Interaction between Enteric Nervous System and Immune System in the Pathogenesis of Systemic Lupus Erythematosus

• Project/Area Number: 20K08779
• 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: Dokkyo Medical University
• Principal Investigator: Owada Takayoshi 獨協医科大学, 医学部, 講師 (30456016)
• Co-Investigator(Kenkyū-buntansha): 有馬 雅史 獨協医科大学, 医学部, 教授 (00202763) ; 幡野 雅彦 千葉大学, 大学院医学研究院, 教授 (20208523) ; 倉沢 和宏 獨協医科大学, 医学部, 教授 (30282479)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: NCX / Autoimmune disease / Rheumatoid arthritis / 腸内細菌叢 / 自己免疫疾患 / Ncx / 全身性エリテマトーデス

Outline of Research at the Start

関節リウマチやSLEなど自己免疫疾患において腸内細菌叢の不均衡（dysbiosis）による免疫機構の異常が深く関与することが考えられている．しかし，その病理的意義は十分に明らかでない．申請者らは神経堤細胞に特異的に発現するホメオボックス遺伝子Ncxのノックアウト（KO）マウスの腸管で一酸化窒素（NO）産生神経の増加に伴う腸内細菌叢のdysbiosisおよび炎症性腸疾患が誘導されることに着目した．本申請は，Ncx-KoマウスのSLEモデルを解析することによって，SLEの発症・維持機構における腸管の神経・免疫系制御機構やNOの役割を解明し，さらに新規治療の開発に繋がる探索・基盤的研究を行う．

Outline of Final Research Achievements

Dysbisosis with increased nitric oxide (NO) production are induced in the intestinal tract of mice lacking (KO) the homeobox gene Ncx. To elucidate the function of Ncx in autoimmune diseases, we analyzed Ncx-KO mouse models of autoimmune diseases using the SKG mouse genotype as a background and found that Ncx was not involved in the pathogenesis of SLE models, but in RA models, increased Tregs and decreased IL-17 producing T cells in the colonic LPL of KO mice were associated with reduced arthritis. Although the pathological significance of Ncx in arthritis in SKG mice is not clear, the production of intestinal NO may be involved in the reduction of RA-like arthritis through conversion of arthritis-induced dysbiosis.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果は，SLEなど自己免疫疾患の新規治療法の開発に大いに貢献し，さらに様々な免疫性疾患の病態の分子メカニズムの解明することに学術的意義がある．また新規分子標的治療法の開発へとつながる点に社会的意義がある．

Research Products

• [Presentation] Ncx遺伝子欠損による腸管神経形成異常は関節炎の重症化を抑制する (2023)
  • Author(s): 大和田高義
  • Organizer: 第６７回日本リウマチ学会
• [Presentation] The Association Between Continuous Decreases in Serum RF Titers and Radiographic Remission of Joint Damage in RA Patients Treated with Biological or Targeted Synthetic DMARDs. (2020)
  • Author(s): Owada T, Tanaka A, Hirata H, Arima M, Fukushima Y, Kurasawa K
  • Organizer: ACR(American College of Rheumatology’s Annual Meeting),
  • Int'l Joint Research
• [Presentation] TCZ might be a risk factor for worsening of ILD, particularly of chronic ILD. (2020)
  • Author(s): Tanaka A, Owada T, Hasegawa A, Hiyama T, Takamura Y, Miyao T, Yamazaki R, Arai S, Maezawa R, Arima M, Kurasawa K.
  • Organizer: EULAR (European League Against Rheumatism)
  • Int'l Joint Research