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

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1565-1573
Number of pages9
JournalJournal of Investigative Dermatology
Volume135
Issue number6
DOIs
Publication statusPublished - 2015 Jan 1

Fingerprint

Collagen Type VII
Epidermolysis Bullosa Acquisita
Blister
Autoantibodies
Epitopes
Antibodies
Virulence
Phenotype
Skin
Antibody Specificity
Serum
Transgenes
Recombinant Proteins
Autoimmune Diseases
Mucous Membrane
Immunoglobulin G
Rabbits
Mutation
Proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

Cite this

Vorobyev, A., Ujiie, H., Recke, A., Buijsrogge, J. J. A., Jonkman, M. F., Pas, H. H., ... Ludwig, R. J. (2015). Autoantibodies to multiple epitopes on the non-collagenous-1 domain of type VII collagen induce blisters. Journal of Investigative Dermatology, 135(6), 1565-1573. https://doi.org/10.1038/jid.2015.51
Vorobyev, Artem ; Ujiie, Hideyuki ; Recke, Andreas ; Buijsrogge, Jacqueline J.A. ; Jonkman, Marcel F. ; Pas, Hendri H. ; Iwata, Hiroaki ; Hashimoto, Takashi ; Kim, Soo Chan ; Kim, Jong Hoon ; Groves, Richard ; Samavedam, Unni ; Gupta, Yask ; Schmidt, Enno ; Zillikens, Detlef ; Shimizu, Hiroshi ; Ludwig, Ralf J. / Autoantibodies to multiple epitopes on the non-collagenous-1 domain of type VII collagen induce blisters. In: Journal of Investigative Dermatology. 2015 ; Vol. 135, No. 6. pp. 1565-1573.
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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.",
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Vorobyev, A, Ujiie, H, Recke, A, Buijsrogge, JJA, Jonkman, MF, Pas, HH, Iwata, H, Hashimoto, T, Kim, SC, Kim, JH, Groves, R, Samavedam, U, Gupta, Y, Schmidt, E, Zillikens, D, Shimizu, H & Ludwig, RJ 2015, 'Autoantibodies to multiple epitopes on the non-collagenous-1 domain of type VII collagen induce blisters', Journal of Investigative Dermatology, vol. 135, no. 6, pp. 1565-1573. https://doi.org/10.1038/jid.2015.51

Autoantibodies to multiple epitopes on the non-collagenous-1 domain of type VII collagen induce blisters. / Vorobyev, Artem; Ujiie, Hideyuki; Recke, Andreas; Buijsrogge, Jacqueline J.A.; Jonkman, Marcel F.; Pas, Hendri H.; Iwata, Hiroaki; Hashimoto, Takashi; Kim, Soo Chan; Kim, Jong Hoon; Groves, Richard; Samavedam, Unni; Gupta, Yask; Schmidt, Enno; Zillikens, Detlef; Shimizu, Hiroshi; Ludwig, Ralf J.

In: Journal of Investigative Dermatology, Vol. 135, No. 6, 01.01.2015, p. 1565-1573.

Research output: Contribution to journalArticle

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T1 - Autoantibodies to multiple epitopes on the non-collagenous-1 domain of type VII collagen induce blisters

AU - Vorobyev, Artem

AU - Ujiie, Hideyuki

AU - Recke, Andreas

AU - Buijsrogge, Jacqueline J.A.

AU - Jonkman, Marcel F.

AU - Pas, Hendri H.

AU - Iwata, Hiroaki

AU - Hashimoto, Takashi

AU - Kim, Soo Chan

AU - Kim, Jong Hoon

AU - Groves, Richard

AU - Samavedam, Unni

AU - Gupta, Yask

AU - Schmidt, Enno

AU - Zillikens, Detlef

AU - Shimizu, Hiroshi

AU - Ludwig, Ralf J.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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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