Different signaling patterns contribute to loss of keratinocyte cohesion dependent on autoantibody profile in pemphigus

Abstract Pemphigus is an autoimmune blistering skin disease caused primarily by autoantibodies against desmoglein (Dsg)1 and 3. Here, we characterized the mechanisms engaged by pemphigus IgG from patients with different clinical phenotypes and autoantibody profiles. All pemphigus vulgaris (PV) and p...

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Autores principales:	Elias Walter, Franziska Vielmuth, Lukas Rotkopf, Miklós Sárdy, Orsolya N. Horváth, Matthias Goebeler, Enno Schmidt, Rüdiger Eming, Michael Hertl, Volker Spindler, Jens Waschke
Formato:	article
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Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8f58653f8c7c4fc2a2ed76f93520ed9e
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spelling	oai:doaj.org-article:8f58653f8c7c4fc2a2ed76f93520ed9e2021-12-02T16:07:06ZDifferent signaling patterns contribute to loss of keratinocyte cohesion dependent on autoantibody profile in pemphigus10.1038/s41598-017-03697-72045-2322https://doaj.org/article/8f58653f8c7c4fc2a2ed76f93520ed9e2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03697-7https://doaj.org/toc/2045-2322Abstract Pemphigus is an autoimmune blistering skin disease caused primarily by autoantibodies against desmoglein (Dsg)1 and 3. Here, we characterized the mechanisms engaged by pemphigus IgG from patients with different clinical phenotypes and autoantibody profiles. All pemphigus vulgaris (PV) and pemphigus foliaceus (PF) IgG and AK23, a monoclonal mouse antibody against Dsg3, caused loss of cell cohesion, cytokeratin retraction and p38MAPK activation. Strong alterations in Dsg3 distribution were caused by mucosal (aDsg3 antibodies), mucocutaneous (aDsg1 + aDsg3) as well as atypical (aDsg3) PV-IgG. All PV-IgG fractions and AK23 compromised Dsg3 but not Dsg1 binding and enhanced Src activity. In contrast, rapid Ca2+ influx and Erk activation were induced by mucocutaneous PV-IgG and pemphigus foliaceus (PF) IgG (aDsg1) whereas cAMP was increased by mucosal and mucocutaneous PV-IgG only. Selective inhibition of p38MAPK, Src or PKC blocked loss of keratinocyte cohesion in response to all autoantibody fractions whereas Erk inhibition was protective against mucocutaneous PV-IgG and PF-IgG only. These results demonstrate that signaling patterns parallel the clinical phenotype as some mechanisms involved in loss of cell cohesion are caused by antibodies targeting Dsg3 whereas others correlate with autoantibodies against Dsg1. The concept of key desmosome regulators may explain observations from several experimental models of pemphigus.Elias WalterFranziska VielmuthLukas RotkopfMiklós SárdyOrsolya N. HorváthMatthias GoebelerEnno SchmidtRüdiger EmingMichael HertlVolker SpindlerJens WaschkeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Elias Walter Franziska Vielmuth Lukas Rotkopf Miklós Sárdy Orsolya N. Horváth Matthias Goebeler Enno Schmidt Rüdiger Eming Michael Hertl Volker Spindler Jens Waschke Different signaling patterns contribute to loss of keratinocyte cohesion dependent on autoantibody profile in pemphigus
description	Abstract Pemphigus is an autoimmune blistering skin disease caused primarily by autoantibodies against desmoglein (Dsg)1 and 3. Here, we characterized the mechanisms engaged by pemphigus IgG from patients with different clinical phenotypes and autoantibody profiles. All pemphigus vulgaris (PV) and pemphigus foliaceus (PF) IgG and AK23, a monoclonal mouse antibody against Dsg3, caused loss of cell cohesion, cytokeratin retraction and p38MAPK activation. Strong alterations in Dsg3 distribution were caused by mucosal (aDsg3 antibodies), mucocutaneous (aDsg1 + aDsg3) as well as atypical (aDsg3) PV-IgG. All PV-IgG fractions and AK23 compromised Dsg3 but not Dsg1 binding and enhanced Src activity. In contrast, rapid Ca2+ influx and Erk activation were induced by mucocutaneous PV-IgG and pemphigus foliaceus (PF) IgG (aDsg1) whereas cAMP was increased by mucosal and mucocutaneous PV-IgG only. Selective inhibition of p38MAPK, Src or PKC blocked loss of keratinocyte cohesion in response to all autoantibody fractions whereas Erk inhibition was protective against mucocutaneous PV-IgG and PF-IgG only. These results demonstrate that signaling patterns parallel the clinical phenotype as some mechanisms involved in loss of cell cohesion are caused by antibodies targeting Dsg3 whereas others correlate with autoantibodies against Dsg1. The concept of key desmosome regulators may explain observations from several experimental models of pemphigus.
format	article
author	Elias Walter Franziska Vielmuth Lukas Rotkopf Miklós Sárdy Orsolya N. Horváth Matthias Goebeler Enno Schmidt Rüdiger Eming Michael Hertl Volker Spindler Jens Waschke
author_facet	Elias Walter Franziska Vielmuth Lukas Rotkopf Miklós Sárdy Orsolya N. Horváth Matthias Goebeler Enno Schmidt Rüdiger Eming Michael Hertl Volker Spindler Jens Waschke
author_sort	Elias Walter
title	Different signaling patterns contribute to loss of keratinocyte cohesion dependent on autoantibody profile in pemphigus
title_short	Different signaling patterns contribute to loss of keratinocyte cohesion dependent on autoantibody profile in pemphigus
title_full	Different signaling patterns contribute to loss of keratinocyte cohesion dependent on autoantibody profile in pemphigus
title_fullStr	Different signaling patterns contribute to loss of keratinocyte cohesion dependent on autoantibody profile in pemphigus
title_full_unstemmed	Different signaling patterns contribute to loss of keratinocyte cohesion dependent on autoantibody profile in pemphigus
title_sort	different signaling patterns contribute to loss of keratinocyte cohesion dependent on autoantibody profile in pemphigus
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/8f58653f8c7c4fc2a2ed76f93520ed9e
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Different signaling patterns contribute to loss of keratinocyte cohesion dependent on autoantibody profile in pemphigus

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