title: IgG autoantibodies against desmocollin 3 in pemphigus sera induce loss of keratinocyte adhesion.
abstract: Pemphigus is considered an autoimmune bullous skin disorder associated with IgG against the desmosomal components, desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1). This concept is supported by the in vitro and in vivo pathogenicity of anti-Dsg3/Dsg1 IgG and the mucosal blistering phenotype of mice with a genetic deficiency of Dsg3. Mice deficient for another desmosomal adhesion molecule, desmocollin 3 (Dsc3), show a similar pemphigus phenotype, and we investigated the pathogenicity of Dsc3-reactive IgG autoantibodies that were identified previously in a subset of patients with atypical pemphigus. We here demonstrate that IgG against Dsc3 causes loss of adhesion of epidermal keratinocytes. Specifically, IgG against Dsc3 was purified from Dsc3-reactive pemphigus sera by affinity column chromatography using recombinant human Dsc3. Affinity purified IgG was functionally active and did not only react with recombinant Dsc3 but also with epidermis and cultured human keratinocytes. Moreover, Dsc3-reactive IgG induced loss of adhesion of epidermal keratinocytes in a dispase-based keratinocyte dissociation assay that was reversed on pre-adsorption with human Dsc3 but not Dsg3. These findings demonstrate that IgG autoantibodies against an additional component of the desmosomes, Dsc3, induce loss of keratinocyte adhesion and thus may contribute to blister formation in pemphigus.
authors.affiliation: Department of Dermatology and Allergology, Philipps University, Marburg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Rafei
authors.forename: Ralf
authors.initials: R
authors.lastname: Müller
authors.forename: Norito
authors.initials: N
authors.lastname: Ishii
authors.forename: Maria
authors.initials: M
authors.lastname: Llamazares
authors.forename: Takashi
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Michael
authors.initials: M
authors.lastname: Hertl
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Eming
mesh_terms: D000818:Animals; D000918:Antibody Specificity / Q000276:immunology; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology*; D002448:Cell Adhesion / Q000276:immunology; D002846:Chromatography, Affinity; D051187:Desmocollins / Q000276:immunology*; D000882:Haplorhini; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D015603:Keratinocytes / Q000473:pathology*; D051379:Mice; D010392:Pemphigus / Q000097:blood* / Q000276:immunology* / Q000473:pathology; D011994:Recombinant Proteins / Q000276:immunology
chemical_list: D001323:Autoantibodies; C490356:DSC3 protein, human; D051187:Desmocollins; D007074:Immunoglobulin G; D011994:Recombinant Proteins