Multi-omics and longitudinal immune profiling uncover a distinct monocyte phenotype distribution and function in Kawasaki disease 2308476

Abstract Introduction Kawasaki disease (KD) is an acute childhood vasculitis marked by strong monocyte (MO)-driven innate activation. Despite their central role, MO’s dynamics during acute KD and their modulation by intravenous immunoglobulin (IVIG) remain poorly defined. Here, we characterize the MO compartment in KD compared with age- and gender-matched febrile (FC) and healthy controls (HC), before and after IVIG by an integrated multi-omics approach. Methods KD were tested at diagnosis (T0), 48h (T1) and 4 weeks (T2) post-IVIG. MO phenotype and LPS-induced responses assessed by flow cytometry, along with plasma proteomics (Olink PEA), were integrated with clinical and echocardiographic data. MO transcriptomic profiling was performed by Nanopore RNA sequencing. Results Upon LPS stimulation, KD MO showed overall enhanced TNF-α (p < 0.01) and IL-6 (p < 0.05) responses compared with FC. Leiden clustering revealed phenotypical differences among MO subsets. C1, corresponding to classical (CL) MO (CCR2, CD14, CD93), was reduced in KD at T0 compared with HC (p < 0.05). In contrast, C6, sharing a CL MO backbone but displaying activated/proliferative features (Ki67 and CD38), was increased in KD (p < 0.05), indicating a functional reprogramming of the CL compartment, consistent with its expansion in KD and correlates with APBB1IP, a protein differentially expressed between KD and HC and associated with coronary artery involvement (p = 0.01). C9, displaying an immature proliferative profile (Ki67, CD38, lacking subset-defining markers), was enriched in KD T0 versus FC (p < 0.05). At T2, C1 and C9 reverted toward HC levels. Conclusion Overall, this study provides a subset-resolved phenotypic and functional characterization of MO in KD, revealing disease-specific alterations that are partially normalized by IVIG. These findings highlight a central role for MO, particularly pathways linked to activation and extravasation, in KD immunopathogenesis. Ongoing MO RNA-seq analyses will further clarify the transcriptional pathways involved. Funding Source n/a Topic Categories Immune Mechanisms of Human Disease (HUM)