Regulation of pathogenic autoantibody production by Nogo

• Project/Area Number: 17K08874
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Aichi Medical University
• Principal Investigator: Inui Masanori 愛知医科大学, 医学部, 講師 (80443985)
• Project Period (FY): 2017-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 自己抗体 / 自己免疫疾患 / 自己抗体産生 / 自己免疫

Outline of Final Research Achievements

I have shown that Nogo, an endoplasmic reticulum membrane protein, is expressed on macrophages and is essential for the induction of intracellular signaling throught nucleic acid-sensing TLRs. I generated Nogo-deficient mice backcrossed to BXSB mice, a disease model with SLE-like autoimmune symptoms, and found that BXSB.Nogo-deficient mice showed significantly decreased anti-ds-DNA IgG antibody titer while total IgG antibody titer in blood was comparable to BXSB mice. On the other hand, both total IgM and anti-ds-DNA IgM antibody titer in blood were significantly decreased in BXSB.Nogo-deficient mice. These results suggest that Nogo could regulate the class switch recombination to IgG in autoantibody-producing B cells.

Academic Significance and Societal Importance of the Research Achievements

抗体産生細胞であるB細胞の寛容機構の維持が破綻すると，病原性自己抗体の産生が誘導され全身性エリテマトーデス（SLE）など様々な自己免疫疾患の発症につながる。そのためB細胞の寛容誘導機構を解明することは自己免疫疾患の新規な治療法の開発に不可欠である。申請者は小胞体膜タンパクであるNogoが自己抗体産生，さらにはクラススイッチに関与することを明らかにした。本研究課題の遂行により，免疫寛容の成立・維持を制御する新規な概念を提唱できた。

Research Products

• [Journal Article] Cell surface expression of human<scp>RP105</scp>depends on<i>N</i>‐glycosylation of<scp>MD</scp>‐1 (2022)
  • Author(s): Biswas Mrityunjoy、Yamazaki Tatsuya、Tomono Susumu、Karnan Sivasundaram、Takagi Hidekazu、Ichimonji Isao、Inui Masanori、Nagaoka Fumiaki、Hosokawa Yoshitaka、Akashi‐Takamura Sachiko
  • Journal Title: FEBS Letters Volume: 596 Issue: 24 Pages: 3211-3231
  • DOI: 10.1002/1873-3468.14452
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Blockade of checkpoint ILT3/LILRB4/gp49B binding to fibronectin ameliorates autoimmune disease in BXSB/<i>Yaa</i> mice (2021)
  • Author(s): Su Mei-Tzu、Inui Masanori、Wong Yi Li、Takahashi Maika、Sugahara-Tobinai Akiko、Ono Karin、Miyamoto Shotaro、Murakami Keiichi、Itoh-Nakadai Ari、Kezuka Dai、Itoi So、Endo Shota、Hirayasu Kouyuki、Arase Hisashi、Takai Toshiyuki
  • Journal Title: International Immunology Volume: 33 Issue: 8 Pages: 447-458
  • DOI: 10.1093/intimm/dxab028
  • Peer Reviewed / Open Access
• [Journal Article] A Novel Gene Delivery Vector of Agonistic Anti-Radioprotective 105 Expressed on Cell Membranes Shows Adjuvant Effect for DNA Immunization Against Influenza (2020)
  • Author(s): Yamazaki Tatsuya、Biswas Mrityunjoy、Kosugi Kouyu、Nagashima Maria、Inui Masanori、Tomono Susumu、Takagi Hidekazu、Ichimonji Isao、Nagaoka Fumiaki、Ainai Akira、Hasegawa Hideki、Chiba Joe、Akashi-Takamura Sachiko
  • Journal Title: Frontiers in Immunology Volume: 11 Pages: 606518-606518
  • DOI: 10.3389/fimmu.2020.606518
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Phospholipase A2 from bee venom increases poly(I:C)-induced activation in human keratinocytes (2020)
  • Author(s): Nakashima Akina、Tomono Susumu、Yamazaki Tatsuya、Inui Masanori、Morita Naoko、Ichimonji Isao、Takagi Hidekazu、Nagaoka Fumiaki、Matsumoto Misako、Ito Yasuhiko、Yanagishita Takeshi、Miyake Kensuke、Watanabe Daisuke、Akashi-Takamura Sachiko
  • Journal Title: International Immunology Volume: - Issue: 6 Pages: 371-383
  • DOI: 10.1093/intimm/dxaa005
  • Peer Reviewed
• [Journal Article] Augmented ILT3/LILRB4 Expression of Peripheral Blood Antibody Secreting Cells in the Acute Phase of Kawasaki Disease (2019)
  • Author(s): Sugahara-Tobinai Akiko、Inui Masanori、Metoki Takaya、Watanabe Yohei、Onuma Ryoichi、Takai Toshiyuki、Kumaki Satoru
  • Journal Title: The Pediatric Infectious Disease Journal Volume: 38 Issue: 4 Pages: 431-438
  • DOI: 10.1097/inf.0000000000002259
  • Peer Reviewed / Open Access
• [Journal Article] Gp49B is a pathogenic marker for autoantibody-producing plasma cells in lupus-prone BXSB/Yaa mice (2019)
  • Author(s): Wong Yi Li、Su Mei-Tzu、Sugahara-Tobinai Akiko、Itoi So、Kezuka Dai、Endo Shota、Inui Masanori、Takai Toshiyuki
  • Journal Title: International Immunology Volume: 印刷中 Issue: 6 Pages: 397-406
  • DOI: 10.1093/intimm/dxz017
  • Peer Reviewed / Open Access
• [Journal Article] Receptor-destroying enzyme (RDE) from Vibrio cholerae modulates IgE activity and reduces the initiation of anaphylaxis (2019)
  • Author(s): Yamazaki Tatsuya、Inui Masanori、Hiemori Keiko、Tomono Susumu、Itoh Makoto、Ichimonji Isao、Nakashima Akina、Takagi Hidekazu、Biswas Mrityunjoy、Izawa Kumi、Kitaura Jiro、Imai Teruko、Sugiura Nobuo、Tateno Hiroaki、Akashi-Takamura Sachiko
  • Journal Title: Journal of Biological Chemistry Volume: 294 Issue: 17 Pages: 6659-6669
  • DOI: 10.1074/jbc.ra118.006375
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Bone marrow PDGFRa+Sca-1+ enriched mesenchymal stem cells support survival of and antibody production by plasma cells in vitro through IL-6. (2018)
  • Author(s): Atsuko Kayaba, Ari Itoh-Nakadai, Kunimichi Niibe, Matsuyuki Shirota, Ryo Funayama, Akiko Sugahara-Tobinai, Yi Li Wong, Masanori Inui, Keiko Nakayama, and Toshiyuki Takai.
  • Journal Title: Int Immu Volume: in press Issue: 6 Pages: 241-253
  • DOI: 10.1093/intimm/dxy018
  • Peer Reviewed / Open Access