title: Antigen-specific immunoadsorption of pathogenic autoantibodies in pemphigus foliaceus.
abstract: Patients with the autoimmune blistering disease pemphigus foliaceus (PF) have circulating autoantibodies directed against the desmosomal cadherin desmoglein 1 (Dsg1). Based on the fact that purified IgG fractions from PF patients induce loss of cell adhesion in organ culture and in a neonatal mouse model, it has been proposed that these anti-Dsg1 antibodies play a pathogenic role in blister formation. To directly address whether antibodies in PF sera specific for the Dsg1 extracellular domain are indeed pathogenic in the disease, PFIg, a chimeric protein containing the entire extracellular domain of human Dsg1 and the constant region of human IgG1, was produced by baculovirus expression. Incubation of PF patients' sera with the PFIg baculoprotein removed the immunoreactivity of autoantibodies against keratinocyte cell surfaces in all 20 PF and eight Brazilian PF patients' sera tested. This adsorption was conformation dependent, because PFIg protein denatured by low pH or heat was no longer able to adsorb the immunoreactivity of PF sera. Furthermore, the incubation with the PFIg baculoprotein eliminated the pathogenic activity of PF patients' sera and prevented gross blister formation in a neonatal mouse model of pemphigus. Anti-Dsg1 antibodies eluted from the PFIg protein column were pathogenic as they resulted in the appearance of gross blisters in neonatal mice with typical histologic findings of PF. These observations indicate that the extracellular domain of Dsg1 expressed by baculovirus is capable of specifically immunoadsorbing pathogenic autoantibodies from PF patients' sera and provide direct evidence that the anti-Dsg1 autoantibodies in PF sera are indeed pathogenic. The availability of this Dsg1 recombinant protein may facilitate the development of antigen-specific plasmapheresis as a novel therapeutic strategy in pemphigus.
authors.affiliation: Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Amagai
authors.forename: T
authors.initials: T
authors.lastname: Hashimoto
authors.forename: K J
authors.initials: KJ
authors.lastname: Green
authors.forename: N
authors.initials: N
authors.lastname: Shimizu
authors.forename: T
authors.initials: T
authors.lastname: Nishikawa
mesh_terms: D000818:Animals; D000918:Antibody Specificity; D001323:Autoantibodies / Q000032:analysis*; D001324:Autoantigens / Q000276:immunology; D016367:Baculoviridae / Q000737:chemistry; D001768:Blister / Q000209:etiology; D015820:Cadherins / Q000276:immunology*; D003598:Cytoskeletal Proteins / Q000276:immunology; D051183:Desmoglein 1; D051182:Desmogleins; D051180:Desmoplakins; D003896:Desmosomes / Q000276:immunology; D000939:Epitopes; D006801:Humans; D007163:Immunosorbent Techniques; D051379:Mice; D010392:Pemphigus / Q000097:blood / Q000276:immunology*; D014764:Viral Proteins / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D015820:Cadherins; D003598:Cytoskeletal Proteins; C495297:DSG1 protein, human; D051183:Desmoglein 1; D051182:Desmogleins; D051180:Desmoplakins; C495299:Dsg1a protein, mouse; D000939:Epitopes; D014764:Viral Proteins