Elucidation of pathological significance of IgG4 using a novel mouse model

• Project/Area Number: 19K22537
• 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: Kyushu University
• Principal Investigator: Baba Yoshihiro 九州大学, 生体防御医学研究所, 教授 (20415269)
• Project Period (FY): 2019-06-28 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2020: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2019: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: IgG4 / B細胞

Outline of Research at the Start

IgG4関連疾患は様々な臓器の肥厚性病変を認める全身性疾患であり、血中IgG4の高値と、罹患部のIgG4陽性プラズマ細胞の浸潤および線維化を特徴とする。自己免疫機序の関与が想定されているが、未だに原因は不明であり、疾患発症機序の解明と新規治療法の開発が急がれる。本研究では、新規マウスモデルを樹立し、免疫グロブリンIgG4産生B細胞の応答とIgG4抗体の疾患への関与を解明することにより、IgG4関連疾患およびアレルギー疾患病態の理解を目指す。

Outline of Final Research Achievements

IgG4-related disease is characterized by high blood IgG4 antibody levels and fibrosis. In addition, IgG4 has been shown to suppress allergies. Although the relationship between IgG4 and allergic diseases is suspected, the details are unknown. A major reason for the lack of progress in IgG4 research is the absence of IgG4 in mice. Therefore, we gnerated a new mouse that produces human IgG4. We showed that B cell differentiation of this mouse was normal. In addition, IgG4 production was observed by immunization. Thus, the newly created IgG4-producing mouse may be a useful tool for verifying the role of IgG4 in vivo.

Academic Significance and Societal Importance of the Research Achievements

本研究で作成した新規ヒトIgG4産生マウスは、これまで不可能だったIgG4陽性B細胞のin vivoでの活性化や分化、ならびにIgG4抗体の疾患制御の役割を検証することが可能となり、IgG4の病理的意義を直接的に調べることができる。よって、IgG4関連疾患およびアレルギー疾患の理解と予測、さらには、治療の選択に貢献できると考えられる。また、謎の多いIgG4の機能という、基礎免疫学の研究領域の発展に大きく貢献することが期待される。

Research Products

• [Journal Article] Generation and characterization of CD19-iCre mice as a tool for efficient and specific conditional gene targeting in B cells. (2021)
  • Author(s): Yasuda T, Saito Y, Ono C, Kawata K, Baba A, Baba Y.
  • Journal Title: Sci. Rep. Volume: 11 Issue: 1 Pages: 5524-5524
  • DOI: 10.1038/s41598-021-84786-6
  • Peer Reviewed / Open Access
• [Journal Article] Tet2 and Tet3 in B cells are required to repress CD86 and prevent autoimmunity (2020)
  • Author(s): Tanaka, S. Ise, W. Inoue, T. Ito, A. Ono, C. Shima, Y. Sakakibara, S. Nakayama, M. Fujii, K. Miura, I. Sharif, J. Koseki, H. Koni, P. A. Raman, I. Li, Q. Z. Kubo, M. Fujiki, K. Nakato, R. Shirahige, K. Araki, H. Miura, F. Ito, T. Kawakami, E. Baba, Y. Kurosaki, T.
  • Journal Title: Nature Immunology Volume: 21 Issue: 8 Pages: 950-961
  • DOI: 10.1038/s41590-020-0700-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TRPM5 Negatively Regulates Calcium-Dependent Responses in Lipopolysaccharide-Stimulated B Lymphocytes (2020)
  • Author(s): Sakaguchi Taiki、Okumura Ryu、Ono Chisato、Okuzaki Daisuke、Kawai Takafumi、Okochi Yoshifumi、Tanimura Natsuko、Murakami Mari、Kayama Hisako、Umemoto Eiji、Kioka Hidetaka、Ohtani Tomohito、Sakata Yasushi、Miyake Kensuke、Okamura Yasushi、Baba Yoshihiro、Takeda Kiyoshi
  • Journal Title: Cell Reports Volume: 31 Issue: 10 Pages: 107755-107755
  • DOI: 10.1016/j.celrep.2020.107755
  • Peer Reviewed / Open Access
• [Journal Article] B Cell Receptor Signaling. (2020)
  • Author(s): Tanaka S, Baba Y.
  • Journal Title: Adv. Exp. Med. Biol. Volume: 1254 Pages: 23-36
  • DOI: 10.1007/978-981-15-3532-1_2
  • ISBN: 9789811535314, 9789811535321
• [Journal Article] Heterogeneous subsets of B-lineage regulatory cells (Breg cells). (2020)
  • Author(s): Baba Y, Saito Y, Kotetsu Y.
  • Journal Title: Int. Immunol. Volume: 32 Issue: 3 Pages: 155-16
  • DOI: 10.1093/intimm/dxz068
• [Journal Article] GPR40 activation initiates store-operated Ca2+ entry and potentiates insulin secretion via the IP3R1/STIM1/Orai1 pathway in pancreatic β-cells (2019)
  • Author(s): Usui R, Yabe D, Fauzi M, Goto H, Botagarova A, Tokumoto S, Tatsuoka H, Tahara Y, Kobayashi S, Manebe T, Baba Y, Kurosaki T, Herrera PL, Ogura M, Nagashima K, Inagaki N
  • Journal Title: Sci Rep. Volume: 9 Issue: 1 Pages: 15562-15562
  • DOI: 10.1038/s41598-019-52048-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The COMMD3/8 complex determines GRK6 specificity for chemoattractant receptors (2019)
  • Author(s): Nakai Akiko、Fujimoto Jun、Miyata Haruhiko、Stumm Ralf、Narazaki Masashi、Schulz Stefan、Baba Yoshihiro、Kumanogoh Atsushi、Suzuki Kazuhiro
  • Journal Title: Journal of Experimental Medicine Volume: 216 Issue: 7 Pages: 1630-1647
  • DOI: 10.1084/jem.20181494
  • Peer Reviewed / Open Access
• [Journal Article] THE ROLL OF B CELLS IN ALLERGY (2019)
  • Author(s): 齋藤雄一、馬場義裕
  • Journal Title: Japanese Journal of Allergology Volume: 68 Issue: 6 Pages: 661-667
  • DOI: 10.15036/arerugi.68.661
  • NAID: 130007678533
  • ISSN: 0021-4884, 1347-7935
• [Presentation] B細胞の免疫応答制御機構 (2020)
  • Author(s): 馬場義裕
  • Organizer: 第16回皮膚免疫疾患研究会
  • Invited
• [Presentation] B細胞による自己免疫疾患制御 (2020)
  • Author(s): 馬場義裕
  • Organizer: 免疫と神経疾患オンラインセミナー
  • Invited
• [Presentation] B細胞はどのようにして免疫応答を制御するのか (2019)
  • Author(s): 馬場義裕
  • Organizer: 第93回染色体工学研究センターセミナー
  • Invited
• [Presentation] B細胞の免疫応答制御機構 (2019)
  • Author(s): 馬場義裕
  • Organizer: がん免疫セミナー（千葉）
  • Invited
• [Presentation] B細胞の免疫応答制御機構 (2019)
  • Author(s): 馬場義裕
  • Organizer: がん免疫セミナー（東京）
  • Invited
• [Presentation] 第18回レジェンドセミナー (2019)
  • Author(s): 馬場義裕
  • Organizer: 免疫反応を抑制するB細胞
  • Invited
• [Presentation] Role of Fcrl5 in B cell immune response and peripheral tolerance. (2019)
  • Author(s): Ono C, Kochi Y, Tanaka S, Yamamoto K, Baba Y.
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] Ten-eleven translocaion (Tet) in B cells prevent autoimmunity. (2019)
  • Author(s): Tanaka S, Ise W, Kurosaki T, Baba Y
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] Development of IL-17A+ Vγ6 γδ T cells in mouse thymus. (2019)
  • Author(s): Hatano S, Tun X, Matsumoto M, Baba Y, Yoshikai Y.
  • Organizer: 第48回日本免疫学会学術集会
• [Book] 「B細胞分化」標準免疫学 (2021)
  • Author(s): 馬場義裕
  • Total Pages: 9
  • Publisher: 医学書院
  • ISBN: 9784260042383