title: Peptides Targeting the Desmoglein 3 Adhesive Interface Prevent Autoantibody-induced Acantholysis in Pemphigus.
abstract: Pemphigus vulgaris (PV) autoantibodies directly inhibit desmoglein (Dsg) 3-mediated transinteraction. Because cellular signaling also seems to be required for PV pathogenesis, it is important to characterize the role of direct inhibition in pemphigus acantholysis to allow establishment of new therapeutic approaches. Therefore, we modeled the Dsg1 and Dsg3 sequences into resolved cadherin structures and predicted peptides targeting the adhesive interface of both Dsg3 and Dsg1. In atomic force microscopy single molecule experiments, the self-designed cyclic single peptide specifically blocked homophilic Dsg3 and Dsg1 transinteraction, whereas a tandem peptide (TP) consisting of two combined single peptides did not. TP did not directly block binding of pemphigus IgG to their target Dsg antigens but prevented PV-IgG-induced inhibition of Dsg3 transinteraction in cell-free (atomic force microscopy) and cell-based (laser tweezer) experiments, indicating stabilization of Dsg3 bonds. Similarly, PV-IgG-mediated acantholysis and disruption of Dsg3 localization in HaCaT keratinocytes was partially blocked by TP. This is the first evidence that direct inhibition of Dsg3 binding is important for PV pathogenesis and that peptidomimetics stabilizing Dsg transinteraction may provide a novel approach for PV treatment.
authors.affiliation: Department of Anatomy and Cell Biology, University of Würzburg, Koellikerstr. 6, D-97070 Würzburg.
authors.forename: Wolfgang-Moritz
authors.initials: WM
authors.lastname: Heupel
authors.forename: Thomas
authors.initials: T
authors.lastname: Müller
authors.forename: Athina
authors.initials: A
authors.lastname: Efthymiadis
authors.forename: Enno
authors.initials: E
authors.lastname: Schmidt
authors.forename: Detlev
authors.initials: D
authors.lastname: Drenckhahn
authors.forename: Jens
authors.initials: J
authors.lastname: Waschke
mesh_terms: D000051:Acantholysis / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001323:Autoantibodies / Q000276:immunology*; D002460:Cell Line; D051183:Desmoglein 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D051184:Desmoglein 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D015603:Keratinocytes / Q000276:immunology / Q000473:pathology; D008958:Models, Molecular; D010392:Pemphigus / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D001323:Autoantibodies; C495297:DSG1 protein, human; C071894:DSG3 protein, human; D051183:Desmoglein 1; D051184:Desmoglein 3; D007074:Immunoglobulin G; D010455:Peptides