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

Research output: Contribution to journalArticle

52 Citations (Scopus)

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

Fingerprint

Desmoglein 3
pemphigus (skin disease)
blisters
Pemphigus
Blister
Immunoglobulin G
Antibodies
p38 Mitogen-Activated Protein Kinases
antibodies
keratinocytes
endocytosis
Endocytosis
Desmosomal Cadherins
Keratinocytes
mitogen-activated protein kinase
Adhesion
Monoclonal Antibodies
Cluster Analysis
adhesion
monoclonal antibodies

ASJC Scopus subject areas

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

Cite this

Saito, M., Stahley, S. N., Caughman, C. Y., Mao, X., Tucker, D. K., Payne, A. S., ... 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

Signaling Dependent and Independent Mechanisms in Pemphigus Vulgaris Blister Formation. / Saito, Masataka; Stahley, Sara N.; Caughman, Christopher Y.; Mao, Xuming; Tucker, Dana K.; Payne, Aimee S.; Amagai, Masayuki; Kowalczyk, Andrew P.

In: PLoS One, Vol. 7, No. 12, e50696, 03.12.2012.

Research output: Contribution to journalArticle

Saito, M, Stahley, SN, Caughman, CY, Mao, X, Tucker, DK, Payne, AS, Amagai, M & Kowalczyk, AP 2012, 'Signaling Dependent and Independent Mechanisms in Pemphigus Vulgaris Blister Formation', PLoS One, vol. 7, no. 12, e50696. https://doi.org/10.1371/journal.pone.0050696
Saito, Masataka ; Stahley, Sara N. ; Caughman, Christopher Y. ; Mao, Xuming ; Tucker, Dana K. ; Payne, Aimee S. ; Amagai, Masayuki ; Kowalczyk, Andrew P. / Signaling Dependent and Independent Mechanisms in Pemphigus Vulgaris Blister Formation. In: PLoS One. 2012 ; Vol. 7, No. 12.
@article{834eec96bcc14fc4a50865e6e8e62a93,
title = "Signaling Dependent and Independent Mechanisms in Pemphigus Vulgaris Blister Formation",
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.",
author = "Masataka Saito and Stahley, {Sara N.} and Caughman, {Christopher Y.} and Xuming Mao and Tucker, {Dana K.} and Payne, {Aimee S.} and Masayuki Amagai and Kowalczyk, {Andrew P.}",
year = "2012",
month = "12",
day = "3",
doi = "10.1371/journal.pone.0050696",
language = "English",
volume = "7",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "12",

}

TY - JOUR

T1 - Signaling Dependent and Independent Mechanisms in Pemphigus Vulgaris Blister Formation

AU - Saito, Masataka

AU - Stahley, Sara N.

AU - Caughman, Christopher Y.

AU - Mao, Xuming

AU - Tucker, Dana K.

AU - Payne, Aimee S.

AU - Amagai, Masayuki

AU - Kowalczyk, Andrew P.

PY - 2012/12/3

Y1 - 2012/12/3

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84870659354&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84870659354&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0050696

DO - 10.1371/journal.pone.0050696

M3 - Article

C2 - 23226536

AN - SCOPUS:84870659354

VL - 7

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 12

M1 - e50696

ER -