title: Mucosal pemphigus vulgaris anti-Dsg3 IgG is pathogenic to the oral mucosa of humanized Dsg3 mice.
abstract: There are two major clinical subsets of pemphigus vulgaris (PV)-mucosal PV (mPV) and mucocutaneous PV (mcPV). The mPV subset exhibits anti-human desmoglein (Dsg) 3 autoantibodies that fail to recognize murine Dsg3 (mDsg3); thus, passive transfer experiments of mPV IgG into wild-type (WT) mice have been unsuccessful at inducing disease. We therefore generated a fully humanized Dsg3 (hDSG3) murine model utilizing a hDsg3 transgenic animal crossed to the mDsg3 knockout line. Expression of hDsg3 in the mucosa rescues the mDsg3 knockout phenotype. Well-characterized mPV sera bind mucosal epithelia from the hDsg3 mice, but not mucosal tissues from WT mice, as detected by indirect immunofluorescence (IF). The majority of mPV sera preferentially recognize hDsg3 compared with mDsg3 by immunoprecipitation as well. Passive transfer of mPV IgG into adult hDsg3 mice, but not WT mice, induces suprabasilar acantholysis in mucosal tissues, thus confirming the pathogenicity of mPV anti-hDsg3 IgG in vivo. Human anti-hDsg3 antibodies are detected in perilesional mucosa as well as in sera of recipient mice by IF. These findings suggest that the Dsg3 epitopes targeted by pathogenic mPV IgG are human specific. This hDsg3 mouse model will be invaluable in studying the clinical transition from mPV to mcPV.
authors.affiliation: Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. Electronic address: culton@med.unc.edu.
authors.forename: Donna A
authors.initials: DA
authors.lastname: Culton
authors.affiliation: Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Suzanne K
authors.initials: SK
authors.lastname: McCray
authors.affiliation: Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Moonhee
authors.initials: M
authors.lastname: Park
authors.affiliation: Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Roberts
authors.affiliation: Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Zedek
authors.affiliation: Department of Dermatology, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Grant J
authors.initials: GJ
authors.lastname: Anhalt
authors.affiliation: Animal Models Core Facility, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; TransViragen, Research Triangle Park, North Carolina, USA.
authors.forename: Dale O
authors.initials: DO
authors.lastname: Cowley
authors.affiliation: Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Diaz
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000737:chemistry; D022202:Chromosomes, Artificial, Bacterial; D051183:Desmoglein 1 / Q000378:metabolism; D051184:Desmoglein 3 / Q000235:genetics* / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D000939:Epitopes / Q000737:chemistry; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry*; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009061:Mouth Mucosa / Q000378:metabolism; D009092:Mucous Membrane / Q000378:metabolism; D010392:Pemphigus / Q000276:immunology*; D010641:Phenotype; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D001323:Autoantibodies; C495297:DSG1 protein, human; C071894:DSG3 protein, human; D051183:Desmoglein 1; D051184:Desmoglein 3; C495300:Dsg3 protein, mouse; D000939:Epitopes; D007074:Immunoglobulin G; D011994:Recombinant Proteins