (> 12 months of flare). We characterized circulating monocyte subsets during flare and recovery in pediatric patients with PANS, uncovering disease-state–dependent shifts in polarization and trafficking phenotypes. Inflammatory M1-like monocytes and monocyte-derived dendritic cells were elevated during flare, while anti-inflammatory M2-like monocytes were enriched in recovery. We also identified a circulating subset with a surface phenotype consistent with central nervous system (CNS) homing, which was reduced during flare and restored in recovery. These cells were detectable in the cerebrospinal fluid (CSF) of new-onset patients but not in persistent cases, suggesting differential compartmentalization during disease progression. Notably, monocyte phenotypes, including M2 polarization (monocytosis) and circulating CNS-homing profiles, exhibited striking sex-associated differences, particularly during recovery, with several subsets enriched in males but not females. Plasma from flare-phase patients modestly induced CNS-homing markers in monocytes from healthy donors, indicating the presence of circulating modulators. Together, these findings support a model in which distinct myeloid phenotypes—including sex-biased patterns—may contribute to both the pathogenesis and resolution of neuroinflammation in PANS.