Sacco , KeithCastagnoli , RiccardoVakkilainen, SvetlanaLiu, CanDelmonte, Ottavia M.Oguz, CihanKaplan, Ian M.Alehashemi, SaraBurbelo, Peter D.Bhuyan, FarzanaJesus, Adriana A.Dobbs , KerryRosen, Lindsey B.Cheng, AristineShaw, ElanaVakkilainen, Mikko S.Pala , FrancescaLack, JustinZhang, YuFink, Danielle L.Oikonomou, VasileiosSnow , Andrew L.Dalgard, Clifton L.Chen, JinguoSellers, Brian A.Montealegre Sanchez, Gina A.Barron, KarylRey-Jurado, EmmaVial, CeciliaPoli, CeciliaLicari, AmeliaMontagna, DanielaMarseglia, Gian Luigi2022-04-062022-04-062022Sacco, K., Castagnoli, R., Vakkilainen, S. et al. Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19. Nat Med (2022). https://doi.org/10.1038/s41591-022-01724-3https://doi.org/10.1038/s41591-022-01724-3http://hdl.handle.net/11447/5952Francesco Licciardi; Ugo Ramenghi; Valentina Discepolo; Andrea Lo Vecchio; Alfredo Guarino; Eli M. Eisenstein; Luisa Imberti ; Alessandra Sottini; Andrea Biondi; Sayonara Mató; Dana Gerstbacher; Meng Truong; Michael A. Stack; Mary Magliocco; Marita Bosticardo; Tomoki Kawai; Jeffrey J. Danielson; Tyler Hulett; Manor Askenazi; Shaohui Hu; NIAID Immune Response to COVID Group*; Chile MIS-C Group*; Pavia Pediatric; COVID-19 Group*; Jeffrey I. Cohen; Helen C. Su ; Douglas B. Kuhns; Michail S. Lionakis Thomas M. Snyder; Steven M. Holland; Raphaela Goldbach-Mansky; John S. Tsang  and Luigi D. NotarangeloPediatric Coronavirus Disease 2019 (pCOVID-19) is rarely severe; however, a minority of children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might develop multisystem inflammatory syndrome in children (MIS-C), with substantial morbidity. In this longitudinal multi-institutional study, we applied multi-omics (analysis of soluble biomarkers, proteomics, single-cell gene expression and immune repertoire analysis) to profile children with COVID-19 (n= 110) and MIS-C (n= 76), along with pediatric healthy controls (pHCs; n= 76). pCOVID-19 was characterized by robust type I interferon (IFN) responses, whereas prominent type II IFN-dependent and NF-κB-dependent signatures, matrisome activation and increased levels of circulating spike protein were detected in MIS-C, with no correlation with SARS-CoV-2 PCR status around the time of admission. Transient expansion of TRBV11-2 T cell clonotypes in MIS-C was associated with signatures of inflammation and T cell activation. The association of MIS-C with the combination of HLA A*02, B*35 and C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load than pCOVID-19 and pHC. These results identify distinct immunopathological signatures in pCOVID-19 and MIS-C that might help better define the pathophysiology of these disorders and guide therapyenImmunopathogenesisInflammationRNA sequencingSARS-CoV-2Viral infectionArticle