Post-infectious inflammatory disease in MIS-C features elevated cytotoxicity signatures and autoreactivity that correlates with severity

Ramaswamy, A.; Brodsky, N. N.; Sumida, T. S.; Comi, M.; Asashima, H.; Hoehn, K. B.; Li, N.; Liu, Y.; Shah, A.; Ravindra, N. G.; Bishai, J.; Khan, A.; Lau, W.; Sellers, B.; Bansal, N.; Sparks, R.; Unterman, A.; Habet, V.; Rice, A. J.; Catanzaro, J.; Chandnani, H.; Lopez, M.; Kaminski, N.; Dela Cruz, C. S.; Tsang, J. S.; Wang, Z.; Yan, X.; Kleinstein, S. H.; van Dijk, D.; Pierce, R. W.; Hafler, D. A.; Lucas, C. L.

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.