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Signal Regulation Mechanisms for B Cell Development and Self-Tolerance Establishment.

Research Project

Project/Area Number 14207015
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Immunology
Research InstitutionTokyo University of Science

Principal Investigator

KITAMURA Daisuke  Tokyo University of Science, Research Institute for Biological Sciences, Professor, 生命科学研究所, 教授 (70204914)

Co-Investigator(Kenkyū-buntansha) OKAMOTO Noriaki  Tokyo University of Science, Research Institute for Biological Sciences, Research Assistant, 生命科学研究所, 助手 (10318230)
林 克彦  東京理科大学, 生命科学研究所, 助手 (20287486)
Project Period (FY) 2002 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥49,270,000 (Direct Cost: ¥37,900,000、Indirect Cost: ¥11,370,000)
Fiscal Year 2004: ¥13,260,000 (Direct Cost: ¥10,200,000、Indirect Cost: ¥3,060,000)
Fiscal Year 2003: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000)
Fiscal Year 2002: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000)
KeywordsB cells / antigen receptor / adaptor proteins / BASH / BLNK / receptor editing / B cell development / self tolerance
Research Abstract

Pre-B cell receptor (pre-BCR) signaling induces proliferative expansion of large pre-B cells and the following differentiation into small pre-B cells (pre-B cell transition), and inhibits V_H to DJ_H rearrangement of IgH locus (IgH allelic exclusion), the latter also accounting for counter-selection of pro-B cells expressing Dμ protein (Dμ selection). We have previously shown that a B-cell specific adaptor protein, BASH (or BLNK/SLP-65), which is critical for B-cell antigen receptor(BCR) signaling, is important, but not essential, for pre-B cell transition. In this study we have discovered a buck-up role in the pre-BCR signaling for CD19, a B-cell specific co-receptor for BCR. The pre-B cell transition was completely abolished and accumulation of large non-cycling, pre-BCR-expressing cells was augmented in BASH/CD19 double-mutant mice. However, IgH allelic exclusion was intact even in the double-mutant mice, while Dμ selection was abolished in BASH- and the double-mutant mice. Thus, di … More stinct signals are required for these events. In addition, these mice succumbed to pre-B cell leukemia, indicating BASH (and CD19) contributes to tumor suppression.
We also found that editing of self-binding antigen receptors is significantly dependent on BASH, through examining anti-DNA-antibody knock-in mice deficient for BASH. Thus contribution of the receptor editing in the establishment of self-tolerance is clearly documented. In addition, BASH has turned out to be unnecessary for T-independent secondary and memory response, as well as affinity maturation of antibodies.
BASH interacts with signaling molecules such as Btk, PLCγ, Vav, Grb2, HPK1, and the significance of such interactions in BCR signal transduction has been shown. We have identified novel proteins that bind to a conserved N-terminal domain of BASH, and termed them BNAS1 and BNAS2. They are both presumed to be a 4-times membrane-span protein and localize at endoplasmic reticulum, Golgi apparatus and peri-nuclear region. Functional studies utilizing gene targeting methodology are currently underway. Less

Report

(4 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (43 results)

All 2005 2004 2003 2002 Other

All Journal Article (29 results) Book (2 results) Publications (12 results)

  • [Journal Article] Involvement of DNase γ in the resected double-strand DNA breaks in2005

    • Author(s)
      Okamoto, M.
    • Journal Title

      Biochem.Biophys.Res.Commun. 327

      Pages: 76-83

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Involvement of DNase γ in the resected double-strand DNA breaks in immunoglobulin genes.2005

    • Author(s)
      Okamoto, M., Okamoto, N., Yashiro, H., Shiokawa, D., Sunaga, S., Yoshimori, A., Tanuma, S., Kitamura, D.
    • Journal Title

      Biochem.Biophys.Res.Commun. 327

      Pages: 76-83

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Involvement of DNase γ in the resected double-strand DNA breaks in immunoglobulin genes.2005

    • Author(s)
      Okamoto, M.
    • Journal Title

      Biochem.Biophys.Res.Commun. 327

      Pages: 76-83

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Impaired receptor editing in the primary B cell repertoire of BASH-deficient mice.2004

    • Author(s)
      Hayashi, K.
    • Journal Title

      J.Immunol. 173

      Pages: 5980-5988

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Transcriptional regulation of SLP-76 family hematopoietic cell adaptor MIST/Clnk by STAT5.2004

    • Author(s)
      Sasanuma, H.
    • Journal Title

      Biochem.Biophys.Res.Commun. 321

      Pages: 145-153

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] BASH-deficient mice : Limited primary repertoire and antibody formation, but sufficient affinity maturation and memory B cell generation, in anti-NP response2004

    • Author(s)
      Yamamoto, M.
    • Journal Title

      Int.Immunol. 16

      Pages: 1161-1171

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Identification and characterization of a novel BASH N-terminus associated protein, BNAS2.2004

    • Author(s)
      Imamura, Y.
    • Journal Title

      J.Biol.Chem. 279

      Pages: 26425-26432

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Impaired receptor editing in the primary B cell repertoire of BASH-deficient mice.2004

    • Author(s)
      Hayashi, K., Nojima, T., Goitsuka, R., Kitamura.D.
    • Journal Title

      J.Immunol. 173(10)

      Pages: 5980-5988

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Transcriptional regulation of SLP-76 family hematopoietic cell adaptor MIST/Clnk by STAT5.2004

    • Author(s)
      Sasanuma, H., Tatsuno, A., Tsuji, K., Hidano, S., Morita, S., Kitamura, T., Kubo, M., Kitamura, D., Goitsuka, R.
    • Journal Title

      Biochem.Biophys.Res.Commun. 321(1)

      Pages: 145-153

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] BASH-deficient mice : Limited primary repertoire and antibody formation, but sufficient affinity maturation and memory B cell generation, in anti-NP response.2004

    • Author(s)
      Yamamoto, M., Nojima, T., Hayashi, K., Goitsuka, R., Furukawa, K., Azuma, T., Kitamura, D.
    • Journal Title

      Int.Immunol. 16(8)

      Pages: 1161-1171

    • NAID

      10013425465

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Identification and Characterization of a Novel BASH N-terminus Associated Protein, BNAS2.2004

    • Author(s)
      Imamura Y., Katahira, T., Kitamura, D.
    • Journal Title

      J.Biol.Chem. 279(25)

      Pages: 26425-26432

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Identification and characterization of a novel BASH N-terminus associated protein, BNAS2.2004

    • Author(s)
      Imamura Y.
    • Journal Title

      J.Biol.Chem. 279・25

      Pages: 26425-26432

    • Related Report
      2004 Annual Research Report
  • [Journal Article] BASH-deficient mice : Limited primary repertoire and antibody formation, but sufficient affinity maturation and memory B cell generation, in anti-NP reponse.2004

    • Author(s)
      Yamamoto, M.
    • Journal Title

      Int Immunol. 16・8

      Pages: 1161-1171

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Transcriptional regulation of SLP-76 family hematopoietic cell adaptor MIST/Clnk by STAT5.2004

    • Author(s)
      Sasanuma, H.
    • Journal Title

      Biochem.Biophys.Res.Commun. 321・1

      Pages: 145-153

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Impaired receptor editing in the primary B cell repertoire of BASH-deficient mice.2004

    • Author(s)
      Hayashi, K.
    • Journal Title

      J.Immunol. 173・10

      Pages: 5980-5988

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Induction of protective immunity by primed B-1 cells in Toxoplasma gondii-infected B cell-deficient mice.2003

    • Author(s)
      Chen, M.
    • Journal Title

      Microbiol.Immunol. 47

      Pages: 997-1003

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Atomic force microscopy analysis of rolling circle amplification of plasmid DNA.2003

    • Author(s)
      Mizuta, R.
    • Journal Title

      Arch.Histol.Cytol. 66

      Pages: 175-181

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Distinct signaling requirements for Dμ selection, IgH allelic exclusion2003

    • Author(s)
      Hayashi, K.
    • Journal Title

      Immunity. 18

      Pages: 825-836

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Regulation of Vav Localization in Membrane Rafts by Adaptor2003

    • Author(s)
      Johmura, S.
    • Journal Title

      Immunity. 18

      Pages: 777-787

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Targeting of MIST to Src-family kinases via SKAP55-SLAP-130 adaptor complex in mast cells.2003

    • Author(s)
      Fujii, Y.
    • Journal Title

      EBBS Letter 540

      Pages: 111-116

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Molecular visualization of immunoglobulin switch region RNA/DNA complex by atomic force microscope.2003

    • Author(s)
      Mizuta, R.
    • Journal Title

      J.Biol.Chem. 278

      Pages: 4431-4434

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Induction of protective immunity by primed B-1 cells in Toxoplasma gondii-infected B cell-deficient mice.2003

    • Author(s)
      Chen, M., Mun, H.S., Piao, L.X., Aosai, F., Norose, K., Mohamed, R.M., Belal, U.S., Fang, H., Ahmed, A.K., Kang, H.K., Matsuzaki, G., Kitamura, D., Yano, A.
    • Journal Title

      Microbiol.Immunol. 47(12)

      Pages: 997-1003

    • NAID

      50000360286

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Atomic force microscopy analysis of rolling circle amplification of plasmid PNA.2003

    • Author(s)
      Mizuta R., Mizuta, M., Kitamura, D.
    • Journal Title

      Arch.Histol.Cytol. 66(2)

      Pages: 175-181

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Distinct signaling requirements for Dμ selection, IgH allelic exclusion, pre-B cell transition and tumor suppression in B-cell progenitors.2003

    • Author(s)
      Hayashi, K., Yamamoto, M., Nojima, T., Goitsuka, R., Kitamura, D.
    • Journal Title

      Immunity 18(6)

      Pages: 825-836

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Regulation of Vav Localization in Membrane Rafts by Adaptor Molecules Grb2 and BLNK.2003

    • Author(s)
      Johmura, S., Oh-hora, M., Inabe, K., Nishikawa, Y., Hayashi, K., Vigorito, E., Kitamura, D., Turner, M., Shingu, K., Hikida, M., Kurosaki, T.
    • Journal Title

      Immunity 18(6)

      Pages: 777-787

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Targeting of MIST to Src-family kinases via SKAP55-SLAP-130 adaptor complex in mast cells.2003

    • Author(s)
      Fujii, Y., Wakahara, S., Nakao, T., Hara, T., Ohtake, H., Komurasaki, T., Kitamura, K., Tatsuno, A., Fujiwara, N., Hozumi, N., Ra, C., Kitamura, D., Goitsuka, R.
    • Journal Title

      FEBS Lett. 540

      Pages: 111-116

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Molecular visualization of immunoglobulin switch region RNA/DNA complex by atomic force microscope.2003

    • Author(s)
      Mizuta, R., Iwai, K., Shigeno, M., Mizuta, M., Uemura, T., Ushiki, T., Kitamura, D.
    • Journal Title

      J.Biol.Chem. 278

      Pages: 4431-4434

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] RAG2 is down-regulated by cytoplasmic sequestration and ubiquitin-dependent degradation.2002

    • Author(s)
      Mizuta, R.
    • Journal Title

      J.Biol.Chem. 277

      Pages: 41423-41427

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] RAG2 is down-regulated by cytoplasmic sequestration and ubiquitin-dependent degradation.2002

    • Author(s)
      Mizuta, R., Mizuta, M., Araki, S., Kitamura, D.
    • Journal Title

      J.Biol.Chem. 277(44)

      Pages: 41423-41427

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] 免疫20052004

    • Author(s)
      山本睦美
    • Total Pages
      425
    • Publisher
      中山書店
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] キーワードで理解する免疫学イラストマップ2004

    • Author(s)
      北村大介
    • Total Pages
      236
    • Publisher
      羊土社
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Chen, M.: "Induction of protective immunity by primed B-1 cells in Toxoplasma gondii-infected B cell-deficient mice."Microbiol.Immunol.. 47(12). 997-1003 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hayashi, K.: "Distinct signaling requirements for Dμ selection, IgH allelic exclusion, pre-B cell transition and tumor suppression in B-cell progenitors."Immunity. 18(6). 825-836 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Johmura, S.: "Regulation of Vav Localization in Membrane Rafts by Adaptor Molecules Grb2 and BLNK."Immunity. 18(6). 777-787 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Fujii, Y.: "Targeting of MIST to Src-family kinases via SKAP55-SLAP-130 adaptor complex in mast cells."FEBS Letter. 540(1-3). 111-116 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mizuta, R.: "Molecular visualization of immunoglobulin switch region RNA/DNA complex by atomic force microscope."J.Biol.Chem.. 278(7). 4431-4434 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Goitsuka, R.: "MIST functions through distinct domains in immunoreceptor signaling in the presence and absence of LAT"J. Biol. Chem.. 276(38). 36043-36050 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tsuji, S.: "B cell adaptor containing Src Homology 2 domain (BASH) links B cell receptor signaling to the activation of hematopoietic progenitor kinase 1"J. Exp. Med.. 194(4). 529-539 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Morimura, T.: "Notch signaling suppresses IgH gene expression in chicken B cells : implication in spatially restricted expression of Serrate2/Notch1 in the bursa of Fabricius"J. Immunol.. 166(5). 3277-3283 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Morimura, T.: "Cell cycle arrest and apoptosis induced by Notch1 in B cells"J. Biol. Chem.. 275(47). 36523-36531 (2000)

    • Related Report
      2002 Annual Research Report
  • [Publications] Fusaki, N.: "BLNK is associated with the CD72/SHP-1/Grb2 complex in the WEHI231 cell line after membrane IgM cross-linking"Eur. J. Immunol.. 30(5). 1326-1330 (2000)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hayashi, K.: "The B cell-restricted adaptor BASH is required for normal development and antigen receptor-mediated activation of B cells"Proc. Natl. Acad. Sci. USA. 97(6). 2755-2760 (2000)

    • Related Report
      2002 Annual Research Report
  • [Publications] 北村 大介: "Molecular Medicine Vol.37 臨時増刊号「免疫2000-01」"中山書店. 273 (2000)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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