Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening 
post-infectious complication occurring unpredictably weeks after mild or 
asymptomatic SARS-CoV2 infection in otherwise healthy children. Here, we define 
immune abnormalities in MIS-C compared to adult COVID-19 and pediatric/adult 
healthy controls using single-cell RNA sequencing, antigen receptor repertoire 
analysis, unbiased serum proteomics, and in vitro assays. Despite no evidence of 
active infection, we uncover elevated S100A-family alarmins in myeloid cells and 
marked enrichment of serum proteins that map to myeloid cells and pathways 
including cytokines, complement/coagulation, and fluid shear stress in MIS-C 
patients. Moreover, NK and CD8 T cell cytotoxicity genes are elevated, and 
plasmablasts harboring IgG1 and IgG3 are expanded. Consistently, we detect 
elevated binding of serum IgG from severe MIS-C patients to activated human 
cardiac microvascular endothelial cells in culture. Thus, we define 
immunopathology features of MIS-C with implications for predicting and managing 
this SARS-CoV2-induced critical illness in children.