Browsing by Author "Geha, Raif S."

Now showing 1 - 4 of 4
  • Thumbnail Image
    Item
    Clinical, immunological features, treatments, and outcomes of autoimmune hemolytic anemia in patients with RAG deficiency
    (American Society of Hematology, 2024) Wang, Chen; Sun, Bijun; Wu, Kevin; Farmer, Jocelyn R.; Ujhazi, Boglarka; Geier, Christoph B.; Gordon, Sumai; Westermann-Clark, Emma; Savic, Sinisa; Secord, Elizabeth; Sargur, Ravishankar; Chen, Karin; Jin, Jay J.; Dutmer, Cullen M.; Kanariou, Maria G.; Adeli, Mehdi; Palma, Paolo; Bonfim, Carmem; Lycopoulou, Evangelia; Wolska-Kusnierz, Beata; Dbaibo, Ghassan; Bleesing, Jack; Moshous, Despina; Neven, Benedicte; Schuetz, Catharina; Geha, Raif S.; Notarangelo, Luigi D.; Miano, Maurizio; Buchbinder, David K.; Csomos, Krisztian; Wang, Wenjie; Wang, Ji-Yang; Wang, Xiaochuan; Walter, Jolan E.; Pediatrics, School of Medicine
  • Thumbnail Image
    Item
    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.
  • Thumbnail Image
    Item
    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.
  • Thumbnail Image
    Item
    A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency
    (Elsevier, 2014-04) Lee, Yu Nee; Frugoni, Francesco; Dobbs, Kerry; Walter, Jolan E.; Giliani, Silvia; Gennery, Andrew R.; Al-Herz, Waleed; Haddad, Elie; LeDeist, Francoise; Bleesing, Jack H.; Henderson, Lauren A.; Pai, Sung-Yun; Nelson, Robert P.; El-Ghoneimy, Dalia H.; El-Feky, Reem A.; Reda, Shereen M.; Hossny, Elham; Soler-Palacin, Pere; Fuleihan, Ramsay L.; Patel, Niraj C.; Massaad, Michel J.; Geha, Raif S.; Puck, Jennifer M.; Palma, Paolo; Cancrini, Caterina; Chen, Karin; Vihinen, Mauno; Alt, Frederick W.; Notarangelo, Luigi D.; Department of Medicine, Division of Hematology and Oncology, IU School of Medicine
    Background The recombination-activating gene (RAG) 1/2 proteins play a critical role in the development of T and B cells by initiating the VDJ recombination process that leads to generation of a broad T-cell receptor (TCR) and B-cell receptor repertoire. Pathogenic mutations in the RAG1/2 genes result in various forms of primary immunodeficiency, ranging from T−B− severe combined immune deficiency to delayed-onset disease with granuloma formation, autoimmunity, or both. It is not clear what contributes to such heterogeneity of phenotypes. Objective We sought to investigate the molecular basis for phenotypic diversity presented in patients with various RAG1 mutations. Methods We have developed a flow cytometry–based assay that allows analysis of RAG recombination activity based on green fluorescent protein expression and have assessed the induction of the Ighc locus rearrangements in mouse Rag1−/− pro-B cells reconstituted with wild-type or mutant human RAG1 (hRAG1) using deep sequencing technology. Results Here we demonstrate correlation between defective recombination activity of hRAG1 mutant proteins and severity of the clinical and immunologic phenotype and provide insights on the molecular mechanisms accounting for such phenotypic diversity. Conclusions Using a sensitive assay to measure the RAG1 activity level of 79 mutations in a physiologic setting, we demonstrate correlation between recombination activity of RAG1 mutants and the severity of clinical presentation and show that RAG1 mutants can induce specific abnormalities of the VDJ recombination process.