Elucidating roles of plasmin in blister formation of bullous pemphigoid

• Project/Area Number: 25461661
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Dermatology
• Research Institution: Hokkaido University
• Principal Investigator: Nakamura Hideki 北海道大学, 医学(系)研究科(研究院), 助手 (60435956)
• Co-Investigator(Kenkyū-buntansha): NISHIE Wataru 北海道大学, 大学院医学研究科, 准教授 (20443955) ; NATSUGA Ken 北海道大学, 大学病院, 助教 (70645457) ; SHIMIZU Hiroshi 北海道大学, 大学院医学研究科, 教授 (00146672)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 水疱性類天疱瘡 / プラスミン / 17型コラーゲン / 自己免疫性水疱症 / COL17

Outline of Final Research Achievements

Bullous pemphigoid (BP) is an autoimmune blistering disease. The aim of this study is to address the pathogenic roles of plasmin, a protease present in blister fluids of BP, which is known to cleave COL17. We first identified cleavage sites of COL17 by plasmin, and based on this data, cleavage site-specific antibodies were generated. The antibodies revealed that COL17 is actually cleaved by plasmin in lesional skin of certain numbers of BP patients.

Research Products

• [Journal Article] Epitope-Dependent Pathogenicity of Antibodies Targeting a Major Bullous Pemphigoid Autoantigen Collagen XVII/BP180. (2016)
  • Author(s): Wada M, Nishie W, Ujiie H, Izumi K, Iwata H, Natsuga K, Nakamura H, Kitagawa Y, Shimizu H
  • Journal Title: J Invest Dermatol Volume: in press Issue: 5 Pages: 938-946
  • DOI: 10.1016/j.jid.2015.11.030
  • Peer Reviewed
• [Journal Article] Extracellular cleavage of collagen XVII is essential for correct cutaneous basement membrane formation. (2016)
  • Author(s): Nishimura M, Nishie W, Shirafuji Y, Shinkuma S, Natsuga K, Nakamura H, Sawamura D, Iwatsuki K, Shimizu H
  • Journal Title: Hum Mol Genet Volume: 15;25(2) Issue: 2 Pages: 328-39
  • DOI: 10.1093/hmg/ddv478
  • NAID: 120005868259
  • Peer Reviewed / Open Access
• [Journal Article] Context-Dependent Regulation of Collagen XVII Ectodomain Sheddingin Skin. (2015)
  • Author(s): Nishie W, Natsuga K, Iwata H, Izumi K, Ujiie H, Toyonaga E, Hata H, NakamuraH, Shimizu H
  • Journal Title: Am J Pathol Volume: 185(5) Pages: 1361-71
  • Peer Reviewed
• [Journal Article] Skipped exon in COL7A1 determines the clinical phenotypes of dystrophic epidermolysis bullosa. (2015)
  • Author(s): Toyonaga E, Nishie W, Komine M, Murata S, Shinkuma S, Natsuga K, Nakamura H, Ohtsuki M, Shimizu H.
  • Journal Title: British Journal of Dermatology Volume: 172 Issue: 4 Pages: 1141-1144
  • DOI: 10.1111/bjd.13386
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Context-Dependent Regulation of Collagen XVII Ectodomain Shedding in Skin. (2015)
  • Author(s): Nishie W, Natsuga K, Iwata H, Izumi K, Ujiie H, Toyonaga E, Hata H, Nakamura H, Shimizu H.
  • Journal Title: Am J Pathol Volume: in press Issue: 5 Pages: 1361-71
  • DOI: 10.1016/j.ajpath.2015.01.012
  • NAID: 120005752843
  • Peer Reviewed / Open Access
• [Journal Article] Bullous Pemphigoid Autoantibodies Directly Induce Blister Formation without Complement Activation. (2014)
  • Author(s): Ujiie H, Sasaoka T, Izumi K, Nishie W, Shinkuma S, Natsuga K, Nakamura H, Shibaki A, Shimizu H
  • Journal Title: The Journal of Immunology Volume: 193 Issue: 9 Pages: 4415-4428
  • DOI: 10.4049/jimmunol.1400095
  • Peer Reviewed / Open Access
• [Presentation] A single laminin subunit deficiency alters other laminin expression depending on the mutated genes. (2015)
  • Author(s): Natsuga K, Nishie W, Shinkuma S, Nakamura H, Watanabe M, Kambe M, Hatamochi A, Kimura U, Suga Y, Shimizu H
  • Organizer: The 40th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: Okayama convention center, Okayama, Okayama-City
  • Year and Date: 2015-12-11
• [Presentation] One amino acid deletion in collagen XVII-binding domain of plectin with a truncation mutation underlies epidermolysis bullosa simplex. (2014)
  • Author(s): Natsuga K, Nishimura M, Nakamura H, Nihsie W, Shimizu H
  • Organizer: The 39th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: Hotel Hankyu Expo Park, Osaka, Suita-City
  • Year and Date: 2014-12-12 – 2014-12-14
• [Presentation] Context-dependent tight regulation of collagen XVII ectodomain shedding in skin. (2014)
  • Author(s): Nihsie W, Natsuga K, Izumi K, Hata H, Nakamura H, Shimizu H
  • Organizer: The 39th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: Hotel Hankyu Expo Park, Osaka, Suita-City
  • Year and Date: 2014-12-12 – 2014-12-14
• [Presentation] Essential role of collagen XVII in basement membrane formation and keratinocyte migration. (2013)
  • Author(s): Nishimura M, Nihsie W, Shinkuma S, Natsuga K, Nakamura H, Sawamura D, Iwatsuki K, Shimizu H
  • Organizer: The International Investigative Dermatology
  • Place of Presentation: Edinburgh International Conference Centre (Scotland)
• [Presentation] Bullous pemphigoid autoantibodies induce skin fragility in neonatal mice in a complementindependent manner. (2013)
  • Author(s): Sasaoka T, Ujiie H, Nishie W, Shibaki A, Nakamura H, Shimizu H
  • Organizer: The International Investigative Dermatology
  • Place of Presentation: Edinburgh International Conference Centre (Scotland)