Mechanisms for the acquisition of somatic hypermutation activity during the late B cell development

• Project/Area Number: 26670239
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• 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): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2015: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2014: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 免疫学 / 体細胞突然変異 / 胚中心 / B細胞 / 抗体

Outline of Final Research Achievements

Activation-induced deaminase (AID) is essential for both somatic hypermutation (SHM) and class switch recombination (CSR), contributing to antibody affinity maturation. Although both occurs in germinal center (GC) B cells, only CSR is induced in B cells cultured with mitogen, expressing AID. Therefore some mechanism works in germinal center B cells to induce SHM but not in cultured B cells.
We utilized the system called iGB cell culture, in which naive B cells are cultured on feeder cells with IL-4 or IL-21. The cultured B cells greatly proliferate, acquire GC phenotype and undergo CSR, but not SHM. However, memory B cells cultured similarly with Ag stimulation undergo SHM. Blimp1-deficient B cells accumulated even more SHM. Introduction of Bcl6 enabled B cells to proliferate for more than 2 months with accumulating SHM, but eventually only clones with a dominant nuclear AID kept undergoing SHM.

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
• [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
  • 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: Tokyo
  • Year and Date: 2015-07-21
  • Int'l Joint Research / Invited
• [Presentation] JNK regulatory molecule G5PR induces peritoneal B1a cells into IgG autoantibody-producing plasmablasts. (2014)
  • Author(s): Masahiro Kitabatake, Miho Soma, Tianli Zhang, Takuya Nojima, Daisuke Kitamura, Nobuo Sakaguchi
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都国際会館
  • Year and Date: 2014-12-12
• [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
  • Year and Date: 2014-12-11
• [Presentation] A role of IL-9 receptor on B cells in the T-dependent immune responses. (2014)
  • Author(s): Hiroshi Saruwatari, Shogo Takatsuka, 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
  • Year and Date: 2014-12-11
• [Presentation] CD40 signaling quantity may determine the fate of germinal center B cells. (2014)
  • Author(s): Takuya Koike, Shu Horiuchi, 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
  • Year and Date: 2014-12-10
• [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, USA
  • Year and Date: 2014-08-25 – 2014-08-26
• [Patent(Industrial Property Rights)] B細胞集団の製造方法 (2014)
  • Inventor(s): 北村大介、中石智之
  • Industrial Property Rights Holder: 学校法人東京理科大学、株式会社カネカ
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-07-02