Abstract Background:Kawasaki disease (KD) is a multisystemic vasculitis inflammatory syndrome that leads to coronary artery lesions (CALs). The pathogenesis and therapeutic strategies of KD are worth further exploring. Using single-cell RNA sequencing (scRNA-seq), our study aimed to explore the landscape of peripheral blood mononuclear cells (PBMCs) and B cell subsets in patients with KD, providing helpful evidence to understand the mechanism and therapeutic strategy for KD. Methods:We analyzed the scRNA-seq data of three patients with KD and three healthy controls from the GSE168732 dataset. Additionally, we analyzed the immune cell subtypes and explored the immune profiles of patients with KD. Results:Sixteen clusters of immune cells were identified in the PBMCs of patients with KD. Significantly increased B cell and decreased NK cells were observed in the KD group compared with that in the control group. Furthermore, six B cell subsets were identified in the PBMCs of patients with KD. Particularly, plasma cells (CD9+ and S100A9+ B cell clusters) distinctly increased in the KD group. The CD9+ B cell cluster was characterized by vascular endothelial growth factor (VEGF) signaling-associated marker genes and DEGs. Meanwhile the S100A9+ B cell cluster was characterized by platelet aggregation marker genes. As for NK cells, CD16+CD56dim NK cells were enriched in the KD group. Cytotoxicity-related HLA-specific activating receptors (KLRD1,KLRC3) and cytotoxicity-associated genes (PRF1, NKG7, GZMA, GZMH, GNLY) were downregulated in the KD group. Conclusion:Increased plasma cells(CD9+ and S100A9+ B cell clusters) and decreased cytotoxicity of NK cells were observed in KD. Plasma cells may contribute to CALs in KD by upregulating VEGF and activating platelet. In additon,decreased cytotoxicity of NK cells mediated by KLRD1/KLRC3 receptor may play a vital role in the development of KD. Our results suggested that plasma cells and NK cells could be promising targets for the treatment of KD.