• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

自己反応性B細胞の寛容破綻に関わる遺伝的機構とその制御

Research Project

Project/Area Number 13140205
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionJuntendo University

Principal Investigator

広瀬 幸子  順天堂大学, 医学部, 助教授 (00127127)

Co-Investigator(Kenkyū-buntansha) 中村 和裕  順天堂大学, 医学部, 助手 (10327835)
Project Period (FY) 2001 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥131,900,000 (Direct Cost: ¥131,900,000)
Fiscal Year 2005: ¥24,700,000 (Direct Cost: ¥24,700,000)
Fiscal Year 2004: ¥24,700,000 (Direct Cost: ¥24,700,000)
Fiscal Year 2003: ¥27,000,000 (Direct Cost: ¥27,000,000)
Fiscal Year 2002: ¥27,000,000 (Direct Cost: ¥27,000,000)
Fiscal Year 2001: ¥28,500,000 (Direct Cost: ¥28,500,000)
Keywords全身性エリテマトーデス / New Zealand マウス / 感受性遺伝子 / 遺伝子多型 / FcγRIIB / IL-4Rα / recombinant congenic マウス / 主要組織適合遺伝子複合体 / New Zealandマウス / LTK / PI3 kinase / FCγRIIB / 自己感応性B細胞 / 連鎖解析 / 制御領域多型 / gain-of-function型多型 / プロモーター領域多型 / 転写制御
Research Abstract

自己免疫疾患発症には、免疫応答調節に関わる複数の感受性遺伝子が関与している。抗体依存性自己免疫疾患における自己反応性B細胞の出現の原因を遺伝的に解析することで、B細胞免疫寛容破綻の原因を捉えられる。本年度は、全身性エリテマトーデス(SLE)自然発症マウス系を用いた遺伝的解析により得られた、第1染色体上のFcgr2b遺伝子のプロモーター多型、第7染色体上のIL-4Rα鎖の遺伝子多型、第17染色体上の主要組織適合遺伝子複合体(MHC)の多型と自己反応性B細胞の出現との関わりについて解析した。
1.Fcgr2b遺伝子プロモーター領域多型:SLEマウス系に共通して存在するFcgr2bのプロモーター領域のAp-4結合部位の欠損を伴う多型が、実際にSLEの感受性遺伝子であることを、SLE自然発症B×SBマウスのプロモーター多型を正常マウス型に入れ替えることで証明した。また、FcγRIIB分子は、B細胞のみでなく、樹状細胞の増殖と活性化にも働いていると考えられ、現在、その機序を解析中である。
2.IL-4Rα鎖遺伝子多型:IL-4はB細胞を活性化して、抗体産生を亢進させる。IL-4産生能には、マウス間で大きな差がみられ、T細胞によるIL-4産生能の違いは、IL-4Ra鎖のアミノ酸置換を伴う遺伝子多型に起因することを見出した。
3.MHCクラスII領域には、自己反応性B細胞の活性および抑制に働く部位が存在することを、recombinant congenicマウス系の樹立により明らかにした。具体的には、クラスIIのE分子の存在は、SLEを高度に抑制し、その機序の一つに、胸腺での自己反応性T細胞の負の選択にE分子が働いていることを見出した。一方、A分子においては、そのα鎖とβ鎖の遺伝子型の組み合わせの違いは、SLE病態を左右するのみでなく、SLE病態を関節リウマチ(RA)に変換させる可能性を得た。

Report

(5 results)
  • 2005 Annual Research Report
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (28 results)

All 2005 2004 Other

All Journal Article (10 results) Publications (18 results)

  • [Journal Article] Genome-wide scan in novel IgA nephropathy model identifies susceptibility locus on murine chromosome 10, in a region sytenic to human IGAN1 on chromosome 6q22-23.2005

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

      J.Am.Soc.Nephrol. 16

      Pages: 1289-1299

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Chromosomal mapping of a quantitative trait locus for the development of albuminuria in diabetic KK/Ta mice.2005

    • Author(s)
      T.Shike, et al.
    • Journal Title

      Nephrol.Dial.Transplant. 20

      Pages: 879-885

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Fas ligand and TNF-related apoptosis-inducing ligand induction on infiltrating lymphocytes in bladder carcinoma by bacillus Calmette-Guerin treatment.2005

    • Author(s)
      M.Mehmut, et al.
    • Journal Title

      Urol.Int. 75

      Pages: 80-87

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Polymorphism of the mouse gene for the interleukin 10 receptor alpha chain (Il10ra) and its association with the autoimmune phenotype.2005

    • Author(s)
      Z.Qi, et al.
    • Journal Title

      Immunogenetics 57

      Pages: 697-702

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Correlation of aggression with serum IgM level in autoimmune-prone NZB mice.2005

    • Author(s)
      K.Nakamura, et al.
    • Journal Title

      Developmental Brain Research1 59

      Pages: 145-148

    • Related Report
      2005 Annual Research Report
  • [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 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

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Nucleosome-specific regulatory T cells engineered by triple gene trasfer suppress a systemic autoimmune disease.2004

    • Author(s)
      K.Fujio, et al.
    • Journal Title

      J.Immunol. 173

      Pages: 2118-2125

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Dissection of the role of MHC class II A and E genes in autoimmune susceptibility inmurine lupus models with intragenic recombination.2004

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

      Proc.Natl.Acad.Sci.USA 101

      Pages: 13838-13843

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Genome-wide scan in novel IgA nephropathy model identifies susceptibility locus on murine chromosome 10, in a region syntenic to human IGAN1 on chromosome 6q22-23.2004

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

      J.Am.Soc.Neph. (in press)

    • Related Report
      2004 Annual Research Report
  • [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.Fujimura, et al.: "Spontaneous increase of _plasma-like cells with high GAMP expression in the extrafollicular region of lymphoid organs of autoimmune-prone mice."Autoimmunity. 20. 291-301 (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] H.Iwai, et al.: "Involvement of inducible costimulator-B7 homologous protein costimulatory pathway in murine lupus nephritis."J.Immunol.. 171. 2848-2854 (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. Blood, submitted for publication."J.Immunol.. (In press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Miyamoto A, et al.: "Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cδ"Nature. 416. 865-869 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Miura-Shimura Y, et al.: "Clq regulatory region polymorphism down-regulating murine Clq protein levels with linkage to lupus nephritis"J.Immunol.. 169. 1334-1339 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] XieY, et al.: "Transcriptional regulation of Fcgr2b gene by polymorphic promoter region and its contribution to humoral immune responses"J.Immunol.. 169. 4340-4346 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Iwai H, et al.: "Amelioration of collagen-induced arthritis by brokade of inducible costimulator-b7 homologous protein costimulation"J.Immunol.. 169. 4332-4339 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shirai T, et al.: "Genome screening for susceptibility loci in systemic lupus erythematosus"Am.J.Pharmacogenomics. 2. 1-12 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hirose S, et al.: "Genetic basis of systemic lupus erythematosus"Drugs of Today. 38. 167-184 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takasaki Y., et al.: "Reactivity of anti-PCNA murine monoclonal antibodies and human autoantibodies to the PCNA multiprotein complexes involved in cell proliferation"J. Immunol.. 166. 4780-4787 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Shike T. et al.: "Susceptibility and negative epistatic loci contributing to type 2 diabetes mellitus and related phenotypes in a KK/Ta mouse models"Diabetes. 50. 1943-1948 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hirose S., et al.: "Genetic study of SLE : lessons from mouse models"Mod. Rheumatol.. 11. 262 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Jiang Y., et al.: "Polymorphism and chromosomal mapping of the murine gene for B cell activating factor belonging to the TNF family (BAFF) and association with the autoimmune phenotype"Immunogenetics. 53. 810-813 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Shirai T., et al.: "Genome screening for susceptibility loci in systemic lupus erythematosus"Am. J. Pharmacogenomics. 2. 1-12 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hirose S., et al.: "Genetic basis of systemic lupus erythematosus"Drug of Today. (in press). (2002)

    • Related Report
      2001 Annual Research Report

URL: 

Published: 2001-04-01   Modified: 2018-03-28  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi