Induction of pemphigus phenotype by a mouse monoclonal antibody against the amino-terminal adhesive interface of desmoglein 31

Kazuyuki Tsunoda, Takayuki Ota, Miyo Aoki, Taketo Yamada, Tetsuo Nagai, Taneaki Nakagawa, Shigeo Koyasu, Takeji Nishikawa, Masayuki Amagai

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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.

Original languageEnglish
Pages (from-to)2170-2178
Number of pages9
JournalJournal of Immunology
Volume170
Issue number4
Publication statusPublished - 2003 Feb 15

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Desmogleins
Pemphigus
Adhesives
Monoclonal Antibodies
Phenotype
Epitopes
Hybridomas
Blister
Desmoglein 3
Epitope Mapping
Adoptive Transfer
Cadherins
Autoantibodies
Autoimmune Diseases
Histology
Immunoglobulin G
Calcium

ASJC Scopus subject areas

  • Immunology

Cite this

Induction of pemphigus phenotype by a mouse monoclonal antibody against the amino-terminal adhesive interface of desmoglein 31. / Tsunoda, Kazuyuki; Ota, Takayuki; Aoki, Miyo; Yamada, Taketo; Nagai, Tetsuo; Nakagawa, Taneaki; Koyasu, Shigeo; Nishikawa, Takeji; Amagai, Masayuki.

In: Journal of Immunology, Vol. 170, No. 4, 15.02.2003, p. 2170-2178.

Research output: Contribution to journalArticle

Tsunoda, Kazuyuki ; Ota, Takayuki ; Aoki, Miyo ; Yamada, Taketo ; Nagai, Tetsuo ; Nakagawa, Taneaki ; Koyasu, Shigeo ; Nishikawa, Takeji ; Amagai, Masayuki. / Induction of pemphigus phenotype by a mouse monoclonal antibody against the amino-terminal adhesive interface of desmoglein 31. In: Journal of Immunology. 2003 ; Vol. 170, No. 4. pp. 2170-2178.
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