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Molecular basis of keratinocyte desmosomes and acantholysis using imunoelectron microscopy

Research Project

Project/Area Number 15591192
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Dermatology
Research InstitutionKeio University

Principal Investigator

ISHIKO Akira  Keio University, School of Medicine, Assistant Professor, 医学部, 専任講師 (10202988)

Co-Investigator(Kenkyū-buntansha) NISHIKAWA Takeji  Keio University, School of Medicine, Professor, 医学部, 教授 (50051579)
AMAGAI Masayuki  Keio University, School of Medicine, Assistant Professor, 医学部, 専任講師 (90212563)
齋藤 京  慶應義塾大学, 医学部, 助手 (50286548)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
Keywordspemphigus vulgaris / immunoelectron microscopy / desmosome / desmoplakin / desmoglein / plakoglobin / model mouse / cell adhision / 免疫電顕法 / 電子顕微鏡 / 自己免疫疾患
Research Abstract

Pemphigus vulgaris(PV) is an autoimmune blistering skin disease caused by binding of autoantibodies to the desmosomal desmoglein 3 (Dsg3). Although it has been confirmed that the autoantibodies themselves are pathogenic and plays a central role of this disease, the mechanism of blister formation in the epidermis alter binding autoantibodies to the autoantigen has not been clarified, yet. In this project, we have investigated the molecular changes in the desmosomes using PV model mice, which produce anti-Dsg3 autoantibodies as well as clinical, histological and immunological phenotype of PV, Dsg3 knockout(-/-) mice, which produce clinical and histological phenotype mimicking PV, and respective control mice. Desmosomal components including Dsg 1, desmocollin(Dsc) 1, Dsc3, plakoglobin(PG), plakophilin 1(Pp1), desmoplakin (DP) were immunolocalized using post-embedding immunogold electron microscopy in each mouse. All the labeling was measured in terms of distance from plasma membrane and number of labeling per desmosome, and statistically analyzed. As results, in Dsg3 -/- mice, the localization of DP shifted 11 nm toward intracellular direction, suggesting a close relationship between Dsg3 and DP. In addition, number of PG in Dsg3 -/- mice decreased significantly. This might be due to the disturbed recruitment of PG in desmosomal formation by lacking Dsg3. The small shift of DP might be caused by the decrease of PG, which is a major ligand of DP to the desmosomal attachment plaque.
On the other hand, in PV models mice, DP shifted 24 nm, more markedly than Dsg3 -/- mice, but the number of PG labeling showed no significant changes. This suggests that binding of autoantibody to the Dsg3 may transfer some signals to the cytoplasm and keratin retraction may occur accompanying DP. In conclusion, we have shown that molecular mechanism of blister formation underlying PV model mice and Dsg3 -/- mice is different and that cytoplasmic change did occur after autoantibody binding.

Report

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

    (9 results)

All 2005 2004 2003 Other

All Journal Article (8 results) Publications (1 results)

  • [Journal Article] In vivo ultrastructural localization of the desmoglein 3 adhesive interface to the desmosome mid-line2005

    • Author(s)
      Atsushi Shimizu, et al.
    • Journal Title

      J Invest Dermatol 124

      Pages: 984-989

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] In vivo ultrastructural localization of the desmoglein 3 adhesive interface to the desmosome mid-line.2005

    • Author(s)
      Atsushi Shimizu, et al.
    • Journal Title

      J Invest Dermatol 124

      Pages: 984-989

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] IgG binds to desmoglein 3 in desmosomes and causes a desmosomal split without keratin retraction in a pemphigus mouse model.2004

    • Author(s)
      Atsushi Shimizu, et al.
    • Journal Title

      J Invest Dermatol 122

      Pages: 1145-1153

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] IgG binds to desmoglein 3 in desmosomes and cause a desmosomal split without keratin retraction in a pemphigus mouse model.2004

    • Author(s)
      Shimizu A, et al.
    • Journal Title

      J Invest Dermatology 122

      Pages: 1145-1153

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Immunomolecular mapping of adherens junction and desmosomal components in normal human epidermis2003

    • Author(s)
      Akira Ishiko, et al.
    • Journal Title

      Exp Dermatol 12

      Pages: 747-754

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Immunomolecular mapping of adherens junction and desmosomal components in normal human epidermis2003

    • Author(s)
      Ishiko, et al.
    • Journal Title

      Exp Dermatol 12

      Pages: 747-754

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Subcellular localization of desmosomal molecules is different between desmoglein 3 knockout mouse and pemphigus vulgaris model mice.

    • Author(s)
      Hitoshi Saito, et al.
    • Journal Title

      (To be submitted)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] In vivo ultrastructural localization of the desmoglein 3 adhesive interface to the desmosome mid-line.

    • Author(s)
      Shimizu A, et al.
    • Journal Title

      J Invest Dermatology (in press)

    • Related Report
      2004 Annual Research Report
  • [Publications] Shimizu A, et al.: "IgG binds to desmoglein 3 in desmosomes and causes a desmosomal split without keratin retraction in a pemphigus mouse model."J Invest Dermatology. (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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