Browsing by Author "Chatani, Brandon"

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    NFKB2 haploinsufficiency identified via screening for IFN-α2 autoantibodies in children and adolescents hospitalized with SARS-CoV-2-related complications
    (Elsevier, 2023) 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., Jr.; 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; Overcoming COVID-19 Network Study Group Investigators; Geha, Raif S.; DeRisi, Joseph; Campbell, Angela P.; Anderson, Mark; Randolph, Adrienne G.; Pediatrics, School of Medicine
    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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    NFKB2 haploinsufficiency identified via screening for IFNα2 autoantibodies in children and adolescents hospitalized with SARS-CoV-2-related complications
    (Elsevier, 2023-04) Bodansky, Aaron; Vazquez, Sara E.; Chou, Janet; Novak, Tanya; Al-Musa, Amer; Young, Cameron; Newhams, Margaret; Kocukak, 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., Jr.; 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; Overcoming COVID-19 Network Study Group Investigators; Geha, Raif S.; DeRisi, Joseph; Campbell, Angela P.; Anderson, Mark; Randolph, Adrienne G.; Pediatrics, School of Medicine
    Background Autoantibodies against type I interferons (IFNs) occur in approximately 10% of adults with life-threatening COVID-19. The frequency of anti-IFN autoantibodies in children with severe sequelae of SARS-CoV-2 infection is unknown. Objective To quantify anti-Type I IFN autoantibodies in a multi-center cohort of children with severe COVID-19, Multisystem Inflammatory Syndrome in Children (MIS-C), and mild SARS-CoV-2 infections. Methods Circulating anti-IFNa2 antibodies were measured by a radioligand binding assay. Whole exome sequencing (WES), RNA-sequencing, and functional studies of peripheral blood mononuclear cells were used to study any patients with levels of anti-IFNα2 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 one had high levels of anti-IFNα2 antibodies. Anti-IFNα2 autoantibodies were not detected in patients treated with intravenous immunoglobulin prior to sample collection. WES identified a missense variant in the ankyrin domain of NFKB2, encoding the p100 subunit of NF-kB essential for non-canonical NF-kB signaling. Her 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-IFNα2 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. Clinical implications Anti-IFNα2 autoantibodies should prompt diagnostic evaluation for inborn errors of immunity if identified in children or adolescents.