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Role of G-CSF and C-CSF receptor gene polymorphisms for the development of lupus nephritis

Research Project

Project/Area Number 15300145
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Laboratory animal science
Research InstitutionJUNTENDO UNIVERSITY

Principal Investigator

HIROSE Sachiko (2004)  Juntendo Univ., Sch Med,. Dept Pathol., Associate Prof., 医学部, 助教授 (00127127)

姜 奕 (2003)  順天堂大学, 医学部, 助手 (50276466)

Co-Investigator(Kenkyū-buntansha) MATSUOKA Shuji  Juntendo Univ., Sch Med,. Dept Pathol., Instructor, 医学部, 助手 (20286743)
広瀬 幸子  順天堂大学, 医学部, 助教授 (00127127)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥10,300,000 (Direct Cost: ¥10,300,000)
Fiscal Year 2004: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 2003: ¥5,300,000 (Direct Cost: ¥5,300,000)
KeywordsG-CSF / G-CSF receptor / gene polymorphism / lupus nephritis / linkage analysis / susceptibility gene / (NZB x NZW) F1 mouse / Th1 / Th2 balance / 連鎖解 / IL-4 / 自己抗体産生
Research Abstract

Systemic lupus erythematosus(SLE), a complex multigenic disease, is a typical antibody-mediated autoimmune disease characterized by production of autoantibodies against a variety of autoantigens and immune complex(IC)-type tissue inflammation, most prominently in the kidney. In SLE-prone (NZB x NZW) Fl mice, IC-type lupus nephritis more severe than parental NZB develop due to the contribution of susceptibility genes derived from both NZB and NZW strains. Our genome-wide scans to search for susceptibility genes for lupus nephritis in backcross mice of (NZB x NZW) Fl to NZB or NZW mice showed evidence that the NZB gene located in the vicinity of Clq and G-CSF receptor gene on chromosome 4 and NZW gene located in the vicinity of G-CSF gene on chromosome 11 are involved in severe nephritis. Sequence and functional analyses of Clq and G-CSF receptor genes revealed that the candidate gene on chromosome 4 seems to be Clq. Sequence analysis of G-CSF genes showed that there are sequence polymorphisms in 3' UTR region between NZB and NZW. Possibly due to these polymorphisms, G-CSF mRNA level and G-CSF production capacity by macrophages were significantly higher in NZW than in NZB. Furthermore, number of peripheral neutrophil was significantly higher in NZW than in NZB, and NZW neutrophil seemed to be more activated, estimated by enlarged cell size. In addition, in vitro cytokine analysis in anti-CD3 antibody-stimulated splenic T cells showed that G-CSF is able to enhance Th2-type cytokine, IL-4.
Based on these findings, it was suggested that NZW-type polymorphic G-CSF gene possibly contribute to high G-CSF levels, which in turn contribute to the susceptibility to lupus nephritis due to the increase in neutrophil number and activity, and due to the up-regulation of IC-formation through the high level of Th2 cytokine production.

Report

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

    (18 results)

All 2004 2003 Other

All Journal Article (14 results) Publications (4 results)

  • [Journal Article] Gain-of-function polymorphism in mouse and human Ltk : implications for the pathogenesis of systemic lupus erythematosus.2004

    • Author(s)
      N.Li, et al.
    • Journal Title

      Hum.Mol.Genet. 13

      Pages: 171-179

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Transgene-mediated over-expression of interleukin-5 suppresses autoimmune disease, but increases the risk of B cell chronic lymphocytic leukemia.2004

    • Author(s)
      X.Wen, et al.
    • Journal Title

      Eur.J.Immunol. 34

      Pages: 2740-2749

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Dissection of the role of MHC class II A and E genes in autoimmune susceptibility in murine lupus models with intragenic recombination.2004

    • Author(s)
      D.Zhang, et al.
    • Journal Title

      Proc.Natl.Acad.Sci.USA 101

      Pages: 13838-13843

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Gain-of-function polymorphism in mouse and human Ltk : implications for the pathogenesis of systemic lupus erythematosus.2004

    • Author(s)
      Li N, Nakamura K, Jiang Y, Tsurui H, Matsuoka S, Abe M, Ohtsuji M, Nishimura H, Kato K, Kawai T, Atsumi T, Koike T, Shirai T, Ueno H, Hirose S.
    • Journal Title

      Hum.Mol.Genet. 13

      Pages: 171-179

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Transgene-mediated hyper-expression of IL-5 inhibits autoimmune disease, but increases the risk of B-cell chronic lymphocytic leukemia in a model of murine lupus.2004

    • Author(s)
      Wen X, Zhang D, Kikuchi Y, Jiang Y, Nakamura K, Xiu Y, Tsurui H, Takahashi K, Abe M, Ohtsuji M, Nishimura H, Takatsu K, Shirai T, Hirose S.
    • Journal Title

      Eur.J.Immunol. 34

      Pages: 2740-2749

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Dissection of the role of MHC class II A and E genes in autoimmune susceptibility in murine lupus models with intragenic recombination.2004

    • Author(s)
      Zhang D, Fujio K, Jiang Y, Zhao J, Tada N, Sudo K, Tsurui H, Nakamura K, Yamamoto K, Nishimura H, Shirai T, Hirose S.
    • Journal Title

      Proc.Nati.Acad.Sci.USA 101

      Pages: 13838-13843

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Gain-of-function polymorphism in mouse and human Ltk : implications for the pathogenesis of systemic lupus erythematosus.2004

    • Author(s)
      N.Li, et al.
    • Journal Title

      Hum.Mol.Genet 13

      Pages: 171-179

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Transgene-mediated over-expression of interleuldn-5 suppresses autoimmune disease, but increases the risk of B cell chronic lymphocytic leukemia.2004

    • Author(s)
      X.Wen, et al.
    • Journal Title

      Eur.J.Immunol. 34

      Pages: 2740-2749

    • Related Report
      2004 Annual Research Report
  • [Journal Article] A monoclonal antibody to the α2 domain of murine major histocompatibility complex class I that specifically kills activated lymphocytes and blocks liver damage in the concanavalin A hepatitis model.2003

    • Author(s)
      S.Matsuoka, et al.
    • Journal Title

      J.Exp.Med. 198

      Pages: 497-503

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Spontaneous increase of plasma-like cells with high GAMP expression in the extrafollicular region of lymphoid organs of autoimmune-prone mice.2003

    • Author(s)
      S.Fujimura, et al.
    • Journal Title

      J.Autoimmunity 20

      Pages: 291-301

    • 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 inducible costimulator-B7 homologous protein costimulatory pathway in murine lupus nephritis.2003

    • Author(s)
      H.Iwai, et al.
    • Journal Title

      J.Immunol. 171

      Pages: 2848-2854

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] A monoclonal antibody to the a2 domain of murine major histocompatibility complex class I that specifically kills activated lymphocytes and blocks liver damage in the concanavalin A hepatitis model.2003

    • Author(s)
      Matsuoka S, Tsurui H, Abe M, Terashima K, Nakamura K, Hamano Y, Ohtsuji M, Honma N, Serizawa I, Ishii Y, Takiguchi M, Hirose S, Shirai T.
    • Journal Title

      J.Exp.Med. 198

      Pages: 497-503

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Spontaneous increase of plasma-like cells with high GAMP expression in the extrafollicular region of lymphoid organs of autoimmune-prone mice.2003

    • Author(s)
      Fujimura S, Kuwahara K, Ezaki T, Tomita K, Hirose S, Sakaguchi N.
    • Journal Title

      J.Autoimmunity 20

      Pages: 291-301

    • 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 inducible costimulator-B7 homologous protein costimulatory pathway in murine lupus nephritis.2003

    • Author(s)
      Iwai H, Abe M, Hirose S, Tsushima F, Tezuka K, Akiba H, Yagita H, Okumura K, Miyasaka N, Azuma M.
    • Journal Title

      J.Immunol. 171

      Pages: 2848-2854

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] K.Nakamura, et al.: "Genetic dissection of anxiety in autoimmune disease."Hum.Mol.Genet.. 12. 1079-1086 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] S.Matsuoka, et al.: "A monoclonal antibody to the α2 domain of murine major histocompatibility complex class I that specifically kills activated lymphocytes and blocks liver damage in the concanavalin A hepatitis model."J.Exp.Med.. 198. 497-503 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] N.Li, et al.: "Gain-of-function polymorphism in mouse and human Ltk : implications for the pathogenesis of systemic lupus erythematosus."Hum.Mol.Genet.. 13. 171-179 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] X.Wen, et al.: "Transgene-mediated over-expression of interleukin-5 suppresses autoimmune disease, but increases the risk of B cell chronic lymphocytic leukemia."J.Immnunol.. (In press). (2004)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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