Analysis of blister formation mechanism in pemphigus by a novel in vitro bead aggregation assay

• Project/Area Number: 18K08278
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53050:Dermatology-related
• Research Institution: Toho University
• Principal Investigator: ISHII Ken 東邦大学, 医学部, 准教授 (50296670)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 天疱瘡 / 細胞接着 / 自己抗体 / 自己免疫 / 細胞間接着 / 水疱症

Outline of Final Research Achievements

Pemphigus is an intractable autoimmune disease that causes blisters and erosions on the skin and mucous membranes. Autoantibodies target desmoglein (Dsg) 1 and 3, cadherin-type cell adhesion molecules localized at desmosomes. In this study, we developed bead aggregation assays using recombinant Dsg and desmocollin (Dsc) and confirmed that heterophilic binding between Dsg and Dsc has stronger adhesive activity. We also showed that pemphigus autoantibodies directly inhibit adhesion between Dsg and Dsc without intracellular signaling.

Academic Significance and Societal Importance of the Research Achievements

天疱瘡の水疱形成において抗体によるDsgとDscのヘテロフィリック接着の直接阻害が重要であることを直接的に証明することができた。臨床応用としては、今回開発したビーズ凝集法は、天疱瘡の病勢を反映した検査法となる可能性がある。現在天疱瘡の疾患活動性の指標は、ELISAやCLEIA法で測定した抗体価が使用されている。抗体価は、抗原抗体反応を見るため、ときに、寛解期においても抗体価が高い症例があるなど疾患活動性と抗体価が一致しない症例も観察される。ビーズ凝集法はDsg/Dscの接着阻害活性を測定できるため天疱瘡の疾患活動性のより良い評価法と使用できる可能性がある。

Research Products

• [Int'l Joint Research] University of Pennsylvania(米国)
• [Int'l Joint Research] University of Pennsylvania(米国)
• [Int'l Joint Research] University of Pennsylvania(米国)
• [Int'l Joint Research] University of Pennsylvania(米国)
• [Journal Article] 増刊号特集 最近のトピックス2021 Clinical Dermatology 2021 2.皮膚疾患の病態 天疱瘡自己抗体はデスモグレインとデスモコリンのヘテロフィリック結合を直接阻害する (2021)
  • Author(s): 石井 健
  • Journal Title: 臨床皮膚科 Volume: 75 Issue: 5 Pages: 56-60
  • DOI: 10.11477/mf.1412206333
  • ISSN: 0021-4973, 1882-1324
  • Year and Date: 2021-04-10
• [Journal Article] Pemphigus Vulgaris and Foliaceus IgG Autoantibodies Directly Block Heterophilic Transinteraction between Desmoglein and Desmocollin (2020)
  • Author(s): Ishii Ken、Yoshida Kenji、Stanley John R.、Yamagami Jun、Amagai Masayuki、Ishiko Akira
  • Journal Title: Journal of Investigative Dermatology Volume: 140 Issue: 10 Pages: 1919-1926.e7
  • DOI: 10.1016/j.jid.2020.02.010
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 組換えデスモグレイン／デスモコリン- ビーズ凝集法による天疱瘡の疾患活動性評価 (2021)
  • Author(s): 漆畑真理、石井健、石河晃
  • Organizer: 120回日本皮膚科学会総会
• [Presentation] Antibodies to desmocollin (Dsc) 3, but not Dsc1, in pemphigus sera directly block heterophilic transinteraction between desmoglein and Dsc (2021)
  • Author(s): Ken Ishii, Norito Ishii, Akira Ishiko, Takashi Hashimoto
  • Organizer: The 46th Annual Meeting of the Japanese Society for Investigative Dermatology
• [Presentation] Pemphigus vulgaris IgG autoantibodies directly inhibit heterophilic desmoglein 3-desmocollin 3 adhesion by steric hindrance (2019)
  • Author(s): Ken Ishii, Jun Yamagami, Masayuki Amagai, John R Stanley, Akira Ishiko
  • Organizer: 77th Annual Meeting of Society of investigative Dermatology
  • Int'l Joint Research
• [Presentation] Pemphigus autoantibodies directly inhibit heterophilic desmoglein -desmocollin adhesion by steric hindrance (2019)
  • Author(s): Ken Ishii, Kenji Yoshida, Jun Yamagami, Masayuki Amagai, John R Stanley, Akira Ishiko
  • Organizer: 44th Annual meeting of Japanese society of investigative Dermatology
  • Int'l Joint Research
• [Presentation] 落葉状天疱瘡自己抗体はデスモグレイン1とデスモコリン1のトランス結合を阻害する． (2019)
  • Author(s): 石井 健†，吉田憲司†，John R.Stanley, 石河 晃†
  • Organizer: 第40回水疱症研究会
• [Presentation] Pemphigus foliaceus IgG autoantibodies block heterophilic trans-interaction of desmoglein 1 and desmocollin 1 without intracellular signaling. (2018)
  • Author(s): Ishii K†, Yoshida K†, JR. Stanley , Ishiko A.
  • Organizer: International Investigative Dermatology 2018
  • Int'l Joint Research