Development of novel treatment targeting complement for bullous pemphigoid

• Project/Area Number: 23591635
• 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: SHIBAKI Akihiko 北海道大学, 医学(系)研究科(研究院), 客員研究員 (40291231)
• Co-Investigator(Kenkyū-buntansha): SHIMIZU Hiroshi 北海道大学, 大学院医学研究科, 教授 (00146672) ; UJIIE Hideyuki 北海道大学, 北海道大学病院, 助教 (60374435)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2012: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2011: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: 自己免疫疾患 / 水疱性類天疱瘡 / 17型コラーゲン / ヒト化マウス / 疾患モデル動物 / IgG1/IgG4 / 抗体サブクラス / 補体活性化

Research Abstract

Complement activation and subsequent recruitment of inflammatory cells at the dermal-epidermal junction are believed to be essential for blister formation in bullous pemphigoid (BP), an autoimmune blistering disease induced by autoantibodies against COL17; however, the involvement of complement-independent pathways has recently been proposed. To directly examine the necessity of the complement activation in blister formation, we generated C3-deficient COL17-humanized mice and monoclonal antibodies against COL17 with different ability of complement activation. By using them, we demonstrate that the deposition of antibodies, and not complements, is relevant to the induction of blister formation. BP autoantibodies reduced the amount of COL17 in cultured normal human keratinocytes, and the COL17-depletion was associated with a ubiquitin-proteasome pathway. In conclusion, the COL17-depletion induced by BP autoantibodies, and not complement activation, is essential for the blister formation.

Research Products

• [Journal Article] Evidence for pathogenicity of autoreactive T cells in autoimmune bullous diseases shown by animal disease models (2012)
  • Author(s): Ujiie H, Shimizu H
  • Journal Title: Experimental Dermatology Volume: 21 Issue: 12 Pages: 901-5
  • DOI: 10.1111/exd.12011
  • Peer Reviewed
• [Journal Article] Antibodies to pathogenic epitopes on type XVII collagen cause skin fragility in a complement-dependent and independent manner (2012)
  • Author(s): Natsuga K, Nishie W, Shinkuma S, Ujiie H, Nishimura M, Sawamura D, Shimizu H
  • Journal Title: J Immunol Volume: (in press) Issue: 11 Pages: 5792-5799
  • DOI: 10.4049/jimmunol.1003402
  • NAID: 10031131103
  • Peer Reviewed
• [Journal Article] Noncollagenous 16A domain of type XVII collagen-reactive CD4(+) T cells play a pivotal role in the development of active disease in experimental bullous pemphigoid model (2012)
  • Author(s): Ujiie H, Shibaki A, Nishie W, Shinkuma S, Moriuchi R, Qiao H, Shimizu H
  • Journal Title: Clin Immunol Volume: 142 Issue: 2 Pages: 167-175
  • DOI: 10.1016/j.clim.2011.10.002
  • Peer Reviewed
• [Presentation] Bullous pemphigoid autoantibodies induce skin fragility in neonatal mice in a complement-independent manner (2013)
  • Author(s): Sasaoka T, Ujiie H, Nishie W, Shibaki A, Nakamura H, Shimizu H
  • Organizer: The 6th International Investigative Dermatology 2013
  • Place of Presentation: イギリス
  • Year and Date: 2013-05-09
• [Presentation] Bullous pemphigoid autoantibodies induce skin fragility in neonatal mice in a complement-independent manner. (2013)
  • Author(s): Sasaoka T, Ujiie H, Nishie W, Shibaki A, Nakamura H, Shimizu H
  • Organizer: The 6th International Investigative Dermatology 2013
  • Place of Presentation: Edinburgh International Conference Centre （イギリス）
• [Presentation] Monoclonal human IgG1 and IgG4 against COL17 induce skin fragility in neonatal COL17-humanized mice in a complement-independent manner (2012)
  • Author(s): Sasaoka T, Ujiie H, Nishie W, Shibaki A, Shinkuma S, Tanabe M, Nakamura H, Shimizu H
  • Organizer: The 37th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: 沖縄県
  • Year and Date: 2012-12-07
• [Presentation] Monoclonal human IgG1 and IgG4 against COL17 induce skin fragility in neonatal COL17-humanized mice in a complement-independent manner. (2012)
  • Author(s): Sasaoka T, Ujiie H, Nishie W, Shibaki A, Shinkuma S, Tanabe M, Nakamura H, Shimizu H
  • Organizer: The 37th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: ロワジールホテル＆スパタワー那覇（沖縄県）