Initially, the global outbreak of COVID-19 caused by severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2) spared children TRANS from severe disease MESHD. However, after the initial wave of infections MESHD, clusters of a novel hyperinflammatory disease MESHD have been reported in regions with ongoing SARS-CoV-2 epidemics. While the characteristic clinical features are becoming clear, the pathophysiology remains unknown. Herein, we report on the immune profiles of eight Multisystem Inflammatory Syndrome MESHD in Children TRANS (MIS-C) cases. We document that all MIS-C patients had evidence of prior SARS-CoV-2 exposure, mounting an antibody SERO response with normal isotype-switching and neutralization capability. We further profiled the secreted immune response by high-dimensional cytokine assays, which identified elevated signatures of inflammation MESHD (IL-18 and IL-6), lymphocytic and myeloid chemotaxis and activation (CCL3, CCL4, and CDCP1) and mucosal immune dysregulation HP (IL-17A, CCL20, CCL28). Mass cytometry immunophenotyping of peripheral blood SERO revealed reductions of mDC1 and non-classical monocytes, as well as both NK- and T- lymphocytes, suggesting extravasation to affected tissues. Markers of activated myeloid function were also evident, including upregulation of ICAM1 and FcR1 in neutrophil and non-classical monocytes, well-documented markers in autoinflammation and autoimmunity HP that indicate enhanced antigen presentation and Fc-mediated responses. Finally, to assess the role for autoimmunity HP secondary to infection MESHD, we profiled the auto-antigen reactivity of MIS-C plasma SERO, which revealed both known disease MESHD-associated autoantibodies (anti-La) and novel candidates that recognize endothelial, gastrointestinal and immune-cell antigens. All patients were treated with anti- IL6R antibody SERO or IVIG, which led to rapid disease MESHD resolution tracking with normalization of inflammatory markers.