The role of type 2 innate lymphoid cells in the pulmonary arterial hypertension

• Project/Area Number: 17K09965
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Tohoku Medical and Pharmaceutical University (2018-2021); Tohoku University (2017)
• Principal Investigator: Shirota Yuko 東北医科薬科大学, 医学部, 准教授 (20455819)
• Co-Investigator(Kenkyū-buntansha): 石井 智徳 東北大学, 大学病院, 特任教授 (10282138) ; 藤井 博司 東北大学, 医学系研究科, 准教授 (30531321) ; 藤原 亨 東北大学, 大学病院, 講師 (60333796)
• Project Period (FY): 2017-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 肺動脈性肺高血圧症 / 転写因子GATA2 / 2型自然リンパ球 / 転写因子GATA3

Outline of Final Research Achievements

The transcription factor GATA2 is essential for the development of vascular endothelial cells and hematopoietic cells differentiation, and about 10% of patients with GATA2 deficiency develop pulmonary arterial hypertension (PAH), but the details are unknown. We investigated the mechanism of pulmonary arterial hypertension (PAH) induced by GATA2 mutation and the involvement of type 2 innate lymphocytes (ILC2).GATA2-KO mice were kept in a hypoxic environment to induce PAH, and GATA2-KO mice showed significant pulmonary artery remodeling and significant GATA3 expression in the spleen compared to control mice. GATA3 is essential for ILC2 differentiation and maintenance, but the low number of ILC2 cells made it difficult to investigate in details. In GATA2-GFP knock-in mice, GATA-2 was significantly expressed in pulmonary arterioles.
GATA2-KO mice showed pulmonary arteriolar remodeling, suggesting that it may be a factor in the pathogenesis of PAH.

Academic Significance and Societal Importance of the Research Achievements

転写因子GATA1は，造血系の発生・維持や，血管内皮西郷の性質維持に重要であることが知られている．ヒトGATA2欠損症において，肺高血圧症(PH)を認める症例があるが，その詳細は不明である．今回の研究では，GATA2欠損マウスにおけるPH発症機序を明らかにすることを目的とした．GATA2欠損マウスでは，肺細動脈のリモデリングが起きやすいことを確認し,これがPH発症の要因となる可能性を示唆した．さらに,　GATA2欠損マウスでは，GATA3 の発現が上昇していた．GATA3はILC2分化と維持に不可欠であり，ILC2とPH発症の関連についても検討したが，ILC2細胞数が少なく検討に難渋した．

Research Products

• [Journal Article] Clinical efficacy of belimumab in patients with systemic lupus erythematosus and headache. A report of two cases. (2022)
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  • Journal Title: Mod Rheumatol Case Rep. Volume: 6 Issue: 1 Pages: 25-28
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• [Journal Article] Decrease of infectious complications in outpatients with autoimmune diseases from 2019 to 2020 under the COVID-19 pandemic: A single-centre, retrospective cohort study in Japan. (2022)
  • Author(s): Oka Y, Kodera T, Takeshita M, Shirota Y, Takeda T, Tsutsumi T, Kameoka J.
  • Journal Title: Mod Rheumatol． Volume: 32 Issue: 2 Pages: 444-451
  • DOI: 10.1093/mr/roab080
  • Peer Reviewed
• [Journal Article] 転写因子GATA2 の遺伝子変異に伴う免疫不全症． (2021)
  • Author(s): 高井淳、城田祐子、森口尚．
  • Journal Title: 血液内科 Volume: 82 Pages: 642-642
• [Journal Article] Two cases of rheumatoid arthritis complicated by organising pneumonia successfully treated with tofacitinib therapy. (2021)
  • Author(s): Kodera T, Tsutsumi T, Oka Y, Takeda T, Shirota Y, Kameoka J.
  • Journal Title: Mod Rheumatol Case Rep. Volume: 5 Issue: 2 Pages: 218-225
  • DOI: 10.1080/24725625.2021.1899372
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• [Journal Article] A rare case of sporadic inclusion body myositis and rheumatoid arthritis exhibiting ectopic lymphoid follicle-like structures: a case report and literature review. (2021)
  • Author(s): Konomatsu K, Izumi R, Suzuki N, Takai Y, Shirota Y, Saito R, Kuroda H, Aoki M.
  • Journal Title: Neuromuscul Disord. Volume: 31 Issue: 9 Pages: 870-876
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• [Journal Article] Non-immunoglobulin G4-related multifocal fibrosclerosis presenting generalized morphea-like skin lesions. (2021)
  • Author(s): Chiba T, Mizuashi M, Tamabuchi E, Kanbayashi Y, Shirota Y, Fujii H, Yamasaki K, Aiba S.
  • Journal Title: J Dermatol. Volume: 48 Issue: 6 Pages: 271-272
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• [Journal Article] Successful Treatment of Pulmonary Arterial Hypertension in Systemic Sclerosis with Anticentriole Antibody. (2020)
  • Author(s): Ishii Y, Fujii H, Sugimura K, Shirai T, Hoshi Y, Fujita Y, Shirota Y, Ishii T, Shimokawa H, Harigae H.
  • Journal Title: Case Rep Rheumatol. Volume: 2020 Pages: 1-7
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• [Journal Article] Identification of two major autoantigens negatively regulating endothelial activation in Takayasu arteritis. (2020)
  • Author(s): Mutoh T, Shirai T, Ishii T, Shirota Y, Fujishima F, Takahashi F, Kakuta Y, Kanazawa Y, Masamune A, Saiki Y, Harigae H, Fujii H.
  • Journal Title: Nat Commun. Volume: 11(1) Issue: 1 Pages: 1-13
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• [Journal Article] Refractory Takayasu arteritis successfully treated with rituximab: case-based review. (2019)
  • Author(s): Mutoh T, Ishii T, Shirai T, Akita K, Kamogawa Y, Fujita Y, Sato H, Shirota Y, Fujii H, Harigae H.
  • Journal Title: Rheumatol Int. Volume: 39(11) Issue: 11 Pages: 1989-1994
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• [Journal Article] Delayed lupus nephritis in the course of systemic lupus erythematosus is associated with a poorer treatment response: a multicentre, retrospective cohort study in Japan. (2019)
  • Author(s): Nakano M, Kubo K, Shirota Y, Iwasaki Y, Takahashi Y, Igari T, Inaba Y, Takeshima Y, Tateishi S, Yamashita H, Miyazaki M, Sato H, Kanda H, Kaneko H, Ishii T, Fujio K, Tanaka N, Mimori A.
  • Journal Title: Lupus Volume: 28(9) Issue: 9 Pages: 1062-1073
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• [Journal Article] Four distinct clinical phenotypes of vasculitis affecting medium-sized arteries. (2019)
  • Author(s): Shirai T, Shirota Y, Fujii H, Ishii T, Harigae H.
  • Journal Title: Scand J Rheumatol Volume: 48 Issue: 4 Pages: 1-7
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• [Journal Article] Takayasu Arteritis Coexisting with Sclerosing Osteomyelitis (2018)
  • Author(s): Shirai T, Hanaoka R, Goto Y, Kojima I, Ishii Y, Hoshi Y, Fujita Y, Shirota Y, Fujii H, Ishii T, Harigae H.
  • Journal Title: Internal Medicine Volume: 57 Issue: 13 Pages: 1929-1934
  • DOI: 10.2169/internalmedicine.0329-17
  • NAID: 130007387190
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2018-07-01
  • Peer Reviewed / Open Access
• [Journal Article] Nasal Septal Perforation in Propylthiouracil-Induced Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis. (2018)
  • Author(s): Ishii Y, Shirai T, Hoshi Y, Fujita Y, Shirota Y, Fujii H, Ishii T, Harigae H.
  • Journal Title: Case Rep Rheumatol. Volume: 2018 Pages: 4-4
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  • Peer Reviewed
• [Journal Article] Multicenter double-blind randomized controlled trial to evaluate the effectiveness and safety of bortezomib as a treatment for refractory systemic lupus erythematosus. (2018)
  • Author(s): Ishii T, Tanaka Y, Kawakami A, Saito K, Ichinose K, Fujii H, Shirota Y, Shirai T, Fujita Y, Watanabe R, Chiu SW, Yamaguchi T, Harigae H.
  • Journal Title: Modern Rheumatology Volume: - Issue: 6 Pages: 1-7
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• [Journal Article] Bortezomib treatment induces a higher mortality rate in lupus model mice with a higher disease activity. (2017)
  • Author(s): Ikeda T, Fujii H, Nose M, Kamogawa Y, Shirai T, Shirota Y, Ishii T, Harigae H.
  • Journal Title: Arthritis Research & Therapy Volume: 19（1） Issue: 1 Pages: 187-187
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  • Peer Reviewed / Open Access
• [Journal Article] Relapsing Polychondritis Complicated by Myelodysplastic Syndrome Is Resistant to Immunosuppression: Comment on the Article by Dion et al. (2017)
  • Author(s): Shirai T, Fujii H, Saito R, Nasu K, Kamogawa Y, Fukuhara N, Fujita Y, Shirota Y, Ishii T, Harigae H.
  • Journal Title: Arthritis & Rheumatology Volume: 69 Issue: 3 Pages: 682-683
  • DOI: 10.1002/art.39969
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] ニンテダニブ投与後に肺高血圧症による呼吸不全が増悪した全身性強皮症・間質性肺炎の一例． (2022)
  • Author(s): 日渡早紀，城田祐子，武田朋樹，堤智美，岡友美子，小寺隆雄，亀岡淳一．
  • Organizer: 第31回 日本リウマチ学会，北海道・東北支部学術集会．
• [Presentation] COVID-19 mRNAワクチン接種後に急性肝炎をきたした抗RNP抗体陽性の一例． (2022)
  • Author(s): 石川理紗，小寺隆雄，武田朋樹，堤智美，岡友美子，城田祐子，亀岡淳一．
  • Organizer: 第31回 日本リウマチ学会，北海道・東北支部学術集会．
• [Presentation] ウパダシチニブへの他のJAK阻害薬からの切り替えについて． (2022)
  • Author(s): 小寺隆雄，武田朋樹，堤智美，岡友美子，城田祐子，亀岡淳一．
  • Organizer: 第31回 日本リウマチ学会，北海道・東北支部学術集会．
• [Presentation] COVID-19による生活様式の変化の前後，2019年と2020年の当院リウマチ膠原病外来患者の感染症の状況について． (2021)
  • Author(s): 岡友美子，堤智美，武田朋樹，城田祐子，小寺隆雄，亀岡淳一.
  • Organizer: 日本リウマチ学会総会，学術集会．2021 東京
• [Presentation] 膠原病性肺動脈性肺高血圧症における各種自己抗体別にみた長期予後の違いについての検討. (2019)
  • Author(s): 城田祐子 , 白井剛志, 藤井博司, 小寺隆雄, 亀岡淳一, 石井智徳, 張替秀郎
  • Organizer: 第63回 日本リウマチ学会学術集会総会.
• [Presentation] 日本人関節リウマチ患者におけるステロイド投与の安全性について (2019)
  • Author(s): 小寺隆雄, 武田朋樹, 堤智美, 岡友美子, 城田祐子, 竹下美紀, 亀岡淳一
  • Organizer: 第63回 日本リウマチ学会学術集会総会
• [Presentation] 関節リウマチの治療中に全身性エリテマトーデスを合併し, バリシチニブが有効であった1例. (2019)
  • Author(s): 2.佐藤和彦, 城田祐子, 岡友美子, 武田朋樹, 堤智美, 小寺隆雄, 亀岡淳一
  • Organizer: 第29回 日本リウマチ学会 北海道・東北支部学術集会.
• [Presentation] 膠原病性肺動脈性肺高血圧症における予後予測因子と死因について (2018)
  • Author(s): 城田 祐子, 星 陽介,佐藤紘子, 藤田 洋子, 白井 剛志, 藤井 博司, 石井 智徳, 張替 秀郎.
  • Organizer: 第62回日本リウマチ学会総会・学術集会
• [Presentation] Autoantibodies and Clinical outcome in Pulmonary Arterial Hypertension associated with Connective Tissue Diseases. (2018)
  • Author(s): Shirota Y, Shirai T, Fujii H, Ishii T, Harigae H.
  • Organizer: Annual Meeting of American Collage of Rheumatorogy 2018
  • Int'l Joint Research
• [Presentation] Severe atelectasis by complete occlusion of left main bronchus in granulomatosis with polyangiitis. (2018)
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  • Organizer: Annual Meeting of American Collage of Rheumatorogy 2018
  • Int'l Joint Research
• [Presentation] 11C-BF-227-PETによる全身アミロイド計測を試みたアミロイドーシス6症例の検討 (2017)
  • Author(s): 城田祐子、石井悠翔、星陽介、藤田洋子、白井剛志、藤井博司、石井智徳、張替秀郎
  • Organizer: 第61回日本リウマチ学会総会・学術集会
• [Remarks] 東北大学血液・免疫病学分野
  • URL: http://www.rh.med.tohoku.ac.jp/index.html