title: Autoantibodies to Multiple Epitopes on the Non-Collagenous-1 Domain of Type VII Collagen Induce Blisters.
abstract: Epidermolysis bullosa acquisita (EBA) is an autoimmune blistering disease of the skin and mucous membranes, characterized by autoantibodies against type VII collagen (COL7), a major component of anchoring fibrils. Different clinical EBA phenotypes are described, including mechanobullous and inflammatory variants. Most EBA patients' sera react with epitopes located within the non-collagenous 1 (NC1) domain of human COL7. However, it has remained unclear whether antibody binding to these different epitopes is pathogenically relevant. To address this issue, we generated recombinant proteins covering the entire NC1 domain. IgG reactivity with these proteins was analyzed in sera of 69 EBA patients. Most recognized clusters of epitopes throughout the NC1 domain. No correlation was detected between antibody specificity and clinical phenotype. To study the pathogenicity of antibodies specific to different NC1 subdomains, rabbit antibodies were generated. All these antibodies caused dermal-epidermal separation ex vivo. Antibodies against two of these subdomains were injected into mice carrying null mutations of mouse COL7 and the human COL7 transgene and induced subepidermal blisters. We here document that autoantibodies to COL7, independent of the targeted epitopes, induce blisters both ex vivo and in vivo. In addition, using COL7-humanized mice, we provide in vivo evidence of pathogenicity of autoantibodies binding to human COL7.
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany. Electronic address: artem.vorobyev@uksh.de.
authors.forename: Artem
authors.initials: A
authors.lastname: Vorobyev
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ujiie
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Recke
authors.affiliation: Department of Dermatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Jacqueline J A
authors.initials: JJA
authors.lastname: Buijsrogge
authors.affiliation: Department of Dermatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Marcel F
authors.initials: MF
authors.lastname: Jonkman
authors.affiliation: Department of Dermatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Hendri H
authors.initials: HH
authors.lastname: Pas
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Iwata
authors.affiliation: Department of Dermatology, Kurume University School of Medicine and Kurume University Institute of Cutaneous Cell Biology, Fukuoka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Department of Dermatology and Cutaneous Biology Research Institute, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Soo-Chan
authors.initials: SC
authors.lastname: Kim
authors.affiliation: Department of Dermatology and Cutaneous Biology Research Institute, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jong
authors.initials: J
authors.lastname: Hoon Kim
authors.affiliation: Department of Immunodermatology, St John's Institute of Dermatology, St Thomas' Hospital, London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Groves
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Unni
authors.initials: U
authors.lastname: Samavedam
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Yask
authors.initials: Y
authors.lastname: Gupta
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Enno
authors.initials: E
authors.lastname: Schmidt
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Detlef
authors.initials: D
authors.lastname: Zillikens
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimizu
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Ralf J
authors.initials: RJ
authors.lastname: Ludwig
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry; D001323:Autoantibodies / Q000737:chemistry* / Q000276:immunology; D001768:Blister / Q000378:metabolism*; D024143:Collagen Type VII / Q000737:chemistry*; D020405:Dermis / Q000378:metabolism; D004817:Epidermis / Q000378:metabolism; D016107:Epidermolysis Bullosa Acquisita / Q000378:metabolism*; D000939:Epitopes / Q000737:chemistry*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D007249:Inflammation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D017434:Protein Structure, Tertiary; D011817:Rabbits; D011994:Recombinant Proteins / Q000737:chemistry; D019076:Transgenes
chemical_list: D000906:Antibodies; D001323:Autoantibodies; D024143:Collagen Type VII; D000939:Epitopes; D007074:Immunoglobulin G; D011994:Recombinant Proteins