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Immunoregulatory function of Lnk/Sh2b3, a common risk factor gene for immune, hematopoietic and cardiovascular diseases

Research Project

Project/Area Number 25293097
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field Experimental pathology
Research InstitutionNational Center for Global Health and Medicine

Principal Investigator

Takaki Satoshi  国立研究開発法人国立国際医療研究センター, 研究所, 免疫制御研究部長 (10242116)

Project Period (FY) 2013-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000)
Fiscal Year 2015: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2014: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2013: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Keywords疾患関連遺伝子 / 自己免疫 / 高血圧 / 糖尿病 / シグナル伝達 / 骨髄増殖性疾患 / 免疫学
Outline of Final Research Achievements

Mutations in the LNK/SH2B3 gene are found in myeloproliferative disease patients, and LNK/SH2B3 polymorphisms have been reported to be associated with several autoimmune diseases and cardiovascular diseases. The intracellular adaptor Lnk/Sh2b3 regulates cytokine signals that control lymphohematopoiesis, However, the functions of Lnk/Sh2b3 related to autoimmune inflammation or cardiovascular dysfunction have not been understood. We have revealed that the ability of DCs to support Th1 response was altered by Lnk-deficiency. We have shown that Lnk/Sh2b3 plays a role in preventing pathogenic expansion and activation of CD8+ T cells leading to intestinal tissue damage in Lnk-/- mice. IFN-gamma-producing CD8+ T cells were increased in kidney and arteries, resulting in increased susceptibility for hypertension. We also found that Lnk-/- mice showed impaired glucose tolerance that was largely depend on the abnormality of hematopoietic cells.

Report

(4 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Annual Research Report
  • 2013 Annual Research Report
  • Research Products

    (20 results)

All 2016 2015 2014 2013 Other

All Int'l Joint Research (1 results) Journal Article (8 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 8 results,  Open Access: 2 results) Presentation (11 results)

  • [Int'l Joint Research] ヴァンダービルト大学/アトランタ大学/国立心肺血液研究所(米国)

    • Related Report
      2015 Annual Research Report
  • [Journal Article] Interferon-gamma Constrains Cytokine Production of Group 2 Innate Lymphoid Cells2016

    • Author(s)
      Kudo, F. Ikutani, M. Seki, Y. Otsubo, T. Kawamura, Y. I. Dohi, T. Oshima, K. Hattori, M. Nakae, S. Takatsu, K. Takaki, S.
    • Journal Title

      Immunology

      Volume: 147 Issue: 1 Pages: 21-29

    • DOI

      10.1111/imm.12537

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Lymphocyte adaptor protein LNK deficiency exacerbates hypertension and end-organ inflammation.2015

    • Author(s)
      Saleh MA, McMaster WG, Wu J, Norlander AE, Funt SA, Thabet SR, Kirabo A, Xiao L, Chen W, Itani HA, Michell D, Huan T, Zhang Y, Takaki S, Titze J, Levy D, Harrison DG, Madhur MS.
    • Journal Title

      J Clin Invest.

      Volume: 125 Issue: 3 Pages: 1189-1202

    • DOI

      10.1172/jci76327

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Lnk prevents inflammatory CD8+ T-cell proliferation and contributes to intestinal homeostasis.2014

    • Author(s)
      Katayama H., Mori T., Seki Y., Anraku M., Iseki M., Ikutani M., Iwasaki Y., Yoshida N., Takatsu K., Takaki S.
    • Journal Title

      European Journal of Immunology

      Volume: 44 Issue: 6 Pages: 1622-1632

    • DOI

      10.1002/eji.201343883

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Lnk/Sh2b3 controls the production and function of dendritic cells, regulates the induction of IFN-gamma-producing T cells.2014

    • Author(s)
      Mori T., Iwasaki Y., Seki Y., Iseki M., Katayama H., Yamamoto K., Takatsu K., Takaki S.
    • Journal Title

      The Journal of Immunology

      Volume: 193 Issue: 4 Pages: 1728-36

    • DOI

      10.4049/jimmunol.1303243

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Nov/ccn3 regulates long-term repopulating activity of murine hematopoietic stem cells via integrin αvβ32014

    • Author(s)
      J. Ishihara, et al
    • Journal Title

      International Journal of Hematology

      Volume: (印刷中) Issue: 4 Pages: 393-406

    • DOI

      10.1007/s12185-014-1534-x

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Generation of engraftable hematopoietic stem cells from induced pluripotent stem cells by way of teratoma formation.2013

    • Author(s)
      Suzuki N, Yamazaki S, Yamaguchi T, Okabe M, Masaki H, Takaki S, Otsu M, Nakauchi H.
    • Journal Title

      Mol Ther.

      Volume: 21 Issue: 7 Pages: 1424-31

    • DOI

      10.1038/mt.2013.71

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Adipose natural regulatory B cells negatively control adipose tissue inflammation2013

    • Author(s)
      Nishimura S, Manabe I, Takaki S, Nagaskai M, Ostu M, Yamashita H, Sugita J, Yoshimura K, Eto K, Komuro I, Kadowaki T, Nagai R
    • Journal Title

      Cell Metabolism

      Volume: 18 Issue: 5 Pages: 759-766

    • DOI

      10.1016/j.cmet.2013.09.017

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] TWEAK/Fn14 pathway promotes a T helper 2-type chronic colitis with fibrosis in mice2013

    • Author(s)
      Son A, Oshio T, Kawamura YI, Hagiwara T, Yamazaki M, Inagaki-Ohara K, Okada T, Wu P, Iseki M, Takaki S, Burkly LC, Dohi T
    • Journal Title

      Mucosal Immunology

      Volume: 6 Issue: 6 Pages: 1131-1142

    • DOI

      10.1038/mi.2013.10

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Presentation] An autoimmune disease-associated gene, Lnk/Sh2b3 controls inflammation in adipose tissue and reduces the risk for onset of diabetes.2015

    • Author(s)
      Mori T, Yamazaki N, Takaki S.
    • Organizer
      第44回 日本免疫学会学術集会
    • Place of Presentation
      札幌
    • Year and Date
      2015-11-18
    • Related Report
      2015 Annual Research Report
  • [Presentation] Inhibitory effects of interferon-γ on cytokine production in group 2 innate lymphoid cells.2015

    • Author(s)
      Kudo F, Takaki S.
    • Organizer
      第44回 日本免疫学会学術集会
    • Place of Presentation
      札幌
    • Year and Date
      2015-11-18
    • Related Report
      2015 Annual Research Report
  • [Presentation] Germinal center B cell survival and optimal IgE production are controled by Lnk/Sh2b family adaptor protein Aps/Sh2b2.2015

    • Author(s)
      Iseki M, Kudo F, Takaki S.
    • Organizer
      第44回 日本免疫学会学術集会
    • Place of Presentation
      札幌
    • Year and Date
      2015-11-18
    • Related Report
      2015 Annual Research Report
  • [Presentation] Lnk/Sh2b3 adaptor protein controls cytokine responses of dendritic cells, and regulates the induction of IFN-γ-producing T cells.2014

    • Author(s)
      Mori T, Iseki M, Takaki S.
    • Organizer
      第43回 日本免疫学会学術集会
    • Place of Presentation
      京都
    • Year and Date
      2014-12-10 – 2014-12-12
    • Related Report
      2014 Annual Research Report
  • [Presentation] IgM+ plasma cells contribute to the sufficient production of IgG by secreting IL-10 and IL-13.2014

    • Author(s)
      Yamazaki N, Takaki S.
    • Organizer
      第43回 日本免疫学会学術集会
    • Place of Presentation
      京都
    • Year and Date
      2014-12-10 – 2014-12-12
    • Related Report
      2014 Annual Research Report
  • [Presentation] Lnk/Sh2b family adaptor protein Aps/Sh2b2 in B cells contributes to germinal center B cell survival and optimal IgE production in vivo.2014

    • Author(s)
      Iseki M, Kudo F, Takaki S.
    • Organizer
      第43回 日本免疫学会学術集会
    • Place of Presentation
      京都
    • Year and Date
      2014-12-10 – 2014-12-12
    • Related Report
      2014 Annual Research Report
  • [Presentation] Suppression of cytokine production from group 2 innate lymphoid cells by interferon-γ.2014

    • Author(s)
      Kudo F, Seki Y, Takaki S.
    • Organizer
      第43回 日本免疫学会学術集会
    • Place of Presentation
      京都
    • Year and Date
      2014-12-10 – 2014-12-12
    • Related Report
      2014 Annual Research Report
  • [Presentation] Lnk/Sh2b3, an intracellular adaptor associated with celiac disease and autoimmune diabetes, regulates accumulation of inflammatory T cells and prevents intestinal villous atrophy. The 15th International Congress of Immunology.2013

    • Author(s)
      Mori T, Katayama H, Iwasaki Y, Seki Y, Iseki M, Ikutani M, Yoshida N, Takatsu K, Takaki S.
    • Organizer
      The 15th International Congress of Immunology
    • Place of Presentation
      Milan, Italy
    • Related Report
      2013 Annual Research Report
  • [Presentation] Lnk/Sh2b3 adaptor protein prevents the accumulation of inflammatory CD8+ T cells and intestinal villous atrophy.2013

    • Author(s)
      Seki Y, Katayama H, Mori T, Iseki M, Takaki S.
    • Organizer
      第42回 日本免疫学会学術集会
    • Place of Presentation
      千葉
    • Related Report
      2013 Annual Research Report
  • [Presentation] An autoimmune disease-associated gene, Lnk/SH2B3 controls production and functions of DC subsets and regulates inflammatory T cell differentiation.2013

    • Author(s)
      Mori T, Seki Y, Iwasaki Y, Yamazaki-Suzuki N, Iseki M, Takaki S.
    • Organizer
      第42回 日本免疫学会学術集会
    • Place of Presentation
      千葉
    • Related Report
      2013 Annual Research Report
  • [Presentation] IgE production and germinal center formation are regulated by the adaptor protein Aps/Sh2b2 in B cells.2013

    • Author(s)
      Iseki M, Kudo F, Takaki S.
    • Organizer
      第42回 日本免疫学会学術集会
    • Place of Presentation
      千葉
    • Related Report
      2013 Annual Research Report

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Published: 2013-05-21   Modified: 2022-01-27  

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