NFKB2 haploinsufficiency identified via screening for IFN-α2 autoantibodies in children and adolescents hospitalized with SARS-CoV-2–related complications

Overcoming COVID-19 Network Study Group Investigators

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Background: 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.

Original languageEnglish (US)
Pages (from-to)926-930.e2
JournalJournal of Allergy and Clinical Immunology
Volume151
Issue number4
DOIs
StatePublished - Apr 2023

Keywords

  • Anti-interferon autoantibody
  • COVID-19
  • MIS-C
  • NFKB2
  • inborn errors of immunity

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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