Signaling Dependent and Independent Mechanisms in Pemphigus Vulgaris Blister Formation

• Type of Material: Article
• Authors: Masataka Saito, Emory University; Sara N. Stahley, Emory University; Christopher Y. Caughman, Emory University; Xuming Mao, University of Pennsylvania; Dana K. Tucker, Emory University; Aimee S. Payne, University of Pennsylvania; Masayuki Amagai, Keio University, Japan; Andrew Kowalczyk, Emory University
• Language: English
• Date: 2012-12-03
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2012 Saito et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0050696
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 7
• Issue: 12
• Start Page: e50696
• End Page: e50696
• Grant/Funding Information: This work was supported by NIH R01AR048266 to APK, National Institutes of Health (NIH) R01-AR057001 to ASP, and NIH P30-AR057217 (University of Pennsylvania Skin Disease Research Center), Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Health and Labor Sciences Research Grants for Research on Measures for Intractable Diseases from the Ministry of Health, Labor and Welfare of Japan.
• Research Categories: Biology, Cell

Abstract

Pemphigus vulgaris (PV) is an autoimmune epidermal blistering disease caused by autoantibodies directed against the desmosomal cadherin desmoglein-3 (Dsg3). Significant advances in our understanding of pemphigus pathomechanisms have been derived from the generation of pathogenic monoclonal Dsg3 antibodies. However, conflicting models for pemphigus pathogenicity have arisen from studies using either polyclonal PV patient IgG or monoclonal Dsg3 antibodies. In the present study, the pathogenic mechanisms of polyclonal PV IgG and monoclonal Dsg3 antibodies were directly compared. Polyclonal PV IgG cause extensive clustering and endocytosis of keratinocyte cell surface Dsg3, whereas pathogenic mouse monoclonal antibodies compromise cell-cell adhesion strength without causing these alterations in Dsg3 trafficking. Furthermore, tyrosine kinase or p38 MAPK inhibition prevents loss of keratinocyte adhesion in response to polyclonal PV IgG. In contrast, disruption of adhesion by pathogenic monoclonal antibodies is not prevented by these inhibitors either in vitro or in human skin explants. Our results reveal that the pathogenic activity of polyclonal PV IgG can be attributed to p38 MAPK-dependent clustering and endocytosis of Dsg3, whereas pathogenic monoclonal Dsg3 antibodies can function independently of this pathway. These findings have important implications for understanding pemphigus pathophysiology, and for the design of pemphigus model systems and therapeutic interventions.