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Stabilization of Keratinocyte Monolayer Integrity in the Presence of Anti-Desmoglein-3 Antibodies through FcRn Blockade with Efgartigimod: Novel Treatment Paradigm for Pemphigus?

Pemphigus vulgaris is an autoimmune blistering disease of the epidermis, caused by autoantibodies against desmosomal proteins, mainly desmogleins 1 and 3, which induce an impairment of desmosomal adhesion and blister formation. Recent findings have shown that inhibition of immunoglobulin G binding o...

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Autores principales: Zakrzewicz, Anna, Würth, Celina, Beckert, Benedikt, Feldhoff, Simon, Vanderheyden, Katrien, Foss, Stian, Andersen, Jan Terje, de Haard, Hans, Verheesen, Peter, Bobkov, Vladimir, Tikkanen, Ritva
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8946243/
https://www.ncbi.nlm.nih.gov/pubmed/35326398
http://dx.doi.org/10.3390/cells11060942
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author Zakrzewicz, Anna
Würth, Celina
Beckert, Benedikt
Feldhoff, Simon
Vanderheyden, Katrien
Foss, Stian
Andersen, Jan Terje
de Haard, Hans
Verheesen, Peter
Bobkov, Vladimir
Tikkanen, Ritva
author_facet Zakrzewicz, Anna
Würth, Celina
Beckert, Benedikt
Feldhoff, Simon
Vanderheyden, Katrien
Foss, Stian
Andersen, Jan Terje
de Haard, Hans
Verheesen, Peter
Bobkov, Vladimir
Tikkanen, Ritva
author_sort Zakrzewicz, Anna
collection PubMed
description Pemphigus vulgaris is an autoimmune blistering disease of the epidermis, caused by autoantibodies against desmosomal proteins, mainly desmogleins 1 and 3, which induce an impairment of desmosomal adhesion and blister formation. Recent findings have shown that inhibition of immunoglobulin G binding on the neonatal Fc receptor, FcRn, results in reduced autoantibody recycling and shortens their half-life, providing a valid treatment option for PV. We have here analyzed the role of FcRn in human keratinocytes treated with antibodies isolated from pemphigus vulgaris patient or with recombinant anti-desmoglein-3 antibodies that induce pathogenic changes in desmosomes, such as loss of monolayer integrity, aberrant desmoglein-3 localization and degradation of desmoglein-3. We show that blocking IgG binding on FcRn by efgartigimod, a recombinant Fc fragment undergoing clinical studies for pemphigus, stabilizes the keratinocyte monolayer, whereas the loss of desmoglein-3 is not prevented by efgartigimod. Our data show that FcRn may play a direct role in the pathogenesis of pemphigus at the level of the autoantibody target cells, the epidermal keratinocytes. Our data suggest that in keratinocytes, FcRn may have functions different from its known function in IgG recycling. Therefore, stabilization of keratinocyte adhesion by FcRn blocking entities may provide a novel treatment paradigm for pemphigus.
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spelling pubmed-89462432022-03-25 Stabilization of Keratinocyte Monolayer Integrity in the Presence of Anti-Desmoglein-3 Antibodies through FcRn Blockade with Efgartigimod: Novel Treatment Paradigm for Pemphigus? Zakrzewicz, Anna Würth, Celina Beckert, Benedikt Feldhoff, Simon Vanderheyden, Katrien Foss, Stian Andersen, Jan Terje de Haard, Hans Verheesen, Peter Bobkov, Vladimir Tikkanen, Ritva Cells Article Pemphigus vulgaris is an autoimmune blistering disease of the epidermis, caused by autoantibodies against desmosomal proteins, mainly desmogleins 1 and 3, which induce an impairment of desmosomal adhesion and blister formation. Recent findings have shown that inhibition of immunoglobulin G binding on the neonatal Fc receptor, FcRn, results in reduced autoantibody recycling and shortens their half-life, providing a valid treatment option for PV. We have here analyzed the role of FcRn in human keratinocytes treated with antibodies isolated from pemphigus vulgaris patient or with recombinant anti-desmoglein-3 antibodies that induce pathogenic changes in desmosomes, such as loss of monolayer integrity, aberrant desmoglein-3 localization and degradation of desmoglein-3. We show that blocking IgG binding on FcRn by efgartigimod, a recombinant Fc fragment undergoing clinical studies for pemphigus, stabilizes the keratinocyte monolayer, whereas the loss of desmoglein-3 is not prevented by efgartigimod. Our data show that FcRn may play a direct role in the pathogenesis of pemphigus at the level of the autoantibody target cells, the epidermal keratinocytes. Our data suggest that in keratinocytes, FcRn may have functions different from its known function in IgG recycling. Therefore, stabilization of keratinocyte adhesion by FcRn blocking entities may provide a novel treatment paradigm for pemphigus. MDPI 2022-03-10 /pmc/articles/PMC8946243/ /pubmed/35326398 http://dx.doi.org/10.3390/cells11060942 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zakrzewicz, Anna
Würth, Celina
Beckert, Benedikt
Feldhoff, Simon
Vanderheyden, Katrien
Foss, Stian
Andersen, Jan Terje
de Haard, Hans
Verheesen, Peter
Bobkov, Vladimir
Tikkanen, Ritva
Stabilization of Keratinocyte Monolayer Integrity in the Presence of Anti-Desmoglein-3 Antibodies through FcRn Blockade with Efgartigimod: Novel Treatment Paradigm for Pemphigus?
title Stabilization of Keratinocyte Monolayer Integrity in the Presence of Anti-Desmoglein-3 Antibodies through FcRn Blockade with Efgartigimod: Novel Treatment Paradigm for Pemphigus?
title_full Stabilization of Keratinocyte Monolayer Integrity in the Presence of Anti-Desmoglein-3 Antibodies through FcRn Blockade with Efgartigimod: Novel Treatment Paradigm for Pemphigus?
title_fullStr Stabilization of Keratinocyte Monolayer Integrity in the Presence of Anti-Desmoglein-3 Antibodies through FcRn Blockade with Efgartigimod: Novel Treatment Paradigm for Pemphigus?
title_full_unstemmed Stabilization of Keratinocyte Monolayer Integrity in the Presence of Anti-Desmoglein-3 Antibodies through FcRn Blockade with Efgartigimod: Novel Treatment Paradigm for Pemphigus?
title_short Stabilization of Keratinocyte Monolayer Integrity in the Presence of Anti-Desmoglein-3 Antibodies through FcRn Blockade with Efgartigimod: Novel Treatment Paradigm for Pemphigus?
title_sort stabilization of keratinocyte monolayer integrity in the presence of anti-desmoglein-3 antibodies through fcrn blockade with efgartigimod: novel treatment paradigm for pemphigus?
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8946243/
https://www.ncbi.nlm.nih.gov/pubmed/35326398
http://dx.doi.org/10.3390/cells11060942
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