title: Deletion of the major bullous pemphigoid epitope region of collagen XVII induces blistering, autoimmunization, and itching in mice.
abstract: Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering skin disease with a characteristic of pruritus and blistering. BP patients carry inflammation-triggering autoantibodies against the collagen XVII (ColXVII, also known as BP180) juxtamembraneous extracellular noncollagenous 16A (NC16A) domain involved in ectodomain shedding. Deletion of the corresponding NC14A region in a genetically modified mouse model (ΔNC14A) decreased the amount of ColXVII in skin, but it did not prevent ectodomain shedding. Newborn ΔNC14A mice had no macroscopic phenotypic changes. However, subepidermal microblisters, rudimentary hemidesmosomes, and loose basement membrane zone were observed by microscopy. ΔNC14A mice grow normally, but at around 3 months of age they start to scratch themselves and develop crusted erosions. Furthermore, perilesional eosinophilic infiltrations in the skin, eosinophilia, and elevated serum IgE levels are detected. Despite the removal of the major BP epitope region, ΔNC14A mice developed IgG and IgA autoantibodies with subepidermal reactivity, indicating autoimmunization against a dermo-epidermal junction component. Moreover, IgG autoantibodies recognized a 180-kDa keratinocyte protein, which was sensitive to collagenase digestion. We show here that ΔNC14A mice provide a highly reproducible BP-related mouse model with spontaneous breakage of self-tolerance and development of autoantibodies.
authors.affiliation: Department of Dermatology, University of Oulu, Oulu, Finland; Medical Research Center Oulu (MRC Oulu), Oulu University Hospital, Oulu, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Hurskainen
authors.affiliation: Department of Dermatology, University of Oulu, Oulu, Finland; Medical Research Center Oulu (MRC Oulu), Oulu University Hospital, Oulu, Finland.
authors.forename: Nina
authors.initials: N
authors.lastname: Kokkonen
authors.affiliation: Biocenter Oulu, University of Oulu, Oulu, Finland; Department of Pathology, University of Oulu, Finland and Oulu University Hospital, Oulu, Finland.
authors.forename: Raija
authors.initials: R
authors.lastname: Sormunen
authors.affiliation: Laboratory of Genetic Skin Diseases, Inserm UMR1163 and Imagine Institute of Genetic Diseases, Paris, France.
authors.forename: Joanna
authors.initials: J
authors.lastname: Jackow
authors.affiliation: Department of Dermatology, University Medical Center Freiburg and Freiburg Institute of Advanced Studies, University of Freiburg, Freiburg, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Löffek
authors.affiliation: Biocenter Oulu, University of Oulu, Oulu, Finland; Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
authors.forename: Raija
authors.initials: R
authors.lastname: Soininen
authors.affiliation: Department of Dermatology, University Medical Center Freiburg and Freiburg Institute of Advanced Studies, University of Freiburg, Freiburg, Germany.
authors.forename: Claus-Werner
authors.initials: CW
authors.lastname: Franzke
authors.affiliation: Department of Dermatology, University Medical Center Freiburg and Freiburg Institute of Advanced Studies, University of Freiburg, Freiburg, Germany.
authors.forename: Leena
authors.initials: L
authors.lastname: Bruckner-Tuderman
authors.affiliation: Department of Dermatology, University of Oulu, Oulu, Finland; Medical Research Center Oulu (MRC Oulu), Oulu University Hospital, Oulu, Finland. Electronic address: kaisa.tasanen@oulu.fi.
authors.forename: Kaisa
authors.initials: K
authors.lastname: Tasanen
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001324:Autoantigens / Q000235:genetics* / Q000502:physiology; D015551:Autoimmunity / Q000235:genetics* / Q000502:physiology; D001768:Blister / Q000235:genetics* / Q000503:physiopathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000939:Epitopes / Q000235:genetics* / Q000502:physiology; D017353:Gene Deletion; D015603:Keratinocytes / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024041:Non-Fibrillar Collagens / Q000235:genetics* / Q000502:physiology; D010391:Pemphigoid, Bullous / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D011537:Pruritus / Q000235:genetics* / Q000503:physiopathology; D012867:Skin / Q000473:pathology; D000097805:Collagen Type XVII
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D000939:Epitopes; D024041:Non-Fibrillar Collagens; D000097805:Collagen Type XVII