title: Specific immunoadsorption of pathogenic autoantibodies in pemphigus requires the entire ectodomains of desmogleins.
abstract: Pemphigus foliaceus (PF) and pemphigus vulgaris (PV) are life-threatening autoimmune blistering skin diseases. They are characterized by circulating autoantibodies which bind to the ectodomains of desmoglein (Dsg) 1 and Dsg3. These antibodies induce acantholysis in skin and mucous membranes. In severe cases of pemphigus, immunoadsorption is applied to remove total IgG from patient plasma using protein A or other ligands. To develop a specific adsorber for anti-Dsg antibodies, epitope mapping studies of Dsg1 and Dsg3 ectodomains were conducted. Dsg variants were expressed on the surface of HEK-293 cells and analysed for reactivity with pemphigus and control sera by indirect immunofluorescence technique. For Dsg1, a construct consisting of domain 1 directly fused to domain 5, seemed to be suitable for specific immunoadsorption of anti-Dsg1 antibodies. The recognized epitopes were mainly conformation-dependent. However, adsorption of pemphigus foliaceus IgG using this protein coupled to a Sepharose matrix did not completely remove pathogenicity from the sera, as proven by a keratinocyte dissociation assay. In contrast, full-length Dsg1 and Dsg3 ectodomains were able to specifically adsorb anti-Dsg antibodies and to efficiently eliminate pathogenicity. Therefore, the complete and correctly folded ectodomains of both desmogleins are required for therapeutic immunoadsorption.
authors.affiliation: Institute of Experimental Immunology, Euroimmun AG, Lübeck, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Langenhan
authors.forename: Jenny
authors.initials: J
authors.lastname: Dworschak
authors.forename: Sandra
authors.initials: S
authors.lastname: Saschenbrecker
authors.forename: Lars
authors.initials: L
authors.lastname: Komorowski
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schlumberger
authors.forename: Winfried
authors.initials: W
authors.lastname: Stöcker
authors.forename: Jürgen
authors.initials: J
authors.lastname: Westermann
authors.forename: Andreas
authors.initials: A
authors.lastname: Recke
authors.forename: Detlef
authors.initials: D
authors.lastname: Zillikens
authors.forename: Enno
authors.initials: E
authors.lastname: Schmidt
authors.forename: Christian
authors.initials: C
authors.lastname: Probst
mesh_terms: D016022:Case-Control Studies; D051183:Desmoglein 1 / Q000276:immunology*; D051184:Desmoglein 3 / Q000276:immunology*; D018604:Epitope Mapping; D057809:HEK293 Cells; D006801:Humans; D007163:Immunosorbent Techniques; D010392:Pemphigus / Q000276:immunology / Q000628:therapy*; D017434:Protein Structure, Tertiary
chemical_list: C495297:DSG1 protein, human; C071894:DSG3 protein, human; D051183:Desmoglein 1; D051184:Desmoglein 3
keywords: autoantibodies; immunoadsorption; pemphigus