Multisystem inflammatory syndrome in children (MIS-C) is a severe, unexplained complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with an estimated prevalence of ~1 per 10,000 infected children. It typically occurs 4 weeks after infection, without hypoxemic pneumonia. Affected children present with fever, rash, abdominal pain, myocarditis, and other clinical features reminiscent of Kawasaki disease, including lymphadenopathy, coronary aneurysm, and high levels of biological markers of acute inflammation. Sustained monocyte activation is consistently reported as a key immunological feature of MIS-C. A more specific immunological abnormality is the polyclonal expansion of CD4+ and CD8+ T cells bearing the T cell receptor Vβ21.3. The root cause of MIS-C and its immunological and clinical features remains unknown. We hypothesize that monogenic inborn errors of immunity to SARS-CoV-2 may underlie MIS-C in some children. We further hypothesize that the identification of these inborn errors would provide insights into the molecular and cellular mechanisms underlying its immunological and clinical phenotypes. Finally, we hypothesize that a genetic and mechanistic understanding of a few patients would provide a proof of principle that would facilitate studies in other patients.
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