title: PDE4 Inhibition as Potential Treatment of Epidermolysis Bullosa Acquisita.
abstract: Pemphigoid diseases such as epidermolysis bullosa acquisita (EBA) may be difficult to treat. In pemphigoid diseases, mucocutaneous blistering is caused by autoantibodies to hemidesmosomal antigens; in EBA the autoantigen is type VII collagen. Despite growing insights into pemphigoid disease pathogenesis, corticosteroids are still a mainstay of treatment. In experimental EBA, myeloid cell activation is a key event leading to blistering. Activation of these cells depends on phosphodiesterase (PDE) 4. We therefore evaluated the potential for PDE4 inhibition in EBA: PDE4 was highly expressed in inflammatory cells and in the epidermis of patients compared with healthy skin samples. PDE4 inhibitors rolipram, roflumilast, and roflumilast N-oxide prevented the release of immune complex-induced reactive oxygen species from polymorphonuclear leukocytes and separation of the dermal-epidermal junction of skin incubated with antibodies to collagen type VII and polymorphonuclear leukocytes. The PDE4 inhibitors also impaired CD62L shedding and decreased CD11b expression on immune complex-stimulated polymorphonuclear leukocytes. For in vivo validation, experimental EBA was induced in mice by transfer of anti-collagen type VII IgG or immunization with collagen type VII. Roflumilast dose-dependently reduced blistering in antibody transfer-induced EBA and also hindered disease progression in immunization-induced EBA. PDE4 inhibition emerges as a new treatment modality for EBA and possibly other neutrophil-driven pemphigoid diseases.
authors.affiliation: Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany. Electronic address: hiroshi_koga@med.kurume-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Koga
authors.affiliation: Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Recke
authors.affiliation: Department of Experimental Immunohematology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Gestur
authors.initials: G
authors.lastname: Vidarsson
authors.affiliation: Center for Blistering Diseases, Department of Dermatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Hendri H
authors.initials: HH
authors.lastname: Pas
authors.affiliation: Center for Blistering Diseases, Department of Dermatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Marcel F
authors.initials: MF
authors.lastname: Jonkman
authors.affiliation: Kurume University Institute of Cutaneous Cell Biology, Kurume University, Kurume, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Anika
authors.initials: A
authors.lastname: Kasprick
authors.affiliation: Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Saeedeh
authors.initials: S
authors.lastname: Ghorbanalipoor
authors.affiliation: Topadur Pharma AG, Rheinfelden, Switzerland.
authors.forename: Hermann
authors.initials: H
authors.lastname: Tenor
authors.affiliation: Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany; Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Detlef
authors.initials: D
authors.lastname: Zillikens
authors.affiliation: Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany; Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Ralf J
authors.initials: RJ
authors.lastname: Ludwig
mesh_terms: D000631:Aminopyridines / Q000627:therapeutic use*; D000818:Animals; D000936:Antigen-Antibody Complex; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D001549:Benzamides / Q000627:therapeutic use*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000096:biosynthesis* / Q000276:immunology; D003521:Cyclopropanes / Q000627:therapeutic use; D004195:Disease Models, Animal; D004817:Epidermis / Q000276:immunology / Q000473:pathology*; D016107:Epidermolysis Bullosa Acquisita / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D058988:Phosphodiesterase 4 Inhibitors / Q000627:therapeutic use*
chemical_list: D000631:Aminopyridines; D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D001324:Autoantigens; D001549:Benzamides; D003521:Cyclopropanes; D058988:Phosphodiesterase 4 Inhibitors; C424423:Roflumilast; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4