Signaling Dependent and Independent Mechanisms in Pemphigus Vulgaris Blister Formation

Masataka Saito, Sara N. Stahley, Christopher Y. Caughman, Xuming Mao, Dana K. Tucker, Aimee S. Payne, Masayuki Amagai, Andrew P. Kowalczyk

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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.

Original languageEnglish
Article numbere50696
JournalPloS one
Volume7
Issue number12
DOIs
Publication statusPublished - 2012 Dec 3

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Saito, M., Stahley, S. N., Caughman, C. Y., Mao, X., Tucker, D. K., Payne, A. S., Amagai, M., & Kowalczyk, A. P. (2012). Signaling Dependent and Independent Mechanisms in Pemphigus Vulgaris Blister Formation. PloS one, 7(12), [e50696]. https://doi.org/10.1371/journal.pone.0050696