Bodansky, AaronVazquez, Sara E.Chou, JanetNovak, TanyaAl-Musa, AmerYoung, CameronNewhams, MargaretKucukak, SudenZambrano, Laura D.Mitchell, AntheaWang, Chung-YuMoffitt, KristinHalasa, Natasha B.Loftis, Laura L.Schwartz, Stephanie P.Walker, Tracie C.Mack, Elizabeth H.Fitzgerald, Julie C.Gertz, Shira J.Rowan, Courtney M.Irby, KatherineSanders, Ronald C., Jr.Kong, MicheleSchuster, Jennifer E.Staat, Mary A.Zinter, Matt S.Cvijanovich, Natalie Z.Tarquinio, Keiko M.Coates, Bria M.Flori, Heidi R.Dahmer, Mary K.Crandall, HillaryCullimore, Melissa L.Levy, Emily R.Chatani, BrandonNofziger, RyanOvercoming COVID-19 Network Study Group InvestigatorsGeha, Raif S.DeRisi, JosephCampbell, Angela P.Anderson, MarkRandolph, Adrienne G.2023-10-092023-10-092023Bodansky A, Vazquez SE, Chou J, et al. NFKB2 haploinsufficiency identified via screening for IFN-α2 autoantibodies in children and adolescents hospitalized with SARS-CoV-2-related complications. J Allergy Clin Immunol. 2023;151(4):926-930.e2. doi:10.1016/j.jaci.2022.11.020https://hdl.handle.net/1805/36208Background: Autoantibodies against type I IFNs occur in approximately 10% of adults with life-threatening coronavirus disease 2019 (COVID-19). The frequency of anti-IFN autoantibodies in children with severe sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is unknown. Objective: We quantified anti-type I IFN autoantibodies in a multicenter cohort of children with severe COVID-19, multisystem inflammatory syndrome in children (MIS-C), and mild SARS-CoV-2 infections. Methods: Circulating anti-IFN-α2 antibodies were measured by a radioligand binding assay. Whole-exome sequencing, RNA sequencing, and functional studies of peripheral blood mononuclear cells were used to study any patients with levels of anti-IFN-α2 autoantibodies exceeding the assay's positive control. Results: Among 168 patients with severe COVID-19, 199 with MIS-C, and 45 with mild SARS-CoV-2 infections, only 1 had high levels of anti-IFN-α2 antibodies. Anti-IFN-α2 autoantibodies were not detected in patients treated with intravenous immunoglobulin before sample collection. Whole-exome sequencing identified a missense variant in the ankyrin domain of NFKB2, encoding the p100 subunit of nuclear factor kappa-light-chain enhancer of activated B cells, aka NF-κB, essential for noncanonical NF-κB signaling. The patient's peripheral blood mononuclear cells exhibited impaired cleavage of p100 characteristic of NFKB2 haploinsufficiency, an inborn error of immunity with a high prevalence of autoimmunity. Conclusions: High levels of anti-IFN-α2 autoantibodies in children and adolescents with MIS-C, severe COVID-19, and mild SARS-CoV-2 infections are rare but can occur in patients with inborn errors of immunity.en-USPublisher PolicyAnti-interferon autoantibodyCOVID-19MIS-CNFKB2Inborn errors of immunityArticle