title: Induction of pemphigus phenotype by a mouse monoclonal antibody against the amino-terminal adhesive interface of desmoglein 3.
abstract: Pemphigus vulgaris (PV) is a life-threatening autoimmune blistering disease that is caused by IgG autoantibodies against the cadherin-type adhesion molecule desmoglein (Dsg)3. Previously, we have generated an active mouse model for PV by adoptive transfer of Dsg3(-/-) splenocytes. In this study, we isolated eight AK series, anti-Dsg3 IgG mAbs from the PV mouse model, and examined their pathogenic activities in induction of blister formation. Intraperitoneal inoculation of the AK23 hybridoma, but not the other AK hybridomas, induced the virtually identical phenotype to that of PV model mice or Dsg3(-/-) mice with typical histology of PV. Epitope mapping with domain-swapped and point-mutated Dsg1/Dsg3 molecules revealed that AK23 recognized a calcium-dependent conformational epitope on Dsg3, which consisted of the V3, K7, P8, and D59 Dsg3-specific residues that formed the adhesive interface between juxtaposed Dsg, as predicted by the crystal structure. The epitopes of the mAbs that failed to show apparent pathogenic activity were mapped in the middle to carboxyl-terminal extracellular region of Dsg3, where no direct intermolecular interaction was predicted. These findings demonstrate the pathogenic heterogeneity among anti-Dsg3 IgG Abs due to their epitopes, and suggest the direct inhibition of adhesive interaction of Dsg as an initial molecular event of blister formation in pemphigus.
authors.affiliation: Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tsunoda
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ota
authors.forename: Miyo
authors.initials: M
authors.lastname: Aoki
authors.forename: Taketo
authors.initials: T
authors.lastname: Yamada
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nagai
authors.forename: Taneaki
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Shigeo
authors.initials: S
authors.lastname: Koyasu
authors.forename: Takeji
authors.initials: T
authors.lastname: Nishikawa
authors.forename: Masayuki
authors.initials: M
authors.lastname: Amagai
mesh_terms: D000051:Acantholysis / Q000276:immunology; D019264:Adoptive Transfer; D000818:Animals; D000831:Animals, Newborn / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000096:biosynthesis / Q000378:metabolism*; D001201:Ascites / Q000276:immunology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001666:Binding Sites, Antibody; D015820:Cadherins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002118:Calcium / Q000502:physiology; D051184:Desmoglein 3; D004195:Disease Models, Animal; D018604:Epitope Mapping; D016056:Immunodominant Epitopes / Q000378:metabolism; D007074:Immunoglobulin G / Q000096:biosynthesis; D016130:Immunophenotyping; D015603:Keratinocytes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010392:Pemphigus / Q000235:genetics / Q000276:immunology*; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011487:Protein Conformation
chemical_list: D000911:Antibodies, Monoclonal; D001324:Autoantigens; D015820:Cadherins; C071894:DSG3 protein, human; D051184:Desmoglein 3; D016056:Immunodominant Epitopes; D007074:Immunoglobulin G; D010446:Peptide Fragments; D002118:Calcium