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Autoantibodies to Multiple Epitopes on the Non-Collagenous-1 Domain of Type VII Collagen Induce Blisters

 Artem Vorobyev  ;  Hideyuki Ujiie  ;  Andreas Recke  ;  Jacqueline J.A. Buijsrogge  ;  Marcel F. Jonkman  ;  Hendri H. Pas  ;  Hiroaki Iwata  ;  Takashi Hashimoto  ;  Soo-Chan Kim  ;  Jong Hoon Kim  ;  Richard Groves  ;  Unni Samavedam  ;  Yask Gupta  ;  Enno Schmidt  ;  Detlef Zillikens  ;  Hiroshi Shimizu  ;  Ralf J. Ludwig 
 Journal of Investigative Dermatology, Vol.135(6) : 1565-1573, 2015 
Journal Title
 Journal of Investigative Dermatology 
Issue Date
Animals ; Antibodies/chemistry ; Autoantibodies/chemistry* ; Autoantibodies/immunology ; Blister/metabolism* ; Collagen Type VII/chemistry* ; Dermis/metabolism ; Epidermis/metabolism ; Epidermolysis Bullosa Acquisita/metabolism* ; Epitopes/chemistry* ; Female ; Humans ; Immunoglobulin G/chemistry ; Inflammation ; Male ; Mice ; Mice, Transgenic ; Mutation ; Protein Structure, Tertiary ; Rabbits ; Recombinant Proteins/chemistry ; Transgenes
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.
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Dermatology (피부과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Soo Chan(김수찬) ORCID logo https://orcid.org/0000-0002-2327-4755
Kim, Jong Hoon(김종훈) ORCID logo https://orcid.org/0000-0002-3385-8180
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