학술논문
NFKB2 haploinsufficiency identified via screening for IFN-α2 autoantibodies in children and adolescents hospitalized with SARS-CoV-2–related complications
Document Type
article
Author
Bodansky, Aaron; Vazquez, Sara E; Chou, Janet; Novak, Tanya; Al-Musa, Amer; Young, Cameron; Newhams, Margaret; Kucukak, Suden; Zambrano, Laura D; Mitchell, Anthea; Wang, Chung-Yu; Moffitt, Kristin; Halasa, Natasha B; Loftis, Laura L; Schwartz, Stephanie P; Walker, Tracie C; Mack, Elizabeth H; Fitzgerald, Julie C; Gertz, Shira J; Rowan, Courtney M; Irby, Katherine; Sanders, Ronald C; Kong, Michele; Schuster, Jennifer E; Staat, Mary A; Zinter, Matt S; Cvijanovich, Natalie Z; Tarquinio, Keiko M; Coates, Bria M; Flori, Heidi R; Dahmer, Mary K; Crandall, Hillary; Cullimore, Melissa L; Levy, Emily R; Chatani, Brandon; Nofziger, Ryan; Investigators, Overcoming COVID-19 Network Study Group; Yates, Masson; Smith, Chelsea; Zinter, MattS; McLaughlin, Gwenn; Randolph, Adrienne G; Newhams, Margaret M; Moon, Hye Kyung; Kobayashi, Takuma; Melo, Jeni; Chen, Sabrina R; Behl, Supriya; Drapeau, Noelle M; McCulloh, Russell J; Nofziger, Ryan A; Staat, Mary Allen; Rohlfs, Chelsea C; Reed, Nelson; Geha, Raif S; DeRisi, Joseph; Campbell, Angela P; Anderson, Mark
Source
Journal of Allergy and Clinical Immunology. 151(4)
Subject
Language
Abstract
BackgroundAutoantibodies 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.ObjectiveWe 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.MethodsCirculating 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.ResultsAmong 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.ConclusionsHigh 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.