title: Bullous pemphigoid IgG induces BP180 internalization via a macropinocytic pathway.
abstract: Bullous pemphigoid (BP) is an autoimmune blistering skin disease induced by pathogenic autoantibodies against a type II transmembrane protein (BP180, collagen type XVII, or BPAG2). In animal models, BP180 autoantibody-antigen interaction appears insufficient to develop blisters, but involvement of complement and neutrophils is required. However, cultured keratinocytes treated with BP-IgG exhibit a reduction in the adhesive strength and a loss of expression of BP180, suggesting that the autoantibodies directly affect epidermal cell-extracellular matrix integrity. In this study, we explored the consequences of two distinct epithelial cells treated with BP-IgG, particularly the fate of BP180. First, we followed the distribution of green fluorescent protein-tagged BP180 in an epithelial cell line, 804G, and normal human epidermal keratinocytes after autoantibody clustering. After BP-IgG treatment, the adhesive strength of the cells to their substrate was decreased, and BP180 was internalized in both cell types, together with the early endosomal antigen-1. By using various endocytosis inhibitors and a fluid-uptake assay, we demonstrated that BP-IgG-induced BP180 internalization is mediated via a macropinocytic pathway. Moreover, a macropinocytosis inhibitor rescued a BP-IgG-induced reduction in the adhesive strength of the cells from their substrate. The results of this study suggest that BP180 internalization induced by BP-IgG plays an important role in the initiation of disease pathogenesis.
authors: Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors: Sho
authors: S
authors: Hiroyasu
authors: Toshiyuki
authors: T
authors: Ozawa
authors: Hiromi
authors: H
authors: Kobayashi
authors: Masamitsu
authors: M
authors: Ishii
authors: Yumi
authors: Y
authors: Aoyama
authors: Yasuo
authors: Y
authors: Kitajima
authors: Takashi
authors: T
authors: Hashimoto
authors: Jonathan C R
authors: JC
authors: Jones
authors: Daisuke
authors: D
authors: Tsuruta
mesh_terms: D001324:Autoantigens / Q000737:chemistry / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D021941:Caveolae / Q000187:drug effects / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002966:Clathrin / Q000378:metabolism; D003896:Desmosomes / Q000187:drug effects / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology*; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D024041:Non-Fibrillar Collagens / Q000737:chemistry / Q000378:metabolism*; D010391:Pemphigoid, Bullous / Q000276:immunology* / Q000473:pathology*; D010873:Pinocytosis / Q000187:drug effects*; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D055571:Secretory Pathway / Q000187:drug effects* / Q000276:immunology; D000097805:Collagen Type XVII
chemical_list: D001324:Autoantigens; D015415:Biomarkers; D002966:Clathrin; D049452:Green Fluorescent Proteins; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D024041:Non-Fibrillar Collagens; D011505:Protein-Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D000097805:Collagen Type XVII