A study of the regulational mechanisms for IgE+ B cell development and maintenance

• Project/Area Number: 25293116
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Tokyo University of Science
• Principal Investigator: KITAMURA DAISUKE 東京理科大学, 研究推進機構生命医科学研究所, 教授 (70204914)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2015: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2013: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
• Keywords: 免疫学 / 獲得免疫 / アレルギー / IgE / 胚中心 / シグナル伝達 / 免疫記憶 / IgE陽性B細胞 / プラズマ細胞

Outline of Final Research Achievements

IgE is critical in the pathogenesis of allergic diseases, but it emerge only transiently during the immune response and kept low in healthy individuals. B cells switch to IgE in germinal center (GC), but that the IgE+ B cells immediately become short-lived plasma cells (PCs) and not differentiate into long-lived (LL) PCs or memory B cells. We found that the expression of membrane IgE (mIgE) spontaneously induces PC differentiation and apoptosis through signaling pathways from Syk via BLNK or CD19. Notably, mIgE binds to CD19 and activates CD19-PI3kinase-Akt pathway leading to the PC differentiation. In the BLNK-deficient mice, IgE+ GC and memory B cells remained high in number during immune response, and more IgE+ LLPCs and serum IgE were produced, rendering the mice hypersensitive to a secondary challenge. A similar phenotype was also observed in CD19+/- mice. These results suggest that somatic defects of the mIgE signaling pathways through BLNK and CD19 can cause allergic diseases.

Research Products

• [Journal Article] Complex Antigens Drive Permissive Clonal Selection in Germinal Centers. (2016)
  • Author(s): Kuraoka, M., Schmidt, A.G., Nojima, T., Feng, F., Watanabe, A., Kitamura, D., Harrison, S.C., Kepler, T.B. and Kelsoe, G.
  • Journal Title: Immunity Volume: 44 Issue: 3 Pages: 542-552
  • DOI: 10.1016/j.immuni.2016.02.010
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] GIMAP1 Is Essential for the Survival of Naive and Activated B Cells In Vivo. (2016)
  • Author(s): Webb, L.M., Datta, P., Bell, S.E., Kitamura, D., Turner, M. and Butcher, G.W.
  • Journal Title: The Journal of Immunology Volume: 196 Issue: 1 Pages: 207-216
  • DOI: 10.4049/jimmunol.1501582
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 膜型IgEの自発的シグナル伝達によるB細胞記憶形成の制御 (2016)
  • Author(s): 羽生田圭、深尾紗央里、北村大介
  • Journal Title: 臨床免疫・アレルギー科 Volume: 65 Pages: 329-333
• [Journal Article] Ex vivo engineered immune organoids for controlled germinal center reactions. (2015)
  • Author(s): Purwada, A., Jaiswal, M.K., Ahn, H., Nojima, T., Kitamura, D., Gaharwar, A.K., Cerchietti, L. and Singh, A.
  • Journal Title: Biomaterials Volume: 63 Pages: 24-34
  • DOI: 10.1016/j.biomaterials.2015.06.002
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] JNK Regulatory Molecule G5PR Induces IgG Autoantibody-Producing Plasmablasts from Peritoneal B1a Cells. (2015)
  • Author(s): Kitabatake M, Soma M, Zhang T, Kuwahara K, Fukushima Y, Nojima T, Kitamura D, Sakaguchi N.
  • Journal Title: J Immunol. Volume: 194 Issue: 4 Pages: 1480-1488
  • DOI: 10.4049/jimmunol.1401127
  • Peer Reviewed / Open Access
• [Journal Article] Spleen supports a pool of innate-like B cells in white adipose tissue that protects against obesity-associated insulin resistance (2014)
  • Author(s): Wu L, Parekh V V, Hsiao J, Kitamura D, Van Kaer L.
  • Journal Title: Proc Natl Acad Sci USA. Volume: 111 Issue: 43 Pages: 4638-4647
  • DOI: 10.1073/pnas.1324052111
  • Peer Reviewed
• [Journal Article] Gp49B-mediated negative regulation of antibody production by memory and marginal zone B cells. (2014)
  • Author(s): Fukao S, Haniuda K, Nojima T, Takai T, Kitamura D.
  • Journal Title: J Immunol. Volume: 193 Issue: 2 Pages: 635-644
  • DOI: 10.4049/jimmunol.1302772
  • Peer Reviewed / Open Access
• [Journal Article] A novel and effective cancer immunotherapy mouse model using antigen-specific B cells selected in vitro. (2014)
  • Author(s): Moutai T, Yamana H, Nojima T and Kitamura D.
  • Journal Title: PLOS ONE Volume: 9 Issue: 3 Pages: 92732-92732
  • DOI: 10.1371/journal.pone.0092732
  • Peer Reviewed
• [Journal Article] DNase γ Is the Effector Endonuclease for Internucleo- somal DNA Fragmentation in Necrosis (2013)
  • Author(s): Mizuta R., Araki S., Furukawa M., Furukawa Y., Ebara S., Shiokawa D., Hayashi K., Tanuma S., and Kitamura D
  • Journal Title: PLoS One Volume: 8(12) Issue: 12 Pages: 1-8
  • DOI: 10.1371/journal.pone.0080223
  • Peer Reviewed
• [Journal Article] Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis. (2013)
  • Author(s): Caganova M, Carrisi C, Varano G, Mainoldi F, Zanardi F, Germain PL, George L, Alberghini F, Ferrarini L, Talukder AK, Ponzoni M, Testa G, Nojima T, Doglioni C, Kitamura D,
  • Journal Title: J Clin Invest Volume: 123 Issue: 12 Pages: 5009-5022
  • DOI: 10.1172/jci70626
  • Peer Reviewed
• [Presentation] Autonomous signaling from IgE B cell receptor suppresses B cell memory formation. (2015)
  • Author(s): Kei Haniuda, Saori Fukao, Tadahiro Kodama, Hitoshi Hasegawa, Daisuke Kitamura
  • Organizer: The 3rd Symposium of International Immunological Memory and Vaccine Forum.
  • Place of Presentation: Berlin (Germany)
  • Year and Date: 2015-10-30
  • Int'l Joint Research
• [Presentation] BLNK-knockout mice as a model of allergic diseases. (2015)
  • Author(s): Daisuke Kitamura
  • Organizer: International Symposium of the Center for Animal Disease Models 2015.
  • Place of Presentation: 学士会館（東京）
  • Year and Date: 2015-07-21
  • Int'l Joint Research / Invited
• [Presentation] BLNK regulates IgE B-cell receptor signaling and B-cell memory formation. (2014)
  • Author(s): Kei Haniuda, Saori Fukao, Daisuke Kitamura
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都国際会館、京都
  • Year and Date: 2014-12-11
• [Presentation] IgE型B細胞受容体シグナルによるB細胞短命化誘導機構の解明 (2014)
  • Author(s): 茂木瑞恵、羽生田圭、北村大介
  • Organizer: 第58回日本薬学会関東支部大会
  • Place of Presentation: 昭和薬科大学、町田市、東京
  • Year and Date: 2014-10-04
• [Presentation] Molecular mechanisms for the development of B-cell memory. (2014)
  • Author(s): Daisuke Kitamura
  • Organizer: The 2nd Symposium of International Immunological Memory and Vaccine Forum
  • Place of Presentation: La Jolla Institute of Allergy and Immunology, La Jolla, USA
  • Year and Date: 2014-08-25 – 2014-08-26
• [Presentation] Molecular mechanisms for memory B-cell development and function. (2013)
  • Author(s): Daisuke Kitamura, Kei Haniuda, Saori Fukao, Mika Inada, Shu Horiuchi, Shogo Takatsuka, Tatsuya Moutai, Takuya Nojima
  • Organizer: 15th International Congress of Immunology
  • Place of Presentation: Milan, Italy
• [Presentation] Molecular requirements for memory B-cell development. (2013)
  • Author(s): Daisuke Kitamura
  • Organizer: 第42回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ