Induction of autoimmune diseases by glucocorticoids

• Project/Area Number: 20K21525
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 49:Pathology, infection/immunology, and related fields
• Research Institution: Kyoto University
• Principal Investigator: IKUTA Koichi 京都大学, ウイルス・再生医科学研究所, 教授 (90193177)
• Co-Investigator(Kenkyū-buntansha): 崔 广為 京都大学, ウイルス・再生医科学研究所, 助教 (70791276) ; 榛葉 旭恒 京都大学, 医学研究科, 助教 (30812242)
• Project Period (FY): 2020-07-30 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2021: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2020: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: グルココルチコイド / 自己免疫疾患 / Th17細胞 / 実験的自己免疫性脳脊髄炎 / 関節リウマチ

Outline of Research at the Start

グルココルチコイド（GC）は強力な免疫抑制作用を持ち、自己免疫疾患の治療に用いられる。一方、研究代表者らは、日内変動するGCがＴ細胞のリンパ器官への集積を促し免疫機能を高めることを明らかにした。さらに、グルココルチコイド受容体欠損マウスにおいてTh17細胞の分化が障害され、実験的自己免疫性脳脊髄炎の発症が減弱した。本研究では、GCがTh17細胞の分化と機能を高め自己免疫疾患の発症を促進することを、細胞特異的なグルココルチコイド受容体欠損マウスを用いて明らかにする。これにより、強い免疫抑制作用で知られるGCが生理的な濃度では逆に自己免疫疾患を誘導する働きを持つという逆説的な概念を確立する。

Outline of Final Research Achievements

Glucocorticoids (GC) have immunosuppressive effects and are used for treatment of autoimmune diseases. We demonstrated that oscillating GC promote accumulation of T cells into lymphoid organs and enhance immune responses, thereby demonstrating a new physiological function of GC on the immune system. In this study, we demonstrated that GC promote the differentiation and function of inflammation-inducing Th17 cells and enhance the development of autoimmune diseases, by using T cell- and Th17 cell-specific GR-deficient mice. Thus, we established a novel concept that GC with strong immunosuppressive effects induces autoimmune diseases at physiological concentrations.

Academic Significance and Societal Importance of the Research Achievements

グルココルチコイド（GC）は抗炎症作用や免疫抑制作用を持ち、アレルギーや自己免疫疾患の治療によく用いられる。研究代表者らは、体内で日内変動しているGCが、Tリンパ球に作用することでTリンパ球をリンパ器官に集つめ免疫機能を高めていることを示した。本研究では、GCが炎症を誘導するヘルパーTリンパ球の機能を高めて、自己免疫疾患を引き起こすことを、Th17細胞だけでGC受容体を欠損するマウスを用いて明らかにした。このことによって、強い免疫抑制作用で知られるGCが生理的な濃度では逆に自己免疫疾患を惹起する働きを持つという逆説的な考えを確立した。

Research Products

• [Journal Article] High-throughput identification and quantification of single bacterial cells in the microbiota (2022)
  • Author(s): Jin, J., Yamamoto, R., Takeuchi, T., Cui, G., Miyauchi, E., Hojo, N., Ikuta, K., Ohno, H., and Shiroguchi, K.
  • Journal Title: Nat. Commun. Volume: 13 Issue: 1 Pages: 863-863
  • DOI: 10.1038/s41467-022-28426-1
  • Peer Reviewed / Open Access
• [Journal Article] Prolonged high-intensity exercise induces fluctuating immune responses to herpes simplex virus infection via glucocorticoids (2021)
  • Author(s): Adachi, A., Honda, T., Dainichi, T., Egawa, G., Yamamoto, Y., Nomura, T., Nakajima, S., Otsuka, A., Maekawa, M., Mano, N., Koyanagi, N., Kawaguchi, Y., Ohteki, T., Nagasawa, T., Ikuta, K., Kitoh, A., and Kabashima, K.
  • Journal Title: J. Allergy Clin. Immunol. Volume: 148 Issue: 6 Pages: 1575-1588.e7
  • DOI: 10.1016/j.jaci.2021.04.028
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fate of adipocyte progenitors during adipogenesis in mice fed a high-fat diet (2021)
  • Author(s): Bilal M, Nawaz A, Kado T, Rahil Aslam M, Igarashi Y, Nishimura A, Watanabe A, Kuwano T, Liu J, Miwa H, Era T, Ikuta K, Imura J, Yagi K, Nakagawa T, Fujisaka S, Tobe K.
  • Journal Title: Molecular Metabolism Volume: 54 Pages: 101328-101328
  • DOI: 10.1016/j.molmet.2021.101328
  • Peer Reviewed / Open Access
• [Journal Article] The roles of IL-7 and IL-15 in niches for lymphocyte progenitors and immune cells in lymphoid organs (2021)
  • Author(s): Ikuta K, Hara T, Abe S, Asahi T, Takami D, Cui G
  • Journal Title: Curr. Top. Microbiol. Immunol. Volume: 434 Pages: 83-101
  • DOI: 10.1007/978-3-030-86016-5_4
  • ISBN: 9783030860158, 9783030860165
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Lymph node stromal cells: diverse meshwork structures weave functionally subdivided niches (2021)
  • Author(s): Takeuchi, A., Ozawa, M., Cui, G., Ikuta, K., and Katakai, T.
  • Journal Title: Curr. Top. Microbiol. Immunol. Volume: 434 Pages: 103-121
  • DOI: 10.1007/978-3-030-86016-5_5
  • ISBN: 9783030860158, 9783030860165
  • Peer Reviewed
• [Journal Article] IL-4 producing Vg1+/Vd6+ gd T cells sustain germinal center reactions in Peyer's patches of mice (2021)
  • Author(s): Ullrich, L., Lueder, Y., Juergens, A.-L., Wilharm, A., Barros-Martins, J., Bubke, A., Demera, A., Ikuta, K., Patzer, G. E., Janssen, A., Sandrock, I., Prinz, I., and Rampoldi, F.
  • Journal Title: Front. Immunol. Volume: 12 Pages: 729607-729607
  • DOI: 10.3389/fimmu.2021.729607
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Prolonged high-intensity exercise induces fluctuating immune responses to herpes simplex virus infection via glucocorticoids. (2021)
  • Author(s): Adachi A, Honda T, Dainichi T, Egawa G, Yamamoto Y, Nomura T, Nakajima, S, Otsuka A, Maekawa M, Mano N, Koyanagi N, Kawaguchi Y, Ohteki T, Nagasawa T, Ikuta K, Kitoh A, and Kabashima K.
  • Journal Title: J. Allergy Clin. Immunol. Volume: in press
  • Peer Reviewed
• [Journal Article] Glucocorticoids regulate circadian rhythm of innate and adaptive immunity. (2020)
  • Author(s): Shimba A. and Ikuta K.
  • Journal Title: Front. Immunol. Volume: 11 Pages: 2143-2143
  • DOI: 10.3389/fimmu.2020.02143
  • Peer Reviewed / Open Access
• [Journal Article] Immune-enhancing effects of glucocorticoids in response to day-night cycles and stress. (2020)
  • Author(s): Shimba A. and Ikuta K.
  • Journal Title: Int. Immunol. Volume: 32 Issue: 11 Pages: 703-708
  • DOI: 10.1093/intimm/dxaa048
  • Peer Reviewed
• [Journal Article] Control of immunity by glucocorticoids in health and disease. (2020)
  • Author(s): Shimba A. and Ikuta K.
  • Journal Title: Semin. Immunopathol. Volume: 42 Issue: 6 Pages: 669-680
  • DOI: 10.1007/s00281-020-00827-8
  • Peer Reviewed
• [Presentation] 胎児肝臓に由来する1型自然リンパ球の同定 (2021)
  • Author(s): 旭拓真、阿部真也、崔広為、榛葉旭恒、生田宏一
  • Organizer: Kyoto T Cell Conference 第30回学術集会
• [Presentation] ストレスはグルココルチコイドを介してTh17細胞の分化を促進し腸炎を増悪させる (2021)
  • Author(s): 榛葉旭恒、生田宏一
  • Organizer: Kyoto T Cell Conference 第30回学術集会
• [Presentation] ステロイドホルモンによる免疫機能とアレルギーの制御 (2021)
  • Author(s): 生田宏一、榛葉旭恒、江島亜希
  • Organizer: 日本アレルギー学会学術集会
  • Invited