In rare instances, pediatric SARS-CoV-2 infection results in 'multisystem inflammatory syndrome in children' (MIS-C). To date, the pathophysiology of this novel hyperinflammatory disease is only partly understood. We enrolled 37 MIS-C patients in a multi-centric study in Belgium. Preliminary analyses comparing MIS-C patient with patients with severe COVID-19 reveal that MIS-C is associated with vascular endothelitis and gastrointestinal epithelial injury. The cytokine profile is characterised by IFNg release instead of type I interferon and is reminiscent of immune disorders such as hemophagocytic lymphohistiocytosis or toxic shock syndrome. We identified an expanded T cell population expressing TRBV11-2 and displaying hallmarks of a superantigenic activation. With this proposal, we want to characterise the pathophysiology defining MIS-C using single-cell RNA-seq and proximity extension assay to study both the transcriptome and proteome response, respectively. Furthermore, we want to test the viral superantigen hypothesis by (1) illustration of ongoing presence of SARS-CoV-2 antigen during MIS-C, (2) identification of the viral superantigen using an in-vitro Jurkat reporter coculture system and (3) validation of the superantigenic features using in-house developed nanobodies in in-vitro and ex-vivo cell cultures. This project has the potential to add important knowledge to the scarce data that is available on MIS-C and to identify potential preventive and therapeutic options.