title: Epitope-Dependent Pathogenicity of Antibodies Targeting a Major Bullous Pemphigoid Autoantigen Collagen XVII/BP180.
abstract: In bullous pemphigoid, the common autoimmune blistering disorder, IgG autoantibodies target various epitopes on hemidesmosomal transmembrane collagen XVII (COL17)/BP180. Antibodies (Abs) targeting the extracellular noncollagenous 16th A domain of COL17 may be pathogenic; however, the pathogenic roles of Abs targeting non-noncollagenous 16th A regions are poorly understood. In this study using a pathogenic and a nonpathogenic monoclonal antibody (mAb) targeting the noncollagenous 16th A domain (mAb TS39-3) and the C-terminus domain (mAb C17-C1), respectively, we show that endocytosis of immune complexes after binding of Abs to cell surface COL17 is a key phenomenon that induces skin fragility. Passive transfer of IgG1 mouse mAb TS39-3 but not mAb C17-C1 induces dermal-epidermal separation in neonatal human COL17-expressing transgenic mice. Interestingly, mAb C17-C1 strongly binds with the dermal-epidermal junction of the recipient mice skin, suggesting that binding of Abs with COL17 is insufficient to induce skin fragility. In cultured normal human epidermal keratinocytes treated with these mAbs, mAb TS39-3 but not mAb C17-C1 internalizes immune complexes after binding with cell surface COL17 via macropinocytosis, resulting in reduced COL17 expression. This study shows that pathogenicity of Abs targeting COL17 is epitope dependent, which is associated with macropinocytosis-mediated endocytosis of immune complexes and finally results in the depletion of COL17 expression in basal keratinocytes.
authors.affiliation: Department of Dermatology, Hokkaido University, Graduate School of Medicine, Sapporo, Japan; Department of Oral Diagnosis and Medicine, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Wada
authors.affiliation: Department of Dermatology, Hokkaido University, Graduate School of Medicine, Sapporo, Japan. Electronic address: nishie@med.hokudai.ac.jp.
authors.forename: Wataru
authors.initials: W
authors.lastname: Nishie
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, Hokkaido University, Graduate School of Medicine, Sapporo, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Izumi
authors.affiliation: Department of Dermatology, Hokkaido University, Graduate School of Medicine, Sapporo, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Iwata
authors.affiliation: Department of Dermatology, Hokkaido University, Graduate School of Medicine, Sapporo, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Natsuga
authors.affiliation: Department of Dermatology, Hokkaido University, Graduate School of Medicine, Sapporo, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Department of Oral Diagnosis and Medicine, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan.
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Kitagawa
authors.affiliation: Department of Dermatology, Hokkaido University, Graduate School of Medicine, Sapporo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimizu
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000939:Epitopes / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy / Q000379:methods; D024041:Non-Fibrillar Collagens / Q000276:immunology / Q000378:metabolism*; D010391:Pemphigoid, Bullous / Q000276:immunology* / Q000503:physiopathology* / Q000628:therapy; D011897:Random Allocation; D012680:Sensitivity and Specificity; D000097805:Collagen Type XVII
chemical_list: D000911:Antibodies, Monoclonal; D001324:Autoantigens; D000939:Epitopes; D024041:Non-Fibrillar Collagens; D000097805:Collagen Type XVII