Sex-associated and disease state-dependent monocyte polarization and CNS-trafficking phenotypes in PANS
RESEARCH IMPACT:
“Sex-associated and disease state-dependent monocyte polarization and CNS-trafficking phenotypes in PANS” provides strong evidence that PANS involves dynamic, sex-associated innate immune dysregulation marked by shifts in monocyte polarization and CNS-directed trafficking across flare and recovery states. By identifying a novel, potentially regulatory monocyte population linked to disease trajectory and CNS involvement, the study advances mechanistic understanding of PANS and highlights new opportunities for biomarker development and immune-informed stratification of patients in future clinical and translational research.
SUMMARY
“Sex-associated and disease state-dependent monocyte polarization and CNS-trafficking phenotypes in PANS” investigates innate immune dynamics in pediatric acute-onset neuropsychiatric syndrome (PANS) characterizes circulating monocyte and myeloid cell subsets across disease states (flare versus recovery), clinical course, and by sex. Using flow cytometry, intracellular cytokine profiling, cerebrospinal fluid (CSF) analysis, and single-cell RNA sequencing, the authors demonstrate that PANS is associated with marked, disease-state–dependent shifts in monocyte polarization and trafficking phenotypes. During disease flares, male patients showed evidence of monocyte activation, including monocytosis driven by expansion of classical CD14⁺ monocytes, increased pro-inflammatory M1-like polarization, and elevated frequencies of migratory monocytes and monocyte-derived dendritic cells. These changes normalized during recovery. In contrast, female patients did not demonstrate monocyte activation during disease flare, exhibiting relatively stable total monocyte counts and more subtle shifts in intermediate monocyte subsets, underscoring pronounced sex-associated immune differences in PANS.
A key finding is the identification of a distinct subset of CD14⁺ monocytes expressing a surface marker profile consistent with central nervous system (CNS) homing. These cells were reduced in peripheral blood during flare but detected in the CSF of patients with new-onset disease, supporting active redistribution across neuroimmune barriers. In recovery, the same population re-emerged in circulation, whereas patients with a persistent disease course showed sustained depletion in blood and absence in CSF. Functional profiling revealed that these “CNS-homing” monocytes display an anti-inflammatory and potentially neuroprotective cytokine signature, including elevated interleukin-10 and transforming growth factor-β, with transcriptomic data supporting immunoregulatory pathway enrichment. Striking sex-associated differences were observed across multiple monocyte subsets, indicating that biological sex may substantially influence immune trajectories in PANS.
LINK TO PAPER: https://www.nature.com/articles/s41380-025-03127-5
CITATION
Rahman SS, Hussein N, Galfrè SG, Gaertner F, Macaubas C, Chan A, Columbo L, Gao J, Galehdari S, Bayram B, Ma M, Manko C, Miles K, Farhadian B, Silverman M, Thienemann M, Or-Geva N, Van Haren K, Nadeau KC, Tian L, Frankovich J, Mellins ED. Sex-associated and disease state-dependent monocyte polarization and CNS-trafficking phenotypes in pediatric acute-onset neuropsychiatric syndrome (PANS). J Neuroinflammation. 2025 Nov 18;22(1):273. doi: 10.1186/s12974-025-03549-6. PMID: 41254741; PMCID: PMC12625707