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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 Apr; 151(4):926-930.e2.JA

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.

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Authors+Show Affiliations

Bodansky A
Department of Pediatric Critical Care Medicine, University of California, San Francisco, Calif.
Vazquez SE
Department of Biochemistry and Biophysics, University of California, San Francisco, Calif; Diabetes Center, School of Medicine, University of California, San Francisco, Calif.
Chou J
Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass; Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, Mass. Electronic address: Janet.Chou@childrens.harvard.edu.
Novak T
Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Mass; Department of Anesthesia, Harvard Medical School, Boston, Mass.
Al-Musa A
Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
Young C
Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Mass.
Newhams M
Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Mass.
Kucukak S
Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Mass.
Zambrano LD
COVID-19 Response Team, Centers for Disease Control and Prevention, Atlanta, Ga.
Mitchell A
Department of Biochemistry and Biophysics, University of California, San Francisco, Calif; Chan Zuckerberg Biohub, San Francisco, Calif.
Wang CY
Chan Zuckerberg Biohub, San Francisco, Calif.
Moffitt K
Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, Mass; Division of Infectious Diseases, Boston Children's Hospital, Boston, Mass.
Halasa NB
Department of Pediatrics, Division of Pediatric Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tenn.
Loftis LL
Section of Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, Tex.
Schwartz SP
Department of Pediatrics, University of North Carolina at Chapel Hill Children's Hospital, Chapel Hill, NC.
Walker TC
Department of Pediatrics, University of North Carolina at Chapel Hill Children's Hospital, Chapel Hill, NC.
Mack EH
Division of Pediatric Critical Care Medicine, Medical University of South Carolina, Charleston, SC.
Fitzgerald JC
Department of Anesthesiology and Critical Care, Division of Critical Care, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa.
Gertz SJ
Department of Pediatrics, Division of Pediatric Critical Care, Cooperman Barnabas Medical Center, Livingston, NJ.
Rowan CM
Department of Pediatrics, Division of Pediatric Critical Care Medicine, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, Ind.
Irby K
Section of Pediatric Critical Care, Department of Pediatrics, Arkansas Children's Hospital, Little Rock, Ark.
Sanders RC
Section of Pediatric Critical Care, Department of Pediatrics, Arkansas Children's Hospital, Little Rock, Ark.
Kong M
Department of Pediatrics, Division of Pediatric Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Ala.
Schuster JE
Department of Pediatrics, Division of Pediatric Infectious Diseases, Children's Mercy Kansas City, Kansas City, Mo.
Staat MA
Department of Pediatrics, Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Zinter MS
Department of Pediatrics, Divisions of Critical Care and Bone Marrow Transplantation, University of California, San Francisco, Calif.
Cvijanovich NZ
Division of Critical Care Medicine, UCSF Benioff Children's Hospital, Oakland, Calif.
Tarquinio KM
Department of Pediatrics, Division of Critical Care Medicine, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Ga.
Coates BM
Department of Pediatrics, Division of Critical Care Medicine, Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Ill.
Flori HR
Department of Pediatrics, Division of Pediatric Critical Care Medicine, Mott Children's Hospital and University of Michigan, Ann Arbor, Mich.
Dahmer MK
Department of Pediatrics, Division of Pediatric Critical Care Medicine, Mott Children's Hospital and University of Michigan, Ann Arbor, Mich.
Crandall H
Department of Pediatrics, Division of Pediatric Critical Care, Primary Children's Hospital and University of Utah, Salt Lake City, Utah.
Cullimore ML
Department of Pediatrics, University of Nebraska Medical Center, College of Medicine, Children's Hospital and Medical Center, Omaha, Neb.
Levy ER
Department of Pediatric and Adolescent Medicine, Division of Pediatric Infectious Diseases, Division of Pediatric Critical Care Medicine, Mayo Clinic, Rochester, Minn.
Chatani B
Department of Pediatrics, Division of Pediatric Critical Care Medicine, Holtz Children's Hospital, University of Miami Miller School of Medicine, Miami, Fla.
Nofziger R
Department of Pediatrics, Division of Critical Care Medicine, Akron Children's Hospital, Akron, Ohio.
Overcoming COVID-19 Network Study Group Investigators,
No affiliation info available
Geha RS
Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
DeRisi J
Department of Biochemistry and Biophysics, University of California, San Francisco, Calif; Chan Zuckerberg Biohub, San Francisco, Calif.
Campbell AP
COVID-19 Response Team, Centers for Disease Control and Prevention, Atlanta, Ga.
Anderson M
Diabetes Center, School of Medicine, University of California, San Francisco, Calif.
Randolph AG
Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, Mass; Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Mass; Department of Anesthesia, Harvard Medical School, Boston, Mass.

MeSH

AdultHumansChildAdolescentSARS-CoV-2COVID-19AutoantibodiesNF-kappa BHaploinsufficiencyLeukocytes, MononuclearInterferon Type INF-kappa B p52 Subunit

Pub Type(s)

Multicenter Study
Journal Article

Language

eng

PubMed ID

36509151

Citation

Bodansky, Aaron, et al. "NFKB2 Haploinsufficiency Identified Via Screening for IFN-α2 Autoantibodies in Children and Adolescents Hospitalized With SARS-CoV-2-related Complications." The Journal of Allergy and Clinical Immunology, vol. 151, no. 4, 2023, pp. 926-930.e2.
Bodansky 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.
Bodansky, A., Vazquez, S. E., Chou, J., Novak, T., Al-Musa, A., Young, C., Newhams, M., Kucukak, S., Zambrano, L. D., Mitchell, A., Wang, C. Y., Moffitt, K., Halasa, N. B., Loftis, L. L., Schwartz, S. P., Walker, T. C., Mack, E. H., Fitzgerald, J. C., Gertz, S. J., ... Randolph, A. G. (2023). NFKB2 haploinsufficiency identified via screening for IFN-α2 autoantibodies in children and adolescents hospitalized with SARS-CoV-2-related complications. The Journal of Allergy and Clinical Immunology, 151(4), 926-e2. https://doi.org/10.1016/j.jaci.2022.11.020
Bodansky A, 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. PubMed PMID: 36509151.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - NFKB2 haploinsufficiency identified via screening for IFN-α2 autoantibodies in children and adolescents hospitalized with SARS-CoV-2-related complications. AU - Bodansky,Aaron, AU - Vazquez,Sara E, AU - Chou,Janet, AU - Novak,Tanya, AU - Al-Musa,Amer, AU - Young,Cameron, AU - Newhams,Margaret, AU - Kucukak,Suden, AU - Zambrano,Laura D, AU - Mitchell,Anthea, AU - Wang,Chung-Yu, AU - Moffitt,Kristin, AU - Halasa,Natasha B, AU - Loftis,Laura L, AU - Schwartz,Stephanie P, AU - Walker,Tracie C, AU - Mack,Elizabeth H, AU - Fitzgerald,Julie C, AU - Gertz,Shira J, AU - Rowan,Courtney M, AU - Irby,Katherine, AU - Sanders,Ronald C,Jr AU - Kong,Michele, AU - Schuster,Jennifer E, AU - Staat,Mary A, AU - Zinter,Matt S, AU - Cvijanovich,Natalie Z, AU - Tarquinio,Keiko M, AU - Coates,Bria M, AU - Flori,Heidi R, AU - Dahmer,Mary K, AU - Crandall,Hillary, AU - Cullimore,Melissa L, AU - Levy,Emily R, AU - Chatani,Brandon, AU - Nofziger,Ryan, AU - ,, AU - Geha,Raif S, AU - DeRisi,Joseph, AU - Campbell,Angela P, AU - Anderson,Mark, AU - Randolph,Adrienne G, Y1 - 2022/12/09/ PY - 2022/09/08/received PY - 2022/11/21/revised PY - 2022/11/29/accepted PY - 2023/4/11/medline PY - 2022/12/13/pubmed PY - 2022/12/12/entrez KW - Anti-interferon autoantibody KW - COVID-19 KW - MIS-C KW - NFKB2 KW - inborn errors of immunity SP - 926 EP - 930.e2 JF - The Journal of allergy and clinical immunology JO - J Allergy Clin Immunol VL - 151 IS - 4 N2 - 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. SN - 1097-6825 UR - https://www.unboundmedicine.com/medline/citation/36509151/NFKB2_haploinsufficiency_identified_via_screening_for_IFN_α2_autoantibodies_in_children_and_adolescents_hospitalized_with_SARS_CoV_2_related_complications_ DB - PRIME DP - Unbound Medicine ER -