NFKB2 haploinsufficiency identified via screening for IFN-α2 autoantibodies in children and adolescents hospitalized with SARS-CoV-2-related complications
Copyright © 2023. Published by Elsevier Inc..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:151 |
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| Enthalten in: |
The Journal of allergy and clinical immunology - 151(2023), 4 vom: 01. Apr., Seite 926-930.e2 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Bodansky, Aaron [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 11.04.2023 Date Revised 14.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jaci.2022.11.020 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM350212759 |
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| 100 | 1 | |a Bodansky, Aaron |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a NFKB2 haploinsufficiency identified via screening for IFN-α2 autoantibodies in children and adolescents hospitalized with SARS-CoV-2-related complications |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 11.04.2023 | ||
| 500 | |a Date Revised 14.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023. Published by Elsevier Inc. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Multicenter Study | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, P.H.S. | |
| 650 | 4 | |a Anti-interferon autoantibody | |
| 650 | 4 | |a COVID-19 | |
| 650 | 4 | |a MIS-C | |
| 650 | 4 | |a NFKB2 | |
| 650 | 4 | |a inborn errors of immunity | |
| 650 | 7 | |a Autoantibodies |2 NLM | |
| 650 | 7 | |a NF-kappa B |2 NLM | |
| 650 | 7 | |a Interferon Type I |2 NLM | |
| 650 | 7 | |a NFKB2 protein, human |2 NLM | |
| 650 | 7 | |a NF-kappa B p52 Subunit |2 NLM | |
| 700 | 1 | |a Vazquez, Sara E |e verfasserin |4 aut | |
| 700 | 1 | |a Chou, Janet |e verfasserin |4 aut | |
| 700 | 1 | |a Novak, Tanya |e verfasserin |4 aut | |
| 700 | 1 | |a Al-Musa, Amer |e verfasserin |4 aut | |
| 700 | 1 | |a Young, Cameron |e verfasserin |4 aut | |
| 700 | 1 | |a Newhams, Margaret |e verfasserin |4 aut | |
| 700 | 1 | |a Kucukak, Suden |e verfasserin |4 aut | |
| 700 | 1 | |a Zambrano, Laura D |e verfasserin |4 aut | |
| 700 | 1 | |a Mitchell, Anthea |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Chung-Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Moffitt, Kristin |e verfasserin |4 aut | |
| 700 | 1 | |a Halasa, Natasha B |e verfasserin |4 aut | |
| 700 | 1 | |a Loftis, Laura L |e verfasserin |4 aut | |
| 700 | 1 | |a Schwartz, Stephanie P |e verfasserin |4 aut | |
| 700 | 1 | |a Walker, Tracie C |e verfasserin |4 aut | |
| 700 | 1 | |a Mack, Elizabeth H |e verfasserin |4 aut | |
| 700 | 1 | |a Fitzgerald, Julie C |e verfasserin |4 aut | |
| 700 | 1 | |a Gertz, Shira J |e verfasserin |4 aut | |
| 700 | 1 | |a Rowan, Courtney M |e verfasserin |4 aut | |
| 700 | 1 | |a Irby, Katherine |e verfasserin |4 aut | |
| 700 | 1 | |a Sanders, Ronald C |c Jr |e verfasserin |4 aut | |
| 700 | 1 | |a Kong, Michele |e verfasserin |4 aut | |
| 700 | 1 | |a Schuster, Jennifer E |e verfasserin |4 aut | |
| 700 | 1 | |a Staat, Mary A |e verfasserin |4 aut | |
| 700 | 1 | |a Zinter, Matt S |e verfasserin |4 aut | |
| 700 | 1 | |a Cvijanovich, Natalie Z |e verfasserin |4 aut | |
| 700 | 1 | |a Tarquinio, Keiko M |e verfasserin |4 aut | |
| 700 | 1 | |a Coates, Bria M |e verfasserin |4 aut | |
| 700 | 1 | |a Flori, Heidi R |e verfasserin |4 aut | |
| 700 | 1 | |a Dahmer, Mary K |e verfasserin |4 aut | |
| 700 | 1 | |a Crandall, Hillary |e verfasserin |4 aut | |
| 700 | 1 | |a Cullimore, Melissa L |e verfasserin |4 aut | |
| 700 | 1 | |a Levy, Emily R |e verfasserin |4 aut | |
| 700 | 1 | |a Chatani, Brandon |e verfasserin |4 aut | |
| 700 | 1 | |a Nofziger, Ryan |e verfasserin |4 aut | |
| 700 | 0 | |a Overcoming COVID-19 Network Study Group Investigators, |e verfasserin |4 aut | |
| 700 | 1 | |a Geha, Raif S |e verfasserin |4 aut | |
| 700 | 1 | |a DeRisi, Joseph |e verfasserin |4 aut | |
| 700 | 1 | |a Campbell, Angela P |e verfasserin |4 aut | |
| 700 | 1 | |a Anderson, Mark |e verfasserin |4 aut | |
| 700 | 1 | |a Randolph, Adrienne G |e verfasserin |4 aut | |
| 700 | 1 | |a Kong, Michele |e investigator |4 oth | |
| 700 | 1 | |a Sanders, Ronald C |c Jr |e investigator |4 oth | |
| 700 | 1 | |a Yates, Masson |e investigator |4 oth | |
| 700 | 1 | |a Smith, Chelsea |e investigator |4 oth | |
| 700 | 1 | |a Cvijanovich, Natalie Z |e investigator |4 oth | |
| 700 | 1 | |a Zinter, MattS |e investigator |4 oth | |
| 700 | 1 | |a McLaughlin, Gwenn |e investigator |4 oth | |
| 700 | 1 | |a Tarquinio, Keiko M |e investigator |4 oth | |
| 700 | 1 | |a Coates, Bria M |e investigator |4 oth | |
| 700 | 1 | |a Rowan, Courtney M |e investigator |4 oth | |
| 700 | 1 | |a Randolph, Adrienne G |e investigator |4 oth | |
| 700 | 1 | |a Newhams, Margaret M |e investigator |4 oth | |
| 700 | 1 | |a Kucukak, Suden |e investigator |4 oth | |
| 700 | 1 | |a Novak, Tanya |e investigator |4 oth | |
| 700 | 1 | |a Moon, Hye Kyung |e investigator |4 oth | |
| 700 | 1 | |a Kobayashi, Takuma |e investigator |4 oth | |
| 700 | 1 | |a Melo, Jeni |e investigator |4 oth | |
| 700 | 1 | |a Young, Cameron |e investigator |4 oth | |
| 700 | 1 | |a Chen, Sabrina R |e investigator |4 oth | |
| 700 | 1 | |a Chou, Janet |e investigator |4 oth | |
| 700 | 1 | |a Flori, Heidi R |e investigator |4 oth | |
| 700 | 1 | |a Dahmer, Mary K |e investigator |4 oth | |
| 700 | 1 | |a Levy, Emily R |e investigator |4 oth | |
| 700 | 1 | |a Behl, Supriya |e investigator |4 oth | |
| 700 | 1 | |a Drapeau, Noelle M |e investigator |4 oth | |
| 700 | 1 | |a Schuster, Jennifer E |e investigator |4 oth | |
| 700 | 1 | |a Cullimore, Melissa L |e investigator |4 oth | |
| 700 | 1 | |a McCulloh, Russell J |e investigator |4 oth | |
| 700 | 1 | |a Gertz, Shira J |e investigator |4 oth | |
| 700 | 1 | |a Schwartz, Stephanie P |e investigator |4 oth | |
| 700 | 1 | |a Walker, Tracie C |e investigator |4 oth | |
| 700 | 1 | |a Nofziger, Ryan A |e investigator |4 oth | |
| 700 | 1 | |a Staat, Mary Allen |e investigator |4 oth | |
| 700 | 1 | |a Rohlfs, Chelsea C |e investigator |4 oth | |
| 700 | 1 | |a Fitzgerald, Julie C |e investigator |4 oth | |
| 700 | 1 | |a Mack, Elizabeth H |e investigator |4 oth | |
| 700 | 1 | |a Reed, Nelson |e investigator |4 oth | |
| 700 | 1 | |a Halasa, Natasha B |e investigator |4 oth | |
| 700 | 1 | |a Loftis, Laura L |e investigator |4 oth | |
| 700 | 1 | |a Crandall, Hillary |e investigator |4 oth | |
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