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J Invest Dermatol. 2015 Jun;135(6):1565-1573. doi: 10.1038/jid.2015.51. Epub 2015 Feb 17.

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

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Department of Dermatology, University of Lübeck, Lübeck, Germany. Electronic address:
Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Department of Dermatology, University of Lübeck, Lübeck, Germany.
Department of Dermatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Department of Dermatology, Kurume University School of Medicine and Kurume University Institute of Cutaneous Cell Biology, Fukuoka, Japan.
Department of Dermatology and Cutaneous Biology Research Institute, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
Department of Immunodermatology, St John's Institute of Dermatology, St Thomas' Hospital, London, UK.


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.

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