Elucidation of the pathogenesis of bullous pemphigoid by molecular imaging of collagen XVII

• Project/Area Number: 20689021
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Dermatology
• Research Institution: Hokkaido University
• Principal Investigator: NISHIE Wataru 北海道大学, 北海道大学病院, 講師 (20443955)
• Project Period (FY): 2008 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥24,960,000 (Direct Cost: ¥19,200,000、Indirect Cost: ¥5,760,000); Fiscal Year 2011: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2010: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2009: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2008: ¥12,480,000 (Direct Cost: ¥9,600,000、Indirect Cost: ¥2,880,000)
• Keywords: 皮膚病理学 / 生体分子 / 細胞・組織 / タンパク質 / 酵素 / 応用動物

Research Abstract

This study revealed that IgG autoantibodies from bullous pemphigoid (BP) patients directly bind with collagen XVII (COL17) on the cell-surface, resulting in dynamic internalization of the complex into the cells. Furthermore, neoepitopes on the shed ectodomain of COL17 were found to be targeted by certain autoantibodies from BP patients. In addition, this study disclosed that migrating keratinocytes directly shed the COL17 which binds with other extracellular matrix proteins including laminin332 and collagen IV.

Research Products

• [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] Intraepidermal neutrophilic IgA pemphigus successfully treated with dapsone (2012)
  • Author(s): Hirata Y, Abe R, Kikuchi K, Hamasaka A, Shinkuma S, Nomura T, Nishie W, Arita K, Shimizu H
  • Journal Title: Eur J Dermatol Volume: (in press) Issue: 2 Pages: 282-3
  • DOI: 10.1684/ejd.2012.1662
  • Peer Reviewed
• [Journal Article] Mucous membrane pemphigoid with generalized blisters : IgA and IgG autoantibodies target both laminin-332 and type XVII collagen (2012)
  • Author(s): Hayashi I, Shinkuma S, Shimizu S, Natsuga K, Ujiie H, Yasui C, Tsuchiya K, Nishie W, Shimizu H
  • Journal Title: Br J Dermatol Volume: (in press) Issue: 5 Pages: 1116-1120
  • DOI: 10.1111/j.1365-2133.2011.10776.x
  • 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
• [Journal Article] Pathogenesis of bullous pemphigoid (2011)
  • Author(s): Ujiie H, Nishie W, Shimizu H
  • Journal Title: Dermatol Clin Volume: 29 Issue: 3 Pages: 439-446
  • DOI: 10.1016/j.det.2011.03.008
  • Peer Reviewed
• [Journal Article] Dynamic interactions of epidermal collagen XVII with the extracellular matrix : laminin 332 as a major binding partner (2011)
  • Author(s): Nishie W, Kiritsi D, Nystrom A, Hofmann S C, Bruckner-Tuderman L
  • Journal Title: Am J Pathol Volume: 179 Issue: 2 Pages: 829-837
  • DOI: 10.1016/j.ajpath.2011.04.019
  • Peer Reviewed
• [Journal Article] Subepidermal blistering disease with 3 distinct autoantibodies : anti-BP230, anti-laminin gamma-1, and anti-laminin-332 (2011)
  • Author(s): Kikuchi K, Natsuga K, Shinkuma S, Nishie W, Kajita S, Sato H, Shimizu H
  • Journal Title: J Am Acad Dermatol Volume: 65 Issue: 4 Pages: 878-880
  • DOI: 10.1016/j.jaad.2010.09.719
  • Peer Reviewed
• [Journal Article] Development of an ELISA for sensitive and specific detection of IgA autoantibodies against BP180 in pemphigoid diseases (2011)
  • Author(s): Csorba K, Schmidt S, Florea F, Ishii N, Hashimoto T, Hertl M, Karpati S, Bruckner-Tuderman L, Nishie W, Sitaru C
  • Journal Title: Orphanet J Rare Dis Volume: 6 Issue: 1 Pages: 31-31
  • DOI: 10.1186/1750-1172-6-31
  • Peer Reviewed
• [Journal Article] Consequences of two different amino-acid substitutions at the same codon in KRT14 indicate definitive roles of structural distortion in epidermolysis bullosa simplex pathogenesis (2011)
  • Author(s): K.Natsuga, W.Nishie, et al.
  • Journal Title: J Invest Dermatol Volume: 131 Pages: 1869-1876
  • Peer Reviewed
• [Journal Article] Expression of exon-8-skipped kindlin-1 does not compensate for defects of Kindler syndrome (2011)
  • Author(s): K.Natsuga, W.Nishie, et al.
  • Journal Title: J Dermatol Sci Volume: 61 Pages: 38-44
  • NAID: 10030889702
  • Peer Reviewed
• [Journal Article] Blockade of autoantibody-initiated tissue damage by using recombinant fab antibody fragments against pathogenic autoantigen (2010)
  • Author(s): Wang G, Ujiie H, Shibaki A, Nishie W, Tateishi Y, Kikuchi K, Li Q, Mcmillan J R, Morioka H, Sawamura D, Nakamura H, Shimizu H
  • Journal Title: Am J Pathol Volume: 176 Issue: 2 Pages: 914-925
  • DOI: 10.2353/ajpath.2010.090744
  • Peer Reviewed
• [Journal Article] What's new in bullous pemphigoid (2010)
  • Author(s): Ujiie H, Shibaki A, Nishie W, Shimizu H
  • Journal Title: J Dermatol Volume: 37 Issue: 3 Pages: 194-204
  • DOI: 10.1111/j.1346-8138.2009.00792.x
  • NAID: 10027065912
  • Peer Reviewed
• [Journal Article] A novel active mouse model for bullous pemphigoid targeting humanized pathogenic antigen (2010)
  • Author(s): Ujiie H, Shibaki A, Nishie W, Sawamura D, Wang G, Tateishi Y, Li Q, Moriuchi R, Qiao H, Nakamura H, Akiyama M, Shimizu H
  • Journal Title: J Immunol Volume: 184 Issue: 4 Pages: 2166-2174
  • DOI: 10.4049/jimmunol.0903101
  • Peer Reviewed
• [Journal Article] Ectodomain shedding generates Neoepitopes on collagen XVII, the major autoantigen for bullous pemphigoid (2010)
  • Author(s): Nishie W, Lamer S, Schlosser A, Licarete E, Franzke C W, Hofmann S C, Jackow J, Sitaru C, Bruckner-Tuderman L
  • Journal Title: J Immunol Volume: 185 Issue: 8 Pages: 4938-4937
  • DOI: 10.4049/jimmunol.1001524
  • Peer Reviewed
• [Journal Article] Circulating IgA and IgE autoantibodies in antilaminin-332 mucous membrane pemphigoid (2010)
  • Author(s): Natsuga K, Nishie W, Shinkuma S, Moriuchi R, Shibata M, Nishimura M, Hashimoto T, Shimizu H
  • Journal Title: Br J Dermatol Volume: 162 Issue: 3 Pages: 513-517
  • DOI: 10.1111/j.1365-2133.2009.09508.x
  • Peer Reviewed
• [Journal Article] Human IgG1 monoclonal antibody against human collagen 17 noncollagenous 16A domain induces blisters via complement activation in experimental bullous pemphigoid model (2010)
  • Author(s): Li Q, Ujiie H, Shibaki A, Wang G, Moriuchi R, Qiao H J, Morioka H, Shinkuma S, Natsuga K, Long H A, Nishie W, Shimizu H
  • Journal Title: J Immunol Volume: 185 Issue: 12 Pages: 7746-7755
  • DOI: 10.4049/jimmunol.1000667
  • Peer Reviewed
• [Journal Article] Ectodomain shedding generates neoepitopes on collagen XVII, the major autoantigen for bullous pemphigoid. (2010)
  • Author(s): Nishie W, Lamer S, Schlosser A, Licarete E, Franzke C, Hofmann S, Jackow J, Sitaru C, Bruckner-Tuderman L.
  • Journal Title: J Immunol 185 Pages: 4938-4947
  • Peer Reviewed
• [Journal Article] Circulating IgA and IgE autoantibodies in antilaminin-332 mucous membrane pemphigoid. (2010)
  • Author(s): atsuga K, Nishie W, Shinkuma S, Moriuchi R, Shibata M, Nishimura M, Hashimoto T, Shimizu H.
  • Journal Title: Br J Dermatol 162 Pages: 513-517
  • Peer Reviewed
• [Journal Article] Complete paternal isodisomy of chromosome 17 in junctional epidermolysis bullosa with pyloric atresia. (2010)
  • Author(s): Natsuga K, Nishie W, Arita K, Shinkuma S, Nakamura H, Kubota S, Imakado S, Akiyama M, Shimizu H
  • Journal Title: J Invest Dermatol 130 Pages: 2671-2674
  • Peer Reviewed
• [Journal Article] Ectodomain shedding generates neoepitopes on collagen XVII, the major autoantigen for bullous pemphigoid. (2010)
  • Author(s): Nishie W, et al.
  • Journal Title: Journal of Immunology Volume: 185 Pages: 4938-4947
  • Peer Reviewed
• [Journal Article] Plectin deficiency leads to both muscular dystrophy and pyloric atresia in epidermolysis bullosa simplex. (2010)
  • Author(s): K.Natsuga, W.Nishie, et al.
  • Journal Title: Human mutation Volume: 31 Pages: 1687-1698
  • Peer Reviewed
• [Journal Article] A novel active model for bullous pemphigoid targeting humanized pathogenic antigen. (2010)
  • Author(s): Ujiie H, Shibaki A, Nishie W, et al.
  • Journal Title: Journal of Immunology Volume: 184 Pages: 2166-2174
  • Peer Reviewed
• [Journal Article] Plectin expression patterns determine two distinct subtypes of epidermolysis bullosa simplex (2010)
  • Author(s): K.Natsuga, W.Nishie, et al.
  • Journal Title: Human mutation 31 Pages: 308-16
  • Peer Reviewed
• [Journal Article] Collagen XVII participates in keratinocyte adhesion to collagen IV, and in p38MAPK-dependent migration and cell signaling (2009)
  • Author(s): Qiao H, Shibaki A, Long H A, Wang G, Li Q, Nishie W, Abe R, Akiyama M, Shimizu H, Mcmillan J R
  • Journal Title: J Invest Dermatol Volume: 129 Issue: 9 Pages: 2288-2295
  • DOI: 10.1038/jid.2009.20
  • Peer Reviewed
• [Journal Article] A novel humanized neonatal autoimmune blistering skin disease model induced by maternally transferred antibodies (2009)
  • Author(s): Nishie W, Sawamura D, Natsuga K, Shinkuma S, Goto M, Shibaki A, Ujiie H, Olasz E, Yancey K B, Shimizu H
  • Journal Title: J Immunol Volume: 183 Issue: 6 Pages: 4088-4093
  • DOI: 10.4049/jimmunol.0800389
  • Peer Reviewed
• [Journal Article] Autoantibodies against type XVII collagen C-terminal domain in a patient with bullous pemphigoid associated with psoriasis vulgaris (2009)
  • Author(s): Inokuma D, Kodama K, Natsuga K, Kasai M, Abe M, Nishie W, Abe R, Hashimoto T, Shimizu H
  • Journal Title: Br J Dermatol Volume: 160 Issue: 2 Pages: 454-454
  • DOI: 10.1111/j.1365-2133.2008.08961.x
  • Peer Reviewed
• [Journal Article] A severe and refractory case of anti-p200 pemphigoid resulting in multiple skin ulcers and scar formation (2009)
  • Author(s): Goto-Ohguchi Y, Nishie W, Akiyama M, Tateishi Y, Aoyagi S, Tsuji-Abe Y, Sawamura D, Ishii N, Hashimoto T Shimizu H
  • Journal Title: Dermatology Volume: 218 Issue: 3 Pages: 265-271
  • DOI: 10.1159/000182268
  • Peer Reviewed
• [Journal Article] A novel humanized neonatal autoimmune blistering skin disease model induced by maternally transferred antibodies. (2009)
  • Author(s): Nishie W, Sawamura D, Natsuga K, Shinkuma S, Goto M, Shibaki A, Ujiie H, Olasz E, Yancey KB, Shimizu H.
  • Journal Title: J Immunol 183 Pages: 4088-4093
  • Peer Reviewed
• [Journal Article] A novel humanized neonatal autoimmune blistering skin disease model induced by maternally transferred antibodies (2009)
  • Author(s): W.Nishie, et al.
  • Journal Title: Journal of Immunology 183 Pages: 4088-4093
  • Peer Reviewed
• [Journal Article] Circulating IgA and IgE autoantibodies in antilaminin-332 mucous membrane pemphigoid (2009)
  • Author(s): K.Natsuga, W.Nishie, et al.
  • Journal Title: British Journal of Dermatology 162 Pages: 513-517
  • Peer Reviewed
• [Journal Article] A severe and refractory case of anti-p200 pemphigoid resulting in multiple skin ulcers and scar formation (2009)
  • Author(s): Goto-Ohguchi Y, Nishie W, et.al.
  • Journal Title: Dermatology 218 Pages: 451-454
  • Peer Reviewed
• [Journal Article] Morphological and genetic analysis of steatocystoma multiplex in an Asian family with pachyonychia congenital type 2 harbouring a KRT17 missense mutation (2009)
  • Author(s): Kanda M, et.al.
  • Journal Title: Br J Dermatol 160 Pages: 465-468
  • Peer Reviewed
• [Journal Article] Cutaneous pemphigus vulgaris with skin features similar to the classic mucocutaneous type : a case report and review of the literature (2008)
  • Author(s): Shinkuma S, Nishie W, Shibaki A, Sawamura D, Ito K, Tsuji-Abe Y, Natsuga K, Chan P T, Amagai M, Shimizu H
  • Journal Title: Clin Exp Dermatol Volume: 33 Issue: 6 Pages: 724-728
  • DOI: 10.1111/j.1365-2230.2008.02871.x
  • Peer Reviewed
• [Journal Article] Cutaneous type pemphigus vulgaris with skin manifestations similar to the classical mucocutaneous type : a case report and review of the literature (2008)
  • Author(s): Shinkuma S, Nishie W, st al.
  • Journal Title: Clin Exp Dermatol 33 Pages: 724-728
  • Peer Reviewed
• [Journal Article] Dynamic Interactions of Epidermal Collagen XVII with the Extracellular Matrix : Laminin 332 as a Major Binding Partner.
  • Author(s): Nishie W, Kiritsi D, Nystrom A, Hofmann S, Bruckner-Tuderman L.
  • Journal Title: Am J Pathol in press.
  • Peer Reviewed
• [Presentation] Neoepitope on the blocked amino-terminus of the shed ectodomain of collagen XVII/BP180, a major autoantigen for bullous pemphigoid (2012)
  • Author(s): 西江渉、氏家英之、新熊悟、清水宏
  • Organizer: 第19回分子皮膚科フォーラム
  • Place of Presentation: ホテル青森(青森)
• [Presentation] Essential role of alpha-helical coiled-coils in the regulation of collagen XVII ectodomain shedding (2011)
  • Author(s): Nishie W, et al.
  • Organizer: The 41nd Annual Meeting of the European Society for Dermatological Research
  • Place of Presentation: The Barcelona International Convention Center (Spain)
  • Year and Date: 2011-09-09
• [Presentation] Essential role of alpha-helical coiled-coils in the regulation of collagen XVII ectodomain shedding (2011)
  • Author(s): Nishie, W, Franzke CW, Jackow J, Hofmann SC, Bruckner-Tuderman L
  • Organizer: The 41st Annual Meeting of the European Society for Dermatological Research
  • Place of Presentation: Barcelona, Spain
• [Presentation] Role of distinctive proteins interacting with collagen XVII in extracellular matrix. (2010)
  • Author(s): Nishie W, Bruckner-Tuderman L.
  • Organizer: The 35th Annual Meeting of the Japanese Society of Invesitigative Dermatology
  • Place of Presentation: Wakayama
  • Year and Date: 2010-12-03
• [Presentation] Novel cleavage sites and specific neoepitopes on shed ectodomain of collagen XVII/BP180: role in autoimmune blistering diseases. (2010)
  • Author(s): Nishie W, Lamer S, Schlosser A, Licarete E, Franzke CW, Hofmann SC, Jackow J, Sitaru C, Bruckner-Tuderman L.
  • Organizer: The 41st Annual Meeting of the European Society for Dermatological Research
  • Place of Presentation: Helsinki, Finland
  • Year and Date: 2010-09-10
• [Presentation] Novel cleavage sites and specific neoepitopes on shed ectodomain of collagen XVII/BP180 : role in autoimmune blistering diseases. (2010)
  • Author(s): Nishie W, et al.
  • Organizer: The 41st Annual Meeting of the European Society for Dermatological Research
  • Place of Presentation: Helsinki, Finland
  • Year and Date: 2010-09-08
• [Presentation] Role of distinctive proteins interacting with collagen XVII in extracellular matrix (2010)
  • Author(s): Nishie, W, Bruckner-Tuderman L
  • Organizer: The 35th Annual Meeting of the Japanese Society of Invesitigative Dermatology
  • Place of Presentation: Wakayama
• [Presentation] Novel cleavage sites and specific neoepitopes on shed ectodomain of collagen XVII/BP180 : role in autoimmune blistering diseases (2010)
  • Author(s): Nishie, W, Lamer S, Schlosser A, Licarete E, Franzke CW, Hofmann SC, Jackow J, Sitaru C, Bruckner-Tuderman L
  • Organizer: The 40th Annual Meeting of the European Society for Dermatological Research
  • Place of Presentation: Helsinki, Finland
• [Presentation] Dynamics of shed ectodomain of collagen XVII on extracellular matrix (2010)
  • Author(s): Nishie, W, Bruckner-Tuderman L
  • Organizer: Annual Meeting of the German and British Societies for Matrix Biology
  • Place of Presentation: Frankfurt / Main Germany
• [Presentation] Transmembrane collagen XVII: ectodomain shedding generates neo-epitopes. (2009)
  • Author(s): Nishie W, Has C, Bruckner-Tuderman L.
  • Organizer: Gordon Research Conference, Collagen
  • Place of Presentation: New London, NH, USA
  • Year and Date: 2009-07-20
• [Presentation] Transmenbrane collagen XVII : ectodomain shedding generates neo-epitopes (2009)
  • Author(s): W.Nishie
  • Organizer: Gordon Research Conference, Collagen
  • Place of Presentation: Colby-Sawyer College, New London, NH, USA
  • Year and Date: 2009-07-20
• [Presentation] Transmembrane collagen XVII : ectodomain shedding generates neo-epitopes (2009)
  • Author(s): Nishie, W, Has C, Bruckner-Tuderman L
  • Organizer: Gordon Research Conference, Collagen
  • Place of Presentation: New London, NH, USA
• [Presentation] Trap sgenic rescue of epidermolysis bullosa model mice (2008)
  • Author(s): Nishie W
  • Organizer: Network meeting of epidermolysis bullosa
  • Place of Presentation: University Medical Center Freiburg, Freiburg, Germany
  • Year and Date: 2008-11-28