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Molecular Mechanism of Autoimmune Germinal Center Reaction and a New Therapeutic Strategy for Autoimmunity

Research Project

Project/Area Number 18K19648
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 57:Oral science and related fields
Research InstitutionThe University of Tokushima

Principal Investigator

ISHIMARU Naozumi  徳島大学, 大学院医歯薬学研究部(歯学域), 教授 (60314879)

Co-Investigator(Kenkyū-buntansha) 新垣 理恵子  徳島大学, 大学院医歯薬学研究部(歯学域), 准教授 (00193061)
工藤 保誠  徳島大学, 大学院医歯薬学研究部(歯学域), 准教授 (50314753)
Project Period (FY) 2018-06-29 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2018: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Keywords自己免疫疾患 / 自己抗体 / Tfh細胞 / GC反応 / シェーグレン症候群 / 自己免疫性胚中心反応 / Ascl2 / 疾患モデル / GCB細胞 / 胚中心反応
Outline of Final Research Achievements

Follicular helper T (Tfh) cells are known to contribute to various immune responses as well as to the pathogenesis of several immune diseases. However, the precise mechanism underlying the onset or development of autoimmunity via Tfh cells remains unclear. Here, the detailed relationship between autoimmune disease and Tfh cells was analyzed using a murine model for Sjögren’s syndrome (SS) wherein the mice underwent neonatal thymectomy (Tx). The severity of the autoimmune lesions was correlated with the number of Tfh cells detected in the spleen of the SS model mice. Comprehensive gene analysis revealed that several genes associated with Tfh cell differentiation, including achaete-scute homologue 2 (Ascl2), were upregulated in peripheral CD25- CD4+ T cells in SS model mice compared to those in control mice. In conclusion, our results indicate that abnormal Tfh cell differentiation via Ascl2 regulation might contribute to the pathogenesis of autoimmunity.

Academic Significance and Societal Importance of the Research Achievements

自己免疫疾患は自身の臓器や細胞が免疫反応の標的となる疾患であり、自己と非自己を厳密に区別するはずの免疫システムの適切な機能から明らかに逸脱している。全身どの臓器も標的となり、単一の原因ではなく多因子による発症機序が存在しているため、病態メカニズムは複雑で、自己免疫疾患の診断は困難な場合があり、病因論に基づいた根本的な治療法の開発には至っていないのが現状である。本研究では、自己免疫性胚中心反応という新たな概念を提唱するとともに、その詳細な機構を明らかにし、病態と自己抗体の新たな関係を解明した点で、重要な内容を含む研究であり、今後、臨床応用への可能性が十分示された。

Report

(3 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • Research Products

    (51 results)

All 2020 2019 2018 Other

All Journal Article (15 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 12 results,  Open Access: 8 results) Presentation (31 results) (of which Int'l Joint Research: 5 results,  Invited: 1 results) Book (3 results) Remarks (2 results)

  • [Journal Article] Study of the pharmacokinetics of eriodictyol-6-C-β-d-glucoside, a flavonoid of rooibos (Aspalathus linearis) extract, after its oral administration in mice2020

    • Author(s)
      Yuyama Kanako、Nakamura Yoshitaka、Tateyama Riho、Arakaki Rieko、Tsutsui Takuya、Ishimaru Naozumi
    • Journal Title

      Journal of Chromatography B Analyt Technol Biomed Life Sci.

      Volume: 1137 Pages: 121881-121881

    • DOI

      10.1016/j.jchromb.2019.121881

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Achaete-Scute Homologue 2-Regulated Follicular Helper T Cells Promote Autoimmunity in a Murine Model for Sjogren Syndrome.2019

    • Author(s)
      Otsuka K, Yamada A, Saito M, Ushio A, Sato M, Kisoda S, Shao W, Tsunematsu T, Kudo Y, Arakaki R, Ishimaru N.
    • Journal Title

      Am J Pathol.

      Volume: 189(12) Issue: 12 Pages: 2414-2427

    • DOI

      10.1016/j.ajpath.2019.08.008

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Coordination of WNT signaling and ciliogenesis during odontogenesis by piezo type mechanosensitive ion channel component 1.2019

    • Author(s)
      Miyazaki A, Sugimoto A, Yoshizaki K, Kawarabayashi K, Iwata K, Kurogoushi R, Kitamura T, Otsuka K, Hasegawa T, Akazawa Y, Fukumoto S, Ishimaru N, Iwamoto T.
    • Journal Title

      Sci Rep.

      Volume: 9(1) Issue: 1 Pages: 14762-14762

    • DOI

      10.1038/s41598-019-51381-9

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Involvement of adiponectin in age-related increases in tear production in mice2019

    • Author(s)
      Shikama Yosuke、Kurosawa Mie、Furukawa Masae、Ishimaru Naozumi、Matsushita Kenji
    • Journal Title

      Aging

      Volume: 11 Issue: 19 Pages: 8329-8346

    • DOI

      10.18632/aging.102322

    • NAID

      120007146099

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Novel effects of rooibos extract on tear and saliva secretion mediated by the muscarinic acetylcholine receptor 3 in mice2019

    • Author(s)
      Arakaki Rieko、Ushio Aya、Kisoda Satoru、Sato Mami、Nakamura Yoshitaka、Yuyama Kanako、Tateyama Riho、Morishita Satoru、Monoi Noriyuki、Kudo Yasusei、Ishimaru Naozumi
    • Journal Title

      Journal of Oral Biosciences

      Volume: 61 Issue: 3 Pages: 179-182

    • DOI

      10.1016/j.job.2019.06.001

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A novel method for measuring small amounts of saliva in mice.2019

    • Author(s)
      Arakaki R, Ushio A, Otsuka K, Kudo Y, Ishimaru N
    • Journal Title

      Oral Sci Int

      Volume: 1-3 Issue: 3 Pages: 1-3

    • DOI

      10.1002/osi2.1013

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Constitutive activation of the alternative NF-κB pathway disturbs endochondral ossification.2019

    • Author(s)
      Nakatomi C, Nakatomi M, Matsubara T, Komori T, Doi-Inoue T, Ishimaru N, Weih F, Iwamoto T, Matsuda M, Kokabu S, Jimi E.
    • Journal Title

      Bone

      Volume: 121 Issue: 3 Pages: 29-41

    • DOI

      10.5152/eurjrheum.2019.18137

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] シェーグレン症候群における制御性T細胞2019

    • Author(s)
      石丸直澄、山田安希子
    • Journal Title

      医学のあゆみ

      Volume: 268 Pages: 1241-1245

    • Related Report
      2018 Research-status Report
  • [Journal Article] CCL22-Producing Resident Macrophages Enhance T Cell Response in Sjogren's Syndrome.2018

    • Author(s)
      Ushio A, Arakaki R, Otsuka K, Yamada A, Tsunematsu T, Kudo Y, Aota K, Azuma M, Ishimaru N.
    • Journal Title

      Front Immunol.

      Volume: 9 Pages: 2594-2594

    • DOI

      10.3389/fimmu.2018.02594

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Long-term polarization of alveolar macrophages to a profibrotic phenotype after inhalation exposure to multi-wall carbon nanotubes.2018

    • Author(s)
      Otsuka K, Yamada K, Taquahashi Y, Arakaki R, Ushio A, Saito M, Yamada A, Tsunematsu T, Kudo Y, Kanno J, Ishimaru N.
    • Journal Title

      PLoS One.

      Volume: 13(10) Issue: 10 Pages: 1-18

    • DOI

      10.1371/journal.pone.0205702

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inverse correlation between the number of CXCR3+ macrophages and the severity of inflammatory lesions in Sjogren syndrome salivary glands: A pilot study2018

    • Author(s)
      Aota K, Yamanoi T, Kani K, Nakashiro K, Ishimaru N, Azuma M.
    • Journal Title

      J. Oral Pathology and Medicine

      Volume: 47 Issue: 7 Pages: 710-718

    • DOI

      10.1111/jop.12756

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Invasion-related factors as potential diagnostic and therapeutic targets in oral squamous cell carcinoma.2018

    • Author(s)
      Siriwardena SBSM, Tsunematsu T, Qi G, Ishimaru N, Kudo Y.
    • Journal Title

      Int J Mol Sci

      Volume: 19 Issue: 5 Pages: 1462-1462

    • DOI

      10.3390/ijms19051462

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Distinct Regulation of CXCL10 Production by Cytokines in Human Salivary Gland Ductal and Acinar Cells.2018

    • Author(s)
      Aota K, Kani K, Yamanoi T, Nakashiro KI, Ishimaru N, Azuma M.
    • Journal Title

      Inflammation.

      Volume: - Issue: 4 Pages: 1172-1181

    • DOI

      10.1007/s10753-018-0764-0

    • NAID

      120006581608

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 膠原病の病理―今日的視点から―唾液腺病変2018

    • Author(s)
      石丸直澄
    • Journal Title

      病理と臨床

      Volume: 36 Pages: 580-585

    • Related Report
      2018 Research-status Report
  • [Journal Article] シェーグレン症候群研究の最前線2018

    • Author(s)
      牛尾綾、大塚邦紘、新垣理恵子、工藤保誠、石丸直澄
    • Journal Title

      細胞

      Volume: 50 Pages: 528-531

    • Related Report
      2018 Research-status Report
  • [Presentation] 多層化カーボンナノチューブ吸入暴露初期の肺胞マクロファージの動態2019

    • Author(s)
      新垣理恵子、牛尾綾、大塚邦紘、工藤保誠、石丸直澄
    • Organizer
      第108回日本病理学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] シェーグレン症候群疾患モデルにおける肺病変の解析2019

    • Author(s)
      松倉春奈、牛尾綾、大塚邦紘、新垣理恵子、工藤保誠、石丸直澄
    • Organizer
      第108回日本病理学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] シェーグレン症候群病態形成におけるCCL22産生マクロファージの役割2019

    • Author(s)
      牛尾綾、新垣理恵子、佐藤真美、工藤保誠、石丸直澄
    • Organizer
      第108回日本病理学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Role of IL-33 and its receptor in pathogenesis of Sjogren’s syndrome2019

    • Author(s)
      Rieko Arakaki, Mami Sato, Shinichiro Nakayama, Aya Ushio Yasusei Kudo, Naozumi Ishimaru
    • Organizer
      第48回日本免疫学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Effect of multi-wall carbon nanotube exposure on pulmonary immune cells at the early stage2019

    • Author(s)
      Mami Sato, Rieko Arakaki, Aya Ushio, Yasusei Kudo, Naozumi Ishimaru
    • Organizer
      第48回日本免疫学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Analysis of pulmonary lesions in a murine model of Sjogren’s syndrome2019

    • Author(s)
      Aya Ushio, Mami Sato, Rieko Arakaki, Aya Ushio, Yasusei Kudo, Naozumi Ishimaru
    • Organizer
      第48回日本免疫学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Contributions of CXCL12 and its receptor to the T cell autoimmune response in a Sjogren’s syndrome murine model.2018

    • Author(s)
      Naozumi Ishimaru, Mie Kurosawa, Rieko Arakaki, Aya Ushio, Kunihiro Otsuka, Yasusei Kudo
    • Organizer
      14th International Sjogren’s Syndrome Symposium
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] CCL22-producing resident macrophages enhance autoimmune lesions in a mouse model of Sjogren’s syndrome.2018

    • Author(s)
      Aya Ushio, Rieko Arakaki, Kunihiro Otsuka, Akiko Yamada, Yasusei Kudo, and Naozumi Ishimaru
    • Organizer
      11th International Congress on Autoimmunity
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Analysis of follicular helper T cells in a mouse model for Sjogren’s syndrome.2018

    • Author(s)
      Kunihiro Otsuka, Akiko Yamada, Masako Saito, Satoko Kujiraoka, Aya Ushio, Takaaki Tsunematsu, Rieko Arakaki, Yasusei Kudo, Hidehiro Kishimoto, Naozumi Ishimaru
    • Organizer
      11th International Congress on Autoimmunity
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] NF-κB2 Controls the Migratory Activity of Memory T Cells to the Target Tissues in a Mouse Model of Sjogren’s Syndrome by Regulating Expression of CXCR4.2018

    • Author(s)
      Rieko Arakaki, Mie Kurosawa,,Akiko Yamada, Aya Ushio, Satoko Kujiraoka, Kunihiro Otsuka, Takaaki Tsunematsu, Yasusei Kudo, Jonathan Sprent, and Naozumi Ishimaru
    • Organizer
      11th International Congress on Autoimmunity
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] シェーグレン症候群における自己反応性獲得機序の解明2018

    • Author(s)
      石丸直澄
    • Organizer
      第107回日本病理学会総会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] 全身吸入曝露による多層化カーボンナノチューブの肺胞マクロファージへの影響2018

    • Author(s)
      新垣理恵子、牛尾綾、大塚邦紘、工藤保誠、石丸直澄
    • Organizer
      第107回日本病理学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] シェーグレン症候群モデルマウス唾液腺におけるIL-33の発現とその役割2018

    • Author(s)
      中山慎一朗、新垣理恵子、牛尾綾、大塚邦紘、常松貴明、工藤保誠、石丸直澄
    • Organizer
      第107回日本病理学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] CCL22産生唾液腺マクロファージはシェーグレン症候群の病態形成に関与する2018

    • Author(s)
      牛尾綾、新垣理恵子、大塚邦紘、山田安希子、工藤保誠、石丸直澄
    • Organizer
      第107回日本病理学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] シェーグレン症候群疾患モデルの自己免疫病変における濾胞ヘルパーT細胞の役割2018

    • Author(s)
      大塚邦紘、山田安希子、齋藤雅子、牛尾綾、常松貴明、工藤保誠、新垣理恵子、石丸直澄
    • Organizer
      第107回日本病理学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] シェーグレン症候群モデルにおけるNotchシグナルの役割2018

    • Author(s)
      沼田雪乃、大塚邦紘、山田安希子、牛尾綾、常松貴明、工藤保誠、新垣理恵子、石丸直澄
    • Organizer
      第107回日本病理学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] DNAライセンシング因子CDT1の新規ユビキチン分解制御機構とその意義の解明2018

    • Author(s)
      常松貴明、工藤保誠、新垣理恵子、大塚邦紘、牛尾綾、山田安希子、小川博久、常山幸一、石丸直澄
    • Organizer
      第107回日本病理学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] Emi1の過剰発現による人工口腔癌幹細胞の作成2018

    • Author(s)
      西條早紀、常松貴明、大塚邦紘、牛尾綾、山田安希子、新垣理恵子、工藤保誠、石丸直澄
    • Organizer
      第107回日本病理学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] 口腔癌におけるPeriostinスプライシングバリアントの同定とその役割2018

    • Author(s)
      梅田将旭、常松貴明、大塚邦紘、牛尾綾、山田安希子、新垣理恵子、工藤保誠、石丸直澄
    • Organizer
      第107回日本病理学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] APC/C-Cdh1-mediated degradation of Borealin triggers differentiation of pluripotent stem cells.2018

    • Author(s)
      Tsunematsu T, Ishimaru N, Kudo Y
    • Organizer
      FASEB meeting "Ubiquitin and Cellular Regulation"
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] シェーグレン症候群疾患モデルの自己免疫病変における濾胞ヘルパーT細胞の役割2018

    • Author(s)
      大塚邦紘、山田安希子、牛尾綾、木曽田暁、常松貴明、工藤保誠、新垣理恵子、石丸直澄
    • Organizer
      第17回四国免疫フォーラム
    • Related Report
      2018 Research-status Report
  • [Presentation] シェーグレン症候群疾患モデルの自己免疫病変における濾胞ヘルパーT細胞の役割2018

    • Author(s)
      大塚邦紘、山田安希子、齋藤雅子、牛尾綾、木曽田暁、常松貴明、工藤保誠、新垣理恵子、石丸直澄
    • Organizer
      分子病理学研究会37はがくれシンポジウム
    • Related Report
      2018 Research-status Report
  • [Presentation] Ascl2を介した濾胞ヘルパーT細胞分化異常が自己免疫疾患の病態形成に関与する2018

    • Author(s)
      大塚邦紘, 山田安希子, 牛尾綾, 新垣理恵子, 齋藤雅子, 木曽田暁, 常松貴明, 工藤保誠, 石丸直澄
    • Organizer
      先端歯学スクール2018
    • Related Report
      2018 Research-status Report
  • [Presentation] Ascl2を介した濾胞ヘルパーT細胞分化異常が自己免疫疾患の病態形成に関与する2018

    • Author(s)
      大塚邦紘、山田安希子、齋藤雅子、牛尾綾、木曽田暁、常松貴明、工藤保誠、新垣理恵子、石丸直澄
    • Organizer
      第29回日本臨床口腔病理学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] Ascl2を介した濾胞ヘルパーT細胞分化異常が自己免疫疾患の病態形成に関与する2018

    • Author(s)
      大塚邦紘、山田安希子、齋藤雅子、牛尾綾、木曽田暁、常松貴明、工藤保誠、新垣理恵子、石丸直澄
    • Organizer
      第60回歯科基礎医学会学術大会
    • Related Report
      2018 Research-status Report
  • [Presentation] Ascl2を介した濾胞ヘルパーT細胞分化異常が自己免疫疾患の病態形成に関与する2018

    • Author(s)
      大塚邦紘、山田安希子、齋藤雅子、牛尾綾、木曽田暁、常松貴明、工藤保誠、新垣理恵子、石丸直澄
    • Organizer
      第27回日本シェーグレン症候群学会
    • Related Report
      2018 Research-status Report
  • [Presentation] CCL22産生唾液腺マクロファージはシェーグレン症候群の病態形成に関与する2018

    • Author(s)
      牛尾綾、新垣理恵子、大塚邦紘、山田安希子、工藤保誠、石丸直澄
    • Organizer
      第27回日本シェーグレン症候群学会
    • Related Report
      2018 Research-status Report
  • [Presentation] Impairment of the differentiation into follicular helper T cell through Ascl2 enhances autoimmune lesions in a mouse model for Sjogren's syndrome.2018

    • Author(s)
      Kunihiro Otsuka, Akiko Yamada, Aya Ushio, Rieko Arakaki, Takaaki Tsunematsu, Masako Saito, Yasusei Kudo, Naozumi Ishimaru
    • Organizer
      2018 Tokushima Bioscience Retreat
    • Related Report
      2018 Research-status Report
  • [Presentation] A crucial role of follicular helper T cells in autoimmunity of a mouse model for Sjogren's syndrome.2018

    • Author(s)
      Kunihiro Kunihiro, Akiko Yamada, Masako Saito, Aya Ushio, Takaaki Tsunematsu, Rieko Arakaki, Yasusei Kudo, Naozumi Ishimaru
    • Organizer
      第47回日本免疫学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] CCL22-producing macrophages promote T cell autoimmunity in the target organ of Sjogren's syndrome.2018

    • Author(s)
      Aya Ushio, Rieko Arakaki, Kunihiro Otsuka, Akiko Yamada, Yasusei Kudo, and Naozumi Ishimaru:
    • Organizer
      第47回日本免疫学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] The role of the cleaved form IL-33 in pathogenesis of Sjogren’s syndrome2018

    • Author(s)
      Rieko Arakaki, Shinichiro Nakayama, Aya Ushio, Kunihiro Otsuka, Satoshi Kisoda, Takaaki Tsunematsu, Akiko Yamada, Yasusei Kudo, Naozumi Ishimaru
    • Organizer
      第47回日本免疫学会学術集会
    • Related Report
      2018 Research-status Report
  • [Book] シェーグレン症候群における濾胞ヘルパーT細胞の役割2020

    • Author(s)
      大塚邦紘、石丸直澄
    • Total Pages
      8
    • Publisher
      科学評論社
    • Related Report
      2019 Annual Research Report
  • [Book] CCL22と自己免疫疾患2019

    • Author(s)
      牛尾綾、大塚邦紘、新垣理恵子、工藤保誠、石丸直澄
    • Total Pages
      7
    • Publisher
      科学評論社
    • Related Report
      2019 Annual Research Report
  • [Book] シェーグレン症候群の診断と治療マニュアル 改訂第3版2018

    • Author(s)
      石丸直澄、林良夫(分担)
    • Total Pages
      245
    • Publisher
      診断と治療社
    • ISBN
      9784787823694
    • Related Report
      2018 Research-status Report
  • [Remarks] 徳島大学大学院医歯薬学研究部口腔分子病態学分野ホームページ

    • URL

      https://ishimarun.wixsite.com/oralpathol

    • Related Report
      2019 Annual Research Report
  • [Remarks] 徳島大学大学院口腔分子病態学分野

    • URL

      http://www.tokushima-u.ac.jp/dent/research/sousei_kagaku/oral_medicine/illness_state/

    • Related Report
      2018 Research-status Report

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Published: 2018-07-25   Modified: 2021-02-19  

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