Elucidation of the function of pathogenic T cells in Sjogren's syndrome

• Project/Area Number: 17K18092
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Collagenous pathology/Allergology; Pathobiological dentistry/Dental radiology
• Research Institution: Keio University
• Principal Investigator: Iizuka-Koga Mana 慶應義塾大学, 医学部(信濃町), 特任助教 (80734821)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 自己免疫疾患 / T細胞 / CD4+ T細胞 / 免疫学

Outline of Final Research Achievements

Sjogren's syndrome (SS) is a chronic autoimmune disease characterized by infiltration of lymphocytes into lacrimal and salivary glands, and clinically by dry eyes and dry mouth. Immunohistochemical studies have shown that most infiltrating lymphocytes in the labial salivary and lachrymal glands are CD4+ αβ T cells.
In this study, we used the RORγt transgenic (Tg) mice, in which transgene expression was driven by hCD2 promoter and spontaneously developed sialadenitis like SS, in order to clarify the pathogenesis of sialadenitis.

Academic Significance and Societal Importance of the Research Achievements

SSは、唾液腺や涙腺に何らかの自己免疫応答により誘発される慢性炎症性疾患であると考えられているが、その正確な発症機序は未だ解明されていない。そのため、根本的な治療法はなく、対処療法に頼るのみである。
本研究により、SSの発症に関わる病因T細胞の役割が明らかとなり、新たな疾患特異的創薬への応用も期待される。

Research Products

• [Journal Article] Functional Analysis of Dendritic Cells Generated from T-iPSCs from CD4+ T Cell Clones of Sj?gren's Syndrome (2017)
  • Author(s): Iizuka-Koga Mana、Asashima Hiromitsu、Ando Miki、Lai Chen-Yi、Mochizuki Shinji、Nakanishi Mahito、Nishimura Toshinobu、Tsuboi Hiroto、Hirota Tomoya、Takahashi Hiroyuki、Matsumoto Isao、Otsu Makoto、Sumida Takayuki
  • Journal Title: Stem Cell Reports. Volume: 8 Pages: 1155-1163
  • DOI: 10.1016/j.stemcr.2017.04.010
  • Peer Reviewed / Open Access
• [Journal Article] Interleukin-33 produced by M2 macrophages and other immune cells contributes to Th2 immune reaction of IgG4-related disease. (2017)
  • Author(s): Furukawa S, Moriyama M, Miyake K, Nakashima H, Tanaka A, Maehara T, Iizuka-Koga M, Tsuboi H, Hayashida JN, Ishiguro N, Yamauchi M, Sumida T, Nakamura S
  • Journal Title: Scientific Reports Volume: 7 Pages: 42413-42413
  • DOI: 10.1038/srep42413
  • NAID: 120006023386
  • Peer Reviewed / Open Access
• [Journal Article] T-bet over-expression regulates aryl hydrocarbon receptor-mediated T helper type 17 differentiation through an interferon (IFN)γ-independent pathway. (2017)
  • Author(s): Yokosawa M, Kondo Y, Tahara M, Iizuka-Koga M, Segawa S, Kaneko S, Tsuboi H, Yoh K, Takahashi S, Matsumoto I, Sumida T.
  • Journal Title: Clinical & Experimental Immunology Volume: 188 Pages: 22-35
  • DOI: 10.1111/cei.12912
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] RORγt antagonist suppresses M3 muscarinic acetylcholine receptor-induced Sj?gren's syndrome-like sialadenitis (2017)
  • Author(s): Tahara M.、Tsuboi H.、Segawa S.、Asashima H.、Iizuka-Koga M.、Hirota T.、Takahashi H.、Kondo Y.、Matsui M.、Matsumoto I.、Sumida T.
  • Journal Title: Clinical & Experimental Immunology Volume: 187 Pages: 213-224
  • DOI: 10.1111/cei.12868
  • Peer Reviewed
• [Journal Article] Suppression of glucose-6-phosphate-isomerase induced arthritis by oral administration of transgenic rice seeds expressing altered peptide ligands of glucose-6-phosphate-isomerase. (2017)
  • Author(s): Hirota T, Tsuboi H, Iizuka-Koga M, Takahashi H, Asashima H, Yokosawa M, Kondo Y, Ohta M, Wakasa Y, Matsumoto I, Takaiwa F, Sumida T
  • Journal Title: Modern Rheumatology Volume: 印刷中 Pages: 457-465
  • DOI: 10.1080/14397595.2016.1218598
  • Peer Reviewed
• [Journal Article] Induction and maintenance of regulatory T cells by transcription factors and epigenetic modifications (2017)
  • Author(s): Iizuka-Koga Mana、Nakatsukasa Hiroko、Ito Minako、Akanuma Takashi、Lu Qianjin、Yoshimura Akihiko
  • Journal Title: J Autoimmun. Volume: 83 Pages: 113-121
  • DOI: 10.1016/j.jaut.2017.07.002
  • Peer Reviewed
• [Presentation] シェーグレン症候群の病態形成におけるRORγtの役割 (2018)
  • Author(s): 飯塚 麻菜、高橋 智 、松本 功、住田 孝之、吉村 昭彦
  • Organizer: 日本インターフェロンサイトカイン学会
• [Presentation] TCR analysis of infiltrated CD4+ T cells in the salivary glands of Sjogren’s syndrome mice model (2017)
  • Author(s): Mana Iizuka, Satoru Takahashi, Isao Matsumoto, Takayuki Sumida, Akihiko Yoshimura
  • Organizer: International Cytokine & Interferon Society
  • Int'l Joint Research