Lee, D.Pen, J. L.Yatim, A.Dong, B.Aquino, Y.Ogishi, M.Pescarmona, R.Talouarn, E.Rinchai, D.Zhang, P.Perret, M.Liu, Z.Jordan, L.Bozdemir, S. E.Bayhan, G. I.Beaufils, C.Bizien, L.Bisiaux, A.Lei, W.Hasan, M.Chen, J.Gaughan, C.Asthana, A.Libri, V.Luna, Joseph M.Jaffré, FabriceHoffmann, H.Michailidis, E.Moreews, M.Seeleuthner, Y.Bilguvar, K.Mane, S.Flores, C.Zhang, Y.Arias, A. A.Bailey, R.Schlüter, A.Milisavljevic, B.Bigio, B.Voyer, T. L.Materna, M.Gervais, A.Moncada-Velez, M.Pala, F.Lazarov, T.Levy, R.Neehus, A.Rosain, J.Peel, J.Chan, Y.Morin, M.Pino-Ramirez, R. M.Belkaya, SerkanLorenzo, L.Anton, J.Delafontaine, S.Toubiana, J.Bajolle, F.Fumadó, V.DeDiego, M. L.Fidouh, N.Rozenberg, F.Pérez-Tur, J.Chen, S.Evans, T.Geissmann, F.Lebon, P.Weiss, S. R.Bonnet, D.Duval, X.Cohort§, C.Effort, C.Pan-Hammarström, Q.Planas, A. M.Meyts, I.Haerynck, F.Pujol, A.Sancho-Shimizu, V.Dalgard, C.Bustamante, J.Puel, A.Boisson-Dupuis, S.Boisson, B.Maniatis, T.Zhang, Q.Bastard, P.Notarangelo, L.Béziat, V.Diego, R.Rodriguez-Gallego, C.Su, H. C.Lifton, R. P.Jouanguy, E.Cobat, A.Alsina, L.Keles, S.Haddad, E.Abel, L.Belot, A.Quintana-Murci, L.Rice, C. M.Silverman, R. H.Zhang, S.Casanova, J.2024-03-142024-03-142022-12-20036-8075https://hdl.handle.net/11693/114763Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.enCC BY 4.0 DEED (Attribution 4.0 International)https://creativecommons.org/licenses/by/4.0/Article10.1126/sciimmunol.abp8966