Analysis of the association between pathogenic CD4+T cells and microbiota in sialadenitis like Sjogren's syndrome.

• Project/Area Number: 19K08891
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Keio University
• Principal Investigator: IIZUKA Mana 慶應義塾大学, 医学部(信濃町), 特任助教 (80734821)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: シェーグレン症候群 / 自己免疫疾患 / T細胞 / 腸内細菌 / CD4+ T細胞

Outline of Research at the Start

SS様病態の発症に関わる自己反応性CD4+ T細胞に焦点を当て、これまで不明であった病因性CD4+ T細胞が認識する自己抗原と臓器特異的集積機構および疾患特異的病因分子を明らかにする。また、マウスモデルの解析結果を軸に、SS患者における病態発症に関わる特異的分子の機能解析を行い、新たな治療標的を見出す。

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. There are unknown pathogenesis of SS. The most infiltrating lymphocytes in the salivary glands are autoreactive CD4+ T cells, which are involved in the initial phase of pathogenesis and exacerbation of sialadenitis.
In this study, we used SS model mice spontaneously developed sialadenitis like SS, in order to clarify the pathogenesis of sialadenitis. Here, we found that the involvement of the intestinal microbiota in the activation of autoreactive CD4+ T cells.

Academic Significance and Societal Importance of the Research Achievements

SSは慢性唾液腺炎、涙腺炎を主徴とする臓器特異的自己免疫疾患であり、国の指定難病に選定されている。その発症機序は不明であり、確立した治療法はなく、対処療法に頼るのみである。本研究により、SSの発症に関わる自己反応性T細胞の機能および活性化機序が明らかとなり、新たな疾患特異的創薬への応用も期待される。

Research Products

• [Journal Article] Single-Cell Analysis Revealed the Role of CD8+ Effector T Cells in Preventing Cardioprotective Macrophage Differentiation in the Early Phase of Heart Failure (2021)
  • Author(s): Komai Kyoko、Ito Minako、Nomura Seitaro、Shichino Shigeyuki、Katoh Manami、Yamada Shintaro、Ko Toshiyuki、Iizuka-Koga Mana、Nakatsukasa Hiroko、Yoshimura Akihiko
  • Journal Title: Frontiers in Immunology Volume: 12 Pages: 763647-763647
  • DOI: 10.3389/fimmu.2021.763647
  • Peer Reviewed / Open Access
• [Journal Article] Kidney GATA3+ regulatory T cells play roles in the convalescence stage after antibody-mediated renal injury. (2020)
  • Author(s): Sakai R, Ito M, Komai K, Iizuka-Koga M, Matsuo K, Nakayama T, Yoshie O, Amano K, Nishimasu H, Nureki O, Kubo M, Yoshimura A.
  • Journal Title: Cell Mol Immunol. Volume: Sep Issue: 5 Pages: 11-11
  • DOI: 10.1038/s41423-020-00547-x
  • Peer Reviewed / Open Access
• [Presentation] Identifiedpathogenic autoantibodies to induce the development of sialadenitis (2021)
  • Author(s): Mana Iizuka,Satoru Takahashi, Isao Matsumoto,Takayuki Sumida, Akihiko Yoshimura
  • Organizer: 第50回日本免疫学会学術集会
• [Presentation] CD4+ T細胞を軸としたシェーグレン症候群の病態形成機序の解明 (2019)
  • Author(s): 飯塚麻菜、高橋智、松本功、住田孝之、吉村昭彦
  • Organizer: 第28回日本シェーグレン症候群学会学術集会
• [Presentation] A role of pathogenic CD4+ T cells in the development of organ specific autoimmune disease like Sjogren’s syndrome (2019)
  • Author(s): Mana Iizuka, Satoru Takahashi, Isao Matsumoto,Takayuki Sumida, Akihiko Yoshimura
  • Organizer: 第48回日本免疫学会学術集会