Title : Cell type specific immunometabolic dichotomy distinguishes MIS-C from Kawasaki disease
Abstract:
Kawasaki Disease (KD) and Multisystem Inflammatory Syndrome in Children (MIS-C) share overlapping clinical features but differ markedly in severity and cardiac outcomes. Both conditions are characterized by systemic hyperinflammation, yet the cellular and metabolic mechanisms driving their divergent pathogenesis remain unclear. Immune cell function is tightly regulated by metabolic programs, and dysregulation of these pathways can amplify inflammatory responses. We hypothesized that KD and MIS-C are driven by distinct cell-type–specific immunometabolic alterations that underlie their differing clinical phenotypes. Publicly available single-cell RNA sequencing datasets of peripheral blood mononuclear cells from KD and MIS-C patients (GSE184330 & GSE168732) were analyzed. Pathway scores were compared across innate and adaptive immune subsets. A Random Forest machine learning approach was applied to classify disease states and to identify the specific cell types driving diagnostic discrimination. Both KD and MIS-C demonstrated a shared metabolic activation within classical monocytes, including enhanced glycolysis, fatty acid synthesis, and cholesterol metabolism. However, a striking immunometabolic divergence was observed between two diseases. KD was characterized by metabolically hyperactive monocytes with reduced itaconate-associated anti-inflammatory signaling, while adaptive immune cells maintained higher itaconate pathway activity. In contrast, MIS-C showed relative metabolic restraint in monocytes but profound suppression of itaconate-linked regulatory pathways in lymphoid populations, including NK cells, γδ T cells, and regulatory T cells. Random Forest analysis identified lymphocyte-specific loss of itaconate regulation as the strongest feature distinguishing MIS-C from KD. Our findings reveal distinct cellular drivers of inflammation in KD and MIS-C. KD pathogenesis is dominated by innate myeloid metabolic overactivation, whereas MIS-C is defined by failure of metabolic regulation within the adaptive lymphoid compartment. This immunometabolic dichotomy provides mechanistic insight into disease severity and identifies cell-type–specific itaconate pathway activity as a potential biomarker for differential diagnosis and targeted therapeutic strategies.
