New therapeutic strategy targeting cytotoxic Tfh cells for IgG4-related disease

• Project/Area Number: 18K09323
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56050:Otorhinolaryngology-related
• Research Institution: Sapporo Medical University
• Principal Investigator: Kamekura Ryuta 札幌医科大学, 医学部, 講師 (70404697)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: IgG4関連疾患 / 細胞傷害性Tfh細胞 / Tfh細胞 / IgG4関連涙腺・唾液腺炎 / memory B 細胞 / Tph細胞

Outline of Final Research Achievements

We analyzed CD4+CD8+ Tfh cells and B cell subsets from submandibular glands (SMGs) of patients with IgG4-RD by flow cytometry. The percentage of CD4+CD8+ Tfh cells in IgG4-RD SMGs was increased compared with that in tonsils and was negatively correlated with the percentage of memory B cells in IgG4-RD SMGs. In a coculture experiment with CD4+CD8+ Tfh cells and memory B cells from IgG4-RD SMGs, the amount of IgG produced by memory B cells in the culture supernatant was reduced. In vitro experiments also revealed that CD4+CD8+ Tfh cells have a functional capacity for production of a large amount of granzyme. The results suggest that the number of CD4+CD8+ Tfh cells was increased under the condition of chronic inflammation and that the cells exerted cytotoxity to memory B cells. Therefore, CD4+CD8+ Tfh cells inhibit the production of IgG from memory B cells and regulate immune responses in lesions of IgG4-RD.

Academic Significance and Societal Importance of the Research Achievements

現在のところIgG4-RDの病因は不明である。今回我々はIgG4-RDの病変部位に存在するTfh細胞を直接解析することにより、細胞傷害性Tfh細胞という新しい細胞群を発見することができた。細胞傷害性Tfh細胞の機能的役割の解明はIgG4-RDにとどまらず、その他の難治性慢性炎症性疾患の病態の新たな理解や治療法の臨床応用に向けて、これまでにない展開がもたらされることが期待される。細胞傷害性Tfh細胞を標的にするIgG4-RDの新規治療法が実用化されれば、従来のグルココルチコイドに代わる副作用の少ない治療が可能となり、多くのIgG4-RDの患者がその恩恵を受けることになると確信している。

Research Products

• [Journal Article] Cigarette Smoke Underlies the Pathogenesis of Palmoplantar Pustulosis via an IL-17A-Induced Production of IL-36γ in Tonsillar Epithelial Cells (2021)
  • Author(s): Kobayashi K, Kamekura R, Kato J, Kamiya S, Kamiya T, Takano K, Ichimiya S, Uhara H.
  • Journal Title: J Invest Dermatol. Volume: - Issue: 6 Pages: 32277-6
  • DOI: 10.1016/j.jid.2020.09.028
  • Peer Reviewed / Open Access
• [Journal Article] Cytotoxic Tph-like cells are involved in persistent tissue damage in IgG4-related disease. (2020)
  • Author(s): Yabe H, Kamekura R, Yamamoto M, Murayama K, Kamiya S, Ikegami I, Shigehara K, Takaki H, Chiba H, Takahashi H, Takano K, Takahashi H, Ichimiya S.
  • Journal Title: Mod Rheumatol. Volume: Feb 5 Issue: 1 Pages: 1-12
  • DOI: 10.1080/14397595.2020.1719576
  • Peer Reviewed / Open Access
• [Journal Article] Activated circulating T follicular helper cells and skewing of T follicular helper 2 cells are down-regulated by treatment including an inhaled corticosteroid in patients with allergic asthma (2020)
  • Author(s): Miyajima S, Shigehara K, Kamekura R, Takaki H, Yabe H, Ikegami I, Asai Y, Nishikiori H, Chiba H, Uno E, Takahashi H, Ichimiya S.
  • Journal Title: Allergology International Volume: 69 Issue: 1 Pages: 66-77
  • DOI: 10.1016/j.alit.2019.08.008
  • NAID: 130007788688
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Journal Article] IgG4 関連疾患の免疫病態と治療への展望 (2020)
  • Author(s): 矢部勇人、亀倉隆太、千葉弘文、高野賢一、髙橋裕樹、一宮慎吾
  • Journal Title: リウマチ科 Volume: 64 Pages: 559-566
• [Journal Article] Aberrant populations of circulating T follicular helper cells and regulatory B cells underlying idiopathic pulmonary fibrosis (2019)
  • Author(s): Asai Yuichiro、Chiba Hirofumi、Nishikiori Hirotaka、Kamekura Ryuta、Yabe Hayato、Kondo Shun、Miyajima Satsuki、Shigehara Katsunori、Ichimiya Shingo、Takahashi Hiroki
  • Journal Title: Respiratory Research Volume: 20 Issue: 1 Pages: 244-244
  • DOI: 10.1186/s12931-019-1216-6
  • Peer Reviewed / Open Access
• [Journal Article] Bob1 enhances RORγt-mediated IL-17A expression in Th17 cells through interaction with RORγt. (2019)
  • Author(s): Ikegami I, Takaki H, Kamiya S, Kamekura R, Ichimiya S.
  • Journal Title: Biochem Biophys Res Commun. Volume: 514 Issue: 4 Pages: 1167-1171
  • DOI: 10.1016/j.bbrc.2019.05.057
  • Peer Reviewed
• [Journal Article] New insights into IgG4-related disease - emerging new CD4+ T cell subsets. (2019)
  • Author(s): Kamekura R, Takahashi H, Ichimiya S.
  • Journal Title: Curr Opin Rheumatol. Volume: 31 Issue: 1 Pages: 9-15
  • DOI: 10.1097/bor.0000000000000558
  • Peer Reviewed / Open Access
• [Journal Article] シラカバ花粉IgE陽性の口腔咽頭過敏症における各種花粉とプロフィリン（Bet v 2）感作との関係． (2019)
  • Author(s): 山本哲夫，朝倉光司，白崎英明，亀倉隆太，氷見徹夫．
  • Journal Title: 日耳鼻 Volume: 122 Pages: 209-215
  • NAID: 130007629714
  • Peer Reviewed
• [Journal Article] IL-10+ T follicular regulatory cells are associated with the pathogenesis of IgG4-related disease. (2019)
  • Author(s): Ito F, Kamekura R, Yamamoto M, Takano K, Takaki H, Yabe, H, Ikegami I, Shigehara K, Himi T, Takahashi H, Ichimiya S.
  • Journal Title: Immunol Lett. Volume: 207 Pages: 56-63
  • DOI: 10.1016/j.imlet.2019.01.008
  • Peer Reviewed / Open Access
• [Journal Article] Analysis of allergic reaction in IgG4-related disease. (2019)
  • Author(s): Yamamoto M, Takano KI, Kamekura R Aochi S, Suzuki C, Ichimiya S, Takahashi H.
  • Journal Title: Mod Rheumatol. Volume: Jan 24 Issue: 6 Pages: 1-3
  • DOI: 10.1080/14397595.2019.1572488
  • Peer Reviewed
• [Journal Article] Circulating PD-1+CXCR5-CD4+ T cells underlying the immunological mechanisms of IgG4-related disease. (2018)
  • Author(s): Kamekura R, Yamamoto M, Takano K, Yabe H, Ito F, Ikegami I, Takaki H, Shigehara K, Suzuki C, Himi T, Takahashi H, Ichimiya S.
  • Journal Title: Rheumatol Adv Pract. Volume: 2
  • Peer Reviewed / Open Access
• [Journal Article] Predicting therapeutic response in IgG4-related disease based on cluster analysis. (2018)
  • Author(s): Yamamoto M, Takano K, Kamekura R, Suzuki C, Tabeya T, Murakami R, Honda S, Mukai M, Nojima M, Ichimiya S, Himi T, Nakase H, Takahashi H.
  • Journal Title: Immunological Medicine. Volume: 41 Issue: 1 Pages: 30-33
  • DOI: 10.1080/09114300.2018.1451613
  • Peer Reviewed
• [Journal Article] Interleukin 5-producing ST2+ memory Th2 cells in IgG4-related dacryoadenitis and sialadenitis. (2018)
  • Author(s): Yamamoto M, Takano KI, Kamekura R, Aochi S, Suzuki C, Ichimiya S, Nakase H, Himi T, Takahashi H.
  • Journal Title: Mod Rheumatol. Volume: Oct 25 Issue: 5 Pages: 1-5
  • DOI: 10.1080/14397595.2018.1526357
  • Peer Reviewed
• [Journal Article] Stage classification of IgG4-related dacryoadenitis and sialadenitis by the serum cytokine environment (2018)
  • Author(s): Motohisa Yamamoto, Kenichi Takano, Ryuta Kamekura, Chisako Suzuki, Shingo Ichimiya, Tetsuo Himi, Hiroshi Nakase & Hiroki Takahashi
  • Journal Title: Modern Rheumatology Volume: 印刷中 Issue: 6 Pages: 1-5
  • DOI: 10.1080/14397595.2018.1436029
  • Peer Reviewed
• [Journal Article] Potential utility of core needle biopsy in the diagnosis of IgG4-related dacryoadenitis and sialadenitis (2018)
  • Author(s): Takano Kenichi、Okuni Tsuyoshi、Yamamoto Keisuke、Kamekura Ryuta、Yajima Ryoto、Yamamoto Motohisa、Takahashi Hiroki、Himi Tetsuo
  • Journal Title: Modern Rheumatology Volume: in press Issue: 2 Pages: 1-11
  • DOI: 10.1080/14397595.2018.1465665
  • Peer Reviewed
• [Journal Article] Clinical utility of 18F-fluorodeoxyglucose/positron emission tomography in diagnosis of immunoglobulin G4-related sclerosing sialadenitis (2017)
  • Author(s): Takano Kenichi、Yajima Ryoto、Kamekura Ryuta、Yamamoto Motohisa、Takahashi Hiroki、Yama Naoya、Hatakenaka Masamitsu、Himi Tetsuo
  • Journal Title: The Laryngoscope Volume: 128 Issue: 5 Pages: 1120-1125
  • DOI: 10.1002/lary.26945
  • Peer Reviewed
• [Presentation] Cytotoxic peripheral T helper cells are involved in the pathogenesis of IgG4-related disease (2020)
  • Author(s): Ryuta Kamekura, Hayato Yabe, Motohisa Yamamoto, Hiroki Takahashi, Kenichi Takano, Shingo Ichimiya
  • Organizer: The European Academy of Allergy and Clinical Immunology (EAACI) Digital Congress 2020
  • Int'l Joint Research
• [Presentation] オリゴクローナルな血液Tph細胞の増加がIgG4関連疾患の病態形成に関与する. (2019)
  • Author(s): 亀倉隆太, 矢部勇人, 山本元久, 高橋裕樹, 高野賢一, 一宮慎吾.
  • Organizer: 第47回日本臨床免疫学会総会
• [Presentation] IgG4関連疾患の病態形成にオリゴクローナルな血液Tph細胞の増加が関与する. (2019)
  • Author(s): 亀倉隆太, 矢部勇人, 山本元久, 高橋裕樹, 高野賢一, 一宮慎吾.
  • Organizer: 第28回日本シェーグレン症候群学会学術集会
• [Presentation] シンポジウム13 生体バリア機構とアレルギー疾患. アレルギー性鼻炎に関連するエピイムノ―ムの新機能. (2019)
  • Author(s): 亀倉隆太, 矢部勇人, 重原克則, 高野賢一, 一宮慎吾.
  • Organizer: 第68回日本アレルギー学会学術大会
  • Invited
• [Presentation] A unique subset of PD-1+CXCR5-CD4+ T cells is involved in immunological mechanisms of IgG4-related disease. (2019)
  • Author(s): Kamekura R, Yamamoto M, Yabe H, Takaki H, Takano K, Takahashi H, Takahashi H, Himi T, Ichimiya S.
  • Organizer: American Academy of Allergy, Asthma and Immunology (AAAAI) Annual Meeting 2019
  • Int'l Joint Research
• [Presentation] Unique profiles of lesional T follicular helper cells in the pathogenesis of IgG4-related disease. (2018)
  • Author(s): Kamekura R, Yabe H, Takano K, Yamamoto M, Ikegami I, Ito F, Takahashi H, Himi T, Ichimiya S.
  • Organizer: American Academy of Allergy, Asthma and Immunology (AAAAI) Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] 濾胞ヘルパー T 細胞と IgG4 関連疾患 (2018)
  • Author(s): 亀倉隆太, 山本元久, 高橋裕樹, 一宮慎吾.
  • Organizer: ベーシックシンポジウム 2「新規 T 細胞サブセットと疾患」: 第46回日本臨床免疫学会総会
  • Invited
• [Remarks] 北海道公立大学法人 札幌医科大学医学部 フロンティア医学研究所 免疫制御医学部門
  • URL: https://web.sapmed.ac.jp/immunology/index.html
• [Remarks] 札幌医科大学 耳鼻咽喉科学講座
  • URL: https://web.sapmed.ac.jp/otol/
• [Remarks] 札幌医科大学医学部フロンティア医学研究所〔免疫制御医学部門〕ホームページ
  • URL: https://web.sapmed.ac.jp/immunology/
• [Remarks] 札幌医科大学医学部フロンティア医学研究所〔免疫制御医学部門〕ホームページ
  • URL: http://web.sapmed.ac.jp/immunology/staff.html