title: Peptide-mediated desmoglein 3 crosslinking prevents pemphigus vulgaris autoantibody-induced skin blistering.
abstract: In pemphigus vulgaris, a life-threatening autoimmune skin disease, epidermal blisters are caused by autoantibodies primarily targeting desmosomal cadherins desmoglein 3 (DSG3) and DSG1, leading to loss of keratinocyte cohesion. Due to limited insights into disease pathogenesis, current therapy relies primarily on nonspecific long-term immunosuppression. Both direct inhibition of DSG transinteraction and altered intracellular signaling by p38 MAPK likely contribute to the loss of cell adhesion. Here, we applied a tandem peptide (TP) consisting of 2 connected peptide sequences targeting the DSG adhesive interface that was capable of blocking autoantibody-mediated direct interference of DSG3 transinteraction, as revealed by atomic force microscopy and optical trapping. Importantly, TP abrogated autoantibody-mediated skin blistering in mice and was effective when applied topically. Mechanistically, TP inhibited both autoantibody-induced p38 MAPK activation and its association with DSG3, abrogated p38 MAPK-induced keratin filament retraction, and promoted desmosomal DSG3 oligomerization. These data indicate that p38 MAPK links autoantibody-mediated inhibition of DSG3 binding to skin blistering. By limiting loss of DSG3 transinteraction, p38 MAPK activation, and keratin filament retraction, which are hallmarks of pemphigus pathogenesis, TP may serve as a promising treatment option.
authors.affiliation: Institute of Anatomy and Cell Biology, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Spindler
authors.forename: Vera
authors.initials: V
authors.lastname: Rötzer
authors.forename: Carina
authors.initials: C
authors.lastname: Dehner
authors.forename: Bettina
authors.initials: B
authors.lastname: Kempf
authors.forename: Martin
authors.initials: M
authors.lastname: Gliem
authors.forename: Mariya
authors.initials: M
authors.lastname: Radeva
authors.forename: Eva
authors.initials: E
authors.lastname: Hartlieb
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Harms
authors.forename: Enno
authors.initials: E
authors.lastname: Schmidt
authors.forename: Jens
authors.initials: J
authors.lastname: Waschke
mesh_terms: D000051:Acantholysis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D000287:Administration, Topical; D000818:Animals; D000831:Animals, Newborn; D001323:Autoantibodies / Q000008:administration & dosage; D003432:Cross-Linking Reagents; D051184:Desmoglein 3 / Q000008:administration & dosage / Q000737:chemistry* / Q000276:immunology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018625:Microscopy, Atomic Force; D010392:Pemphigus / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D003432:Cross-Linking Reagents; C071894:DSG3 protein, human; D051184:Desmoglein 3; D011994:Recombinant Proteins; D048051:p38 Mitogen-Activated Protein Kinases