Kazuya Takeda1, Shuhei Sakakibara2, Kazuo Yamashita3, Daisuke Motooka4, Shota Nakamura4, Marwa Ali El Hussien5, Jun Katayama5, Yohei Maeda6, Masanobu Nakata7, Shigeyuki Hamada8, Daron M Standley9, Masaki Hayama6, Takashi Shikina6, Hidenori Inohara6, Hitoshi Kikutani10. 1. Laboratory of Immune Regulation, Immunology Frontier Research Center, Osaka, Japan; Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Osaka, Japan. 2. Laboratory of Immune Regulation, Immunology Frontier Research Center, Osaka, Japan. Electronic address: sakakibara@ifrec.osaka-u.ac.jp. 3. Laboratory of System Immunology, Immunology Frontier Research Center, Osaka, Japan. 4. Department of Infection Metagenomics, Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan. 5. Laboratory of Immune Regulation, Immunology Frontier Research Center, Osaka, Japan. 6. Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Osaka, Japan. 7. Department of Oral and Molecular Microbiology, Osaka University Graduate School of Dentistry, Osaka, Japan. 8. Thailand-Japan Research Collaboration Center on Emerging and Re-emerging Infections, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan. 9. Laboratory of System Immunology, Immunology Frontier Research Center, Osaka, Japan; Department of Genome Informatics, Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan. 10. Laboratory of Immune Regulation, Immunology Frontier Research Center, Osaka, Japan. Electronic address: kikutani@biken.osaka-u.ac.jp.
Abstract
BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is characterized by eosinophilic inflammation and polyposis at the nose and paranasal sinus and a high concentration of IgE in nasal polyps (NPs). The causative antigen and pathogenesis of CRSwNP remain unknown. OBJECTIVE: We aimed to identify reactive allergens of IgE antibodies produced locally in NPs of patients with CRSwNP. We also attempted to unravel the differentiation pathway of IgE-producing B cells in NPs. METHODS: IgE reactivity of patients with CRSwNP was investigated by characterizing single cell-derived mAbs. T-cell response against identified allergens was investigated in vitro. NP-infiltrating lymphocytes were characterized by using flow cytometry. Immunoglobulins expressed in NPs were analyzed by using high-throughput DNA sequencing for immunoglobulin. RESULTS: About 20% of isolated IgE antibodies derived from NP-residing plasmablasts specifically recognized surface determinants of nasal bacteria, such as Staphylococcus aureus, Streptococcus pyogenes, and Haemophilus influenzae. A TH2 response against S pyogenes was observed in patients with CRSwNP. Flow cytometric analysis revealed sizable germinal center B-like cell and plasmablast subsets expressing IgE on the cell surface in NPs. High-throughput DNA sequencing immunoglobulin analysis highlighted the clonal connectivity of IgE with IgG and IgA1. The Iε-Cα1 circle transcript was detected in NPs. CONCLUSIONS: In patients with CRSwNP, nasal bacteria-reactive B cells differentiate into IgE-producing B cells through IgG/IgA1-IgE class switching, suggesting that allergic conversion of the mucosal response against nasal bacteria underlies disease pathogenesis.
BACKGROUND:Chronic rhinosinusitis with nasal polyposis (CRSwNP) is characterized by eosinophilic inflammation and polyposis at the nose and paranasal sinus and a high concentration of IgE in nasal polyps (NPs). The causative antigen and pathogenesis of CRSwNP remain unknown. OBJECTIVE: We aimed to identify reactive allergens of IgE antibodies produced locally in NPs of patients with CRSwNP. We also attempted to unravel the differentiation pathway of IgE-producing B cells in NPs. METHODS: IgE reactivity of patients with CRSwNP was investigated by characterizing single cell-derived mAbs. T-cell response against identified allergens was investigated in vitro. NP-infiltrating lymphocytes were characterized by using flow cytometry. Immunoglobulins expressed in NPs were analyzed by using high-throughput DNA sequencing for immunoglobulin. RESULTS: About 20% of isolated IgE antibodies derived from NP-residing plasmablasts specifically recognized surface determinants of nasal bacteria, such as Staphylococcus aureus, Streptococcus pyogenes, and Haemophilus influenzae. A TH2 response against S pyogenes was observed in patients with CRSwNP. Flow cytometric analysis revealed sizable germinal center B-like cell and plasmablast subsets expressing IgE on the cell surface in NPs. High-throughput DNA sequencing immunoglobulin analysis highlighted the clonal connectivity of IgE with IgG and IgA1. The Iε-Cα1 circle transcript was detected in NPs. CONCLUSIONS: In patients with CRSwNP, nasal bacteria-reactive B cells differentiate into IgE-producing B cells through IgG/IgA1-IgE class switching, suggesting that allergic conversion of the mucosal response against nasal bacteria underlies disease pathogenesis.
Authors: Kathleen M Buchheit; Daniel F Dwyer; Jose Ordovas-Montanes; Howard R Katz; Erin Lewis; Marko Vukovic; Juying Lai; Lora G Bankova; Neil Bhattacharyya; Alex K Shalek; Nora A Barrett; Joshua A Boyce; Tanya M Laidlaw Journal: J Allergy Clin Immunol Date: 2020-03-19 Impact factor: 10.793
Authors: William Eschenbacher; Matthew Straesser; Alice Knoeddler; Rung-Chi Li; Larry Borish Journal: Immunol Allergy Clin North Am Date: 2020-09-09 Impact factor: 3.479