Elucidation of the pathogenesis of exacerbation of asthma associated with rhinovirus infection and its control

• Project/Area Number: 18K08153
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Saitama Medical University
• Principal Investigator: Nakagome Kazuyuki 埼玉医科大学, 医学部, 准教授 (60401113)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 喘息増悪 / 気管支喘息 / ライノウィルス

Outline of Final Research Achievements

Polymorphism of cadherin-related family member (CDHR) 3 is associated with severe exacerbation of pediatric asthma, and CDHR3 is reported to be the receptor of rhinovirus (RV)-C which causes severe disease among RV. In addition, mutations in the CDHR3 gene lead to increased cell surface expression and increased the capacity of RV-C replication. Therefore, children with CDHR3 polymorphisms may be more susceptible to RV-C infection and severe asthma exacerbations.
This study revealed that CDHR3 directly activates eosinophils and neutrophils. Activation of eosinophils and neutrophils by CDHR3 may therefore be involved in the exacerbation of airway inflammation in asthma exacerbations.

Academic Significance and Societal Importance of the Research Achievements

本研究では、RVの中で重篤病態を引き起こすとされる、RV-Cの受容体であるCDHR3が、好酸球及び好中球を直接活性化することが明らかとなった。ウィルス感染では好中球が重要な役割を果たすが、ウィルス感染を伴う喘息増悪では、好中球だけでなく好酸球の気道への集積がみられる。
今回の研究でCDHR3が好酸球及び好中球を直接活性化させることを明らかにした。活性化好中球は好酸球の遊走を誘導することも以前に報告しており、CDHR3は様々な機序を介して、ウィルス感染時に気道における好酸球性炎症の誘導に関与する可能性が考えられる。これら好酸球活性化機序の解明は喘息増悪の予防および治療戦略の立脚に重要と考えられた。

Research Products

• [Journal Article] Periostin upregulates the effector functions of neutrophils (2023)
  • Author(s): Noguchi T, Nakagome K, Iemura H, Shimizu T, Kobayashi T, Ueda Y, Katayama K, Soma T, Nakamoto H, Nagata M.
  • Journal Title: Allergology International Volume: 72 Issue: 2 Pages: 343-346
  • DOI: 10.1016/j.alit.2022.11.007
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Journal Article] Innate Immune Responses by Respiratory Viruses, Including Rhinovirus, During Asthma Exacerbation. (2022)
  • Author(s): Nakagome K, Nagata M.
  • Journal Title: Front Immunol. Volume: 13 Pages: 865973-865973
  • DOI: 10.3389/fimmu.2022.865973
  • Peer Reviewed / Open Access
• [Journal Article] Treatment Resistance in Severe Asthma Patients With a Combination of High Fraction of Exhaled Nitric Oxide and Low Blood Eosinophil Counts (2022)
  • Author(s): Hoshino Yuki、Soma Tomoyuki、Uchida Yoshitaka、Shiko Yuki、Nakagome Kazuyuki、Nagata Makoto
  • Journal Title: Frontiers in Pharmacology Volume: 13 Pages: 836635-836635
  • DOI: 10.3389/fphar.2022.836635
  • Peer Reviewed / Open Access
• [Journal Article] Allergen Immunotherapy in Asthma (2021)
  • Author(s): Nakagome K, Nagata M.
  • Journal Title: Pathogens Volume: 10 Issue: 11 Pages: 1406-1406
  • DOI: 10.3390/pathogens10111406
  • Peer Reviewed / Open Access
• [Journal Article] Clinical evaluation of rush immunotherapy using house dust mite allergen in Japanese asthmatics. (2021)
  • Author(s): Uchida T, Nakagome K, Iemura H, Naito E, Miyauchi S, Uchida Y, Soma T, Nagata M.
  • Journal Title: Asia Pac Allergy Volume: 11 Issue: 3 Pages: e32-e32
  • DOI: 10.5415/apallergy.2021.11.e32
  • Peer Reviewed / Open Access
• [Journal Article] Japanese cedar pollen upregulates the effector functions of eosinophils. (2021)
  • Author(s): Miyauchi S, Nakagome K, Noguchi T, Kobayashi T, Ueda Y, Soma T, Nagata M.
  • Journal Title: Asia Pac Allergy Volume: 11 Issue: 3 Pages: e26-e26
  • DOI: 10.5415/apallergy.2021.11.e26
  • Peer Reviewed / Open Access
• [Journal Article] The proton ATPase inhibitor bafilomycin A 1 reduces the release of rhinovirus C and cytokines from primary cultures of human nasal epithelial cells. (2021)
  • Author(s): Yamaya M, Deng X, Kikuchi A, Sugawara M, Sato N, Kubo T, Momma H, Kawase T, Nakagome K, Shimotai Y, Nishimura H.
  • Journal Title: Virus Research Volume: 304 Pages: 198548-198548
  • DOI: 10.1016/j.virusres.2021.198548
  • Peer Reviewed
• [Journal Article] Role of allergen immunotherapy in asthma treatment and asthma development. (2021)
  • Author(s): Nakagome K, Nagata M
  • Journal Title: Allergies Volume: 1 Pages: 33-45
  • Peer Reviewed / Open Access
• [Journal Article] Effects of β2-adrenergic agonists on house dust mite-induced adhesion, superoxide anion generation, and degranulation of human eosinophils. (2021)
  • Author(s): Ueda Y, Nakagome K, Kobayashi T, Noguchi T, Soma T, Ohashi-Doi K, Tokuyama K, Nagata M.
  • Journal Title: Asia Pac Allergy. Volume: 10 Issue: 2 Pages: e15-e15
  • DOI: 10.5415/apallergy.2020.10.e15
  • Peer Reviewed / Open Access
• [Journal Article] Cadherin-related Family Member 3 Upregulates the Effector Functions of Eosinophils (2020)
  • Author(s): Nakagome K, Shimizu T, Bochkov YA, Noguchi T, Kobayashi T, Soma T, Ueki S, Gern JE, Nagata M.
  • Journal Title: Allergy Volume: － Issue: 7 Pages: 1805-1809
  • DOI: 10.1111/all.14229
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Possible Mechanisms of Eosinophil Accumulation in Eosinophilic Pneumonia (2020)
  • Author(s): Nakagome K, Nagata M.
  • Journal Title: Biomolecules Volume: 10 Issue: 4 Pages: 638-638
  • DOI: 10.3390/biom10040638
  • NAID: 40022709989
  • Peer Reviewed / Open Access
• [Journal Article] Eicosanoids seasonally impact pulmonary function in asthmatic patients with Japanese cedar pollinosis (2020)
  • Author(s): Soma T, Uchida Y, Nakagome K, Hoshi R, Nagata M.
  • Journal Title: Allergology International Volume: 69 Issue: 4 Pages: 594-600
  • DOI: 10.1016/j.alit.2020.04.014
  • NAID: 130007926228
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Journal Article] Relationship between airway inflammation and airflow limitation in elderly asthmatics (2020)
  • Author(s): Soma T, Uchida Y, Hoshino Y, Katayama K, Kobayashi T, Nakagome K, Nagata M.
  • Journal Title: Asia Pac Allergy. Volume: 10 Issue: 2 Pages: e17-e17
  • DOI: 10.5415/apallergy.2020.10.e17
  • Peer Reviewed / Open Access
• [Journal Article] Mechanisms of eosinophilic inflammation. (2020)
  • Author(s): Nagata M, Nakagome K, Soma T.
  • Journal Title: Asia Pac Allergy. Volume: 10 Issue: 2 Pages: e14-e14
  • DOI: 10.5415/apallergy.2020.10.e14
  • Peer Reviewed / Open Access
• [Journal Article] Modified eosinophil adhesion in pulmonary alveolar proteinosis caused by <i>CSF2RA</i> deletion (2019)
  • Author(s): Uchida Y, Nakagome K, Tazawa R, Akasaka K, Ito M, Haga Y, Komiyama KI, Soma T, Nakata K, Nagata M.
  • Journal Title: Allergology International Volume: 68 Issue: Supplement.1 Pages: S14-S16
  • DOI: 10.1016/j.alit.2019.05.015
  • NAID: 130007709733
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comparison of extra-fine-particle inhalational corticosteroid add-on therapy with dose-escalation of large-particle inhalational corticosteroid therapy in patients with incompletely controlled asthma (2019)
  • Author(s): Kobayashi T, Soma T, Nakagome K, Nakamoto H, Nagata M.
  • Journal Title: Allergology International Volume: 68 Issue: Supplement.1 Pages: S17-S19
  • DOI: 10.1016/j.alit.2019.05.008
  • NAID: 130007709727
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Journal Article] Implications of prostaglandin D2 and leukotrienes in exhaled breath condensates of asthma. (2019)
  • Author(s): Uchida Y, Soma T, Nakagome K, Kobayashi T, Nagata M.
  • Journal Title: Ann Allergy Asthma Immunol. Volume: in press Issue: 1 Pages: 81-88
  • DOI: 10.1016/j.anai.2019.04.008
  • Peer Reviewed
• [Journal Article] Predictors of adherence to sublingual immunotherapy for Japanese cedar pollinosis: a prospective analysis. (2019)
  • Author(s): Kikkawa S, Kamijo A, Nakagome K, Soma T, Kobayashi T, Uchida Y, Kase Y, Nagata M.
  • Journal Title: Asian Pac J Allergy Immunol. Volume: －
  • DOI: 10.12932/ap-200219-0499
  • Peer Reviewed
• [Journal Article] Sublingual Immunotherapy for Japanese Cedar Pollinosis Attenuates Asthma Exacerbation. (2019)
  • Author(s): Kikkawa S, Nakagome K, Kobayashi T, Soma T, Kamijo A, Nagata M.
  • Journal Title: Allergy Asthma Immunol Res. Volume: 11 Issue: 3 Pages: 438-440
  • DOI: 10.4168/aair.2019.11.3.438
  • Peer Reviewed
• [Journal Article] Dermatophagoides farinae Upregulates the Effector Functions of Eosinophils through αMβ2-Integrin and Protease-Activated Receptor-2. (2019)
  • Author(s): Ueda Y, Nakagome K, Kobayashi T, Noguchi T, Soma T, Ohashi-Doi K, Tokuyama K, Nagata M.
  • Journal Title: Int Arch Allergy Immunol. 2019 Jan 10:1-12. Volume: 10 Issue: 4 Pages: 1-12
  • DOI: 10.1159/000495008
  • Peer Reviewed
• [Journal Article] Elevated Periostin Concentrations in the Bronchoalveolar Lavage Fluid of Patients with Eosinophilic Pneumonia. (2019)
  • Author(s): Nakagome K, Nakamura Y, Kobayashi T, Ohta S, Ono J, Kobayashi K, Ikebuchi K, Noguchi T, Soma T, Yamauchi K, Izuhara K, Nagata M.
  • Journal Title: Int Arch Allergy Immunol. Volume: 178 Issue: 3 Pages: 264-271
  • DOI: 10.1159/000494623
  • Peer Reviewed
• [Journal Article] Involvement and Possible Role of Eosinophils in Asthma Exacerbation. (2018)
  • Author(s): Nakagome K, Nagata M.
  • Journal Title: Front Immunol. Volume: 9 Pages: 2220-2220
  • DOI: 10.3389/fimmu.2018.02220
  • Peer Reviewed / Open Access
• [Journal Article] Effects of β2-adrenergic agonists on periostin-induced adhesion, superoxide anion generation, and degranulation of human eosinophils (2018)
  • Author(s): Noguchi T, Nakagome K, Kobayashi T, Ueda Y, Soma T, Nakamoto H, Nagata M
  • Journal Title: Allergology International Volume: 67 Issue: Supplement.1 Pages: S48-S50
  • DOI: 10.1016/j.alit.2018.04.007
  • NAID: 130007485501
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Journal Article] Implication of fraction of exhaled nitric oxide and blood eosinophil count in severe asthma (2018)
  • Author(s): Soma T, Iemura H, Naito E, Miyauchi S, Uchida Y, Nakagome K, Nagata M.
  • Journal Title: Allergology International Volume: 67 Issue: Supplement.1 Pages: S3-S11
  • DOI: 10.1016/j.alit.2018.04.003
  • NAID: 130007485255
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Presentation] Anti-IgE Ab treatment attenuates OVA-Ag-induced neutrophilic airway inflammation and IL-17 production in the lungs. (2022)
  • Author(s): Nakagome K, Imamura M, Kawano M, Kawahata K, Takagi R, Harada H, Dohi M, Matsushita S, Nagata M
  • Organizer: 第51回日本免疫学会学術集会 ワークショップ
• [Presentation] 抗IgE抗体は、肺におけるIL-17産生を制御することで、OVA惹起好中球性気道炎症を抑制する. (2022)
  • Author(s): 中込一之, 今村充, 川野雅章, 川畑仁人, 高木理英, 原田広顕, 土肥眞, 松下祥, 永田真.
  • Organizer: 第71回日本アレルギー学会学術大会 ミニシンポジウム.
• [Presentation] 抗IgE抗体のマウスOVA惹起性中球性気道炎症モデルに対する効果. (2022)
  • Author(s): 中込一之, 今村充, 川野雅章, 川畑仁人, 高木理英, 原田広顕, 土肥眞, 松下祥, 永田真.
  • Organizer: 第62回日本呼吸器学会学術講演会.
• [Presentation] アレルゲン感作と One airway One disease. (2022)
  • Author(s): 中込一之、永田真.
  • Organizer: 第3回日本喘息学会総会学術大会 シンポジウム
• [Presentation] 標的外アレルゲンへの効果の可能性. (2022)
  • Author(s): 中込一之, 杣知行, 永田真.
  • Organizer: 第71回日本アレルギー学会学術大会 シンポジウム
• [Presentation] ウイルス感染と気管支喘息 (2021)
  • Author(s): 中込 一之、永田 真
  • Organizer: 第61回日本呼吸器学会学術講演会
  • Invited
• [Presentation] 好酸球 (2021)
  • Author(s): 中込 一之、永田 真
  • Organizer: 第2回日本喘息学会総会学術大会
  • Invited
• [Presentation] 感染関連分子による炎症細胞反応の修飾. (2021)
  • Author(s): 中込 一之、杣 知行、永田 真
  • Organizer: 第70回日本アレルギー学会学術大会.
  • Invited
• [Presentation] 気管支喘息の免疫療法 (2021)
  • Author(s): 中込 一之, 杣 知行, 永田 真.
  • Organizer: 第70回日本アレルギー学会学術大会.
  • Invited
• [Presentation] 免疫療法・喘息 (2021)
  • Author(s): 中込 一之
  • Organizer: 第7回総合アレルギー講習会
  • Invited
• [Presentation] Cadherin related family member 3は好中球のエフェクター機能を活性化させる. (2021)
  • Author(s): 清水 寿顕, 中込 一之, 植田 穣, 小林 威仁, 杣 知行, 原田 広顕, 藤尾 圭志, 永田 真
  • Organizer: 第61回日本呼吸器学会学術講演会
• [Presentation] Cadherin related family member 3の好中球への作用 (2021)
  • Author(s): 清水 寿顕, 中込 一之, 植田 穣, 小林 威仁, 杣 知行, 原田 広顕, 藤尾 圭志, 永田 真
  • Organizer: 第70回日本アレルギー学会学術大会.
• [Presentation] 好酸球性疾患の病態を考える (2020)
  • Author(s): 中込 一之、永田 真.
  • Organizer: 第3回日本アレルギー学会関東地方会
  • Invited
• [Presentation] 重症喘息におけるType2炎症 (2020)
  • Author(s): 中込 一之
  • Organizer: 第14回相模原臨床アレルギーセミナー
  • Invited
• [Presentation] アレルゲン免疫療法の進歩. (2020)
  • Author(s): 中込 一之、永田 真.
  • Organizer: JSA/WAO XXVII World Allergy Congress (WAC 2020) conjoint with the APAPARI 2020 Congress
  • Invited
• [Presentation] Transfection with Cadherin-related Family Member 3 Variant Increases Eosinophil Adhesion to Transfected Cells and Superoxide Anion Generation (2020)
  • Author(s): Kazuyuki Nakagome, Toshiaki Shimizu, Yury A. Bochkov, Toru Noguchi, Takehito Kobayashi, Tomoyuki Soma, James E. Gern, and Makoto Nagata.
  • Organizer: 2020 AAAAI Annual Meeting
  • Int'l Joint Research
• [Presentation] アレルゲン皮下注射免疫療法の末梢血単核球サイトカイン産生能におよぼす効果. (2020)
  • Author(s): 中込 一之, 関谷 龍, 杣 知行, 永田 真.
  • Organizer: 第117回日本内科学会総会・講演会
• [Presentation] 好酸球エフェクター機能におよぼすcadherin-related family member 3の作用. (2020)
  • Author(s): 中込 一之, 野口 哲, 小林 威仁, 杣 知行, 永田 真.
  • Organizer: 第117回日本内科学会総会・講演会
• [Presentation] Effect of cadherin-related family member 3 on the effector functions of eosinophils. (2020)
  • Author(s): Kazuyuki Nakagome, Toshiaki Shimizu, Yury A. Bochkov, Toru Noguchi, Takehito Kobayashi, Tomoyuki Soma, James E. Gern, and Makoto Nagata.
  • Organizer: JSA/WAO XXVII World Allergy Congress (WAC 2020) conjoint with the APAPARI 2020 Congress
  • Int'l Joint Research
• [Presentation] Cadherin-related family member 3 は、好酸球のエフェクター機能を活性化する (2020)
  • Author(s): 中込 一之、清水 寿顕、野口 哲、小林 威仁、杣 知行、永田 真.
  • Organizer: アレルギー・好酸球研究会2020
• [Presentation] Transfection with cadherin-related family member 3 variant increases adhesion to transfected cells and superoxide anion generation of eosinophils (2020)
  • Author(s): Kazuyuki Nakagome, Toshiaki Shimizu, Yury A. Bochkov, Toru Noguchi, Takehito Kobayashi, Tomoyuki Soma, James E. Gern, and Makoto Nagata
  • Organizer: XXIX World Congress of Asthma.
  • Int'l Joint Research
• [Presentation] 喘息治療でのアレルゲン免疫療法の効果とその実際 (2019)
  • Author(s): 中込 一之, 杣 知行, 永田 真
  • Organizer: 第1回日本アレルギー学会関東地方会
  • Invited
• [Presentation] 重症喘息におけるIgEの役割 (2019)
  • Author(s): 中込 一之, 永田 真
  • Organizer: 第2回日本アレルギー学会関東地方会
  • Invited
• [Presentation] 喘息 (2019)
  • Author(s): 中込 一之, 永田 真
  • Organizer: 第6回総合アレルギー講習会
  • Invited
• [Presentation] Cadherin-related family member 3の変異遺伝子のtransfectionは,好酸球接着能及び活性酸素産生を増強させる (2019)
  • Author(s): 中込 一之, 清水 寿顕, 野口 哲, 小林 威仁, 杣 知行, 永田 真
  • Organizer: 第59回日本呼吸器学会学術講演会 ミニシンポジウム
• [Presentation] 好酸球性炎症の疾患局所におけるペリオスチンの発現と意義について (2019)
  • Author(s): 中込 一之, 中村 豊, 小林 威仁, 太田 昭一郎, 小野 純也, 野口 哲, 杣 知行, 山内 広平, 出原 賢治, 永田 真
  • Organizer: 第116回日本内科学会総会
• [Presentation] Cadherin-related family member 3 upregulates the effector functions of eosinophils. (2019)
  • Author(s): Kazuyuki Nakagome, Toshiaki Shimizu, Yury A. Bochkov, Toru Noguchi, Takehito Kobayashi, Tomoyuki Soma, James E. Gern, and Makoto Nagata
  • Organizer: EAACI 2019
  • Int'l Joint Research
• [Presentation] Cadherin-related family member 3変異遺伝子の好酸球接着能及び活性酸素産生に対する影響 (2019)
  • Author(s): 中込 一之, 清水 寿顕, 野口 哲, 小林 威仁, 杣 知行, 永田 真.
  • Organizer: 第68回日本アレルギー学会学術大会.
• [Presentation] Effect of cadherin-related family member 3 on eosinophil adhesion (2019)
  • Author(s): Kazuyuki Nakagome, Toshiaki Shimizu, Toru Noguchi, Takehito Kobayashi, Tomoyuki Soma, and Makoto Nagata.
  • Organizer: XXIIIV World Congress of Asthma
  • Int'l Joint Research
• [Presentation] Transfection with cadherin-related family member 3 variant increases eosinophil adhesion to transfected cells and superoxide anion generation. (2019)
  • Author(s): Kazuyuki Nakagome, Yury A. Bochkov, Tomoyuki Soma, James E. Gern and Makoto Nagata.
  • Organizer: 第48回日本免疫学会学術集会ワークショップ
• [Presentation] 重症喘息治療とIgE (2018)
  • Author(s): 中込 一之
  • Organizer: 第58回日本呼吸器学会学術講演会ランチョンセミナー
  • Invited
• [Presentation] 埼玉医科大学アレルギーセンターにおける“チーム・アップ”. (2018)
  • Author(s): 中込 一之, 杣 知行, 中村 晃一郎, 上條 篤, 加瀬 康弘, 徳山 研一, 松下 祥, 永田 真.
  • Organizer: 第67回日本アレルギー学会学術大会シンポジウム
  • Invited
• [Presentation] Cadherin-related family member 3は、好酸球のエフェクター機能を活性化する. (2018)
  • Author(s): 中込 一之, 野口 哲, 小林 威仁, 杣 知行, 永田 真.
  • Organizer: 第58回日本呼吸器学会学術講演会学術部会賞選考講演会.
  • Invited
• [Presentation] Cadherin-related family member 3は, αMβ2 integrinを介して,好酸球のエフェクター機能を活性化する (2018)
  • Author(s): 中込 一之, 野口 哲, 小林 威仁, 杣 知行, 永田 真.
  • Organizer: 第67回日本アレルギー学会学術大会ミニシンポジウム
• [Presentation] Cadherin-related family member 3 upregulates the effector functions of eosinophil. (2018)
  • Author(s): Kazuyuki Nakagome, Yury A. Bochkov, Tomoyuki Soma, James E. Gern and Makoto Nagata.
  • Organizer: 第47回日本免疫学会学術集会ワークショップ.
• [Presentation] Elevated periostin concentrations in the bronchoalveolar lavage fluid of eosinophilic pneumonia. (2018)
  • Author(s): Kazuyuki Nakagome, Yutaka Nakamura, Takehito Kobayashi, Shoichiro Ohta, Junya Ono, Kiyoko Kobayashi, Kenji Ikebuchi, Toru Noguchi, Tomoyuki Soma, Kohei Yamauchi, Kenji Izuhara, Makoto Nagata.
  • Organizer: ATS Conference 2018
  • Int'l Joint Research