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Establishment of knock-in mice for functional analysis of FcyRIIB regulatory region polymorphism

Research Project

Project/Area Number 13680916
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Laboratory animal science
Research InstitutionJuntendo University

Principal Investigator

YI Jiang  Juntendo Univ., Dept. Pathol., Instructor, 医学部, 助手 (50276466)

Co-Investigator(Kenkyū-buntansha) NAKAMURA Kazuhiro  Juntendo Univ., Dept. Pathol., Instructor, 医学部, 助手 (10327835)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2001: ¥1,900,000 (Direct Cost: ¥1,900,000)
Keywordssystemic lupus erythematosus / susceptibility gene / FcyRIIB1 molecule / hyper- IgG / linkage analysis / promoter region polymorphism / AP-4 / germinal center B cells / Fc_γRIIB1分子 / Ap-4 / 転写制御
Research Abstract

FcyRIIB1 serves as negative feedback regulator for BCR-elicited activation of B cells, thus, any impaired FcyRIIB1 function may possibly be related to aberrant B cell activation. We earlier found deletion polymorphism in the Fcgr2b promoter region among mouse strains, in which systemic autoimmune disease-prone NZB, BXSB and MRL. but not NZW, BALB/c and C57BL/6 mice, have two identical deletion sites, consisting of 13 and 3 nucleotides. Here we established congenic C57BL/6 mice for NZB-type Fcgr2b allele and found that NZB-type allele down-regulates FcyRIIB1 expression levels in germinal center (GC) B cells and up-regulates IgG antibody responses. We did luciferase reporter assays to determine if NZB-type deletion polymorphism affects transcriptional regulation of Fcgr2b gene. While NZW-derived segments from position -302 to +585 of Fcgr2b upstream region produced significant levels of luciferase activities, only a limited activity was detected in the NZB-derived sequence. Electrophoretic morbility shift assay and Southwestern analysis revealed that defect in transcription activity in the NZB-derived segment is likely due to absence of trans-activation by AP-4, which binds to the polymorphic 13 nucleotide deletion site. Our data imply that because of the deficient AP-4 binding, the NZB-type Fcgr2b allele polymorphism results in up-regulation of IgG antibody responses through down-regulation of FcyRIIB1 expression levels iu GC B cells, and that such polymorphism may possibly form the basis of autoimmune susceptibility in combination with other background contributing genes.
We are on the way to establish homologous recombination mouse strain for Fcgr2b promoter region polymorphism using 1 29-derived ES cell lines and have obtained two positive clones.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (20 results)

All Other

All Publications (20 results)

  • [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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Miyamoto A, et al.: "Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cδ"Nature. 416. 865-869 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Miura-Shimura Y, et al.: "C1q regulatory region polymorphism down-regulating murine c1q protein levels with linkage to lupus nephritis"J. Immunol.. 169. 1334-1339 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Xie Y, et al.: "Transcriptional regulation of Fcgr2b gene by polymorphic promoter region and its contribution to humoral immune responses"J. Immunol.. 169. 4340-4346 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shirai T, et al.: "Genome screening for susceptibility loci in systemic lupus erythematosus"Am. J. Pharmacogenomics. 2. 1-12 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hirose S, et al.: "Genetic basis of systemic lupus erythematosus"Drugs of Today. 38. 167-184 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Jiang Y., Ohtsuji M, Abe M, Li N, Xiu Y, Wen X, Shirai T, Hieose S: "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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Miyamoto A, Nakayama K, Hirose S, Jiang Y, Abe M,Tsukiyama T, Nagahama H. Ohno S. Hatakeyama S, Nakayama K: "Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cδ"Nature. 416. 865-869 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Miura-Shimura Y, Nakamura K, Ohtsuji M, Tomita H, Jiang Y, Abe M, Zhang D, Hamano Y, Tsuda H, Hashimoto H, Nishimura H, Taki S, Shirai T, Hirose S: "Clq regulatory region polymorphism down-regulating marine Clq protein levels with linkage to lupus nephritis"J Immunol. 169. 1334-1339 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Xie Y, Nakamura K, Abe M, Li N, Wen X-S, Jiang Y, Zhang D, Tsurui H, Matsuoka S, Hamano Y, Fujii H, Ono M, Takai T, Shimokawa T, Ra C, Shirai T, Hirose S: "Transeriptional regulation of Fcgr2b gene by polymorphic promoter region and its contribution to humoral immune responses"J Immunol. 169. 4340-4346 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shirai T, Nishimura H, Jiang Y, Hirose S: "Genome screening for susceptibility loci in systemic lupus erythematosus"Am J Pharmacogenomics. 2. 1-12 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hirose S, Jiang Y, Hamano Y, Nishimura H: "Genetic basis of systemic lupus erythematosus"Drugs of Today. 38. 167-184 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [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.: "C1q regulatory region polymorphism down-regulating murine C1q protein levels with linkage to lupus nephritis"J.Immunol.. 169. 1334-1339 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Xie Y, 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] 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] 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, Prous Science, Barcelona, Spain. (in press). (2002)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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