Cargando…

Granzyme B is elevated in autoimmune blistering diseases and cleaves key anchoring proteins of the dermal-epidermal junction

In healthy skin, epidermis and dermis are anchored together at the dermal-epidermal junction (DEJ), a specialized basement membrane pivotal for skin integrity and function. However, increased inflammation in the DEJ is associated with the disruption and separation of this junction and sub-epidermal...

Descripción completa

Detalles Bibliográficos
Autores principales: Russo, Valerio, Klein, Theo, Lim, Darielle J., Solis, Nestor, Machado, Yoan, Hiroyasu, Sho, Nabai, Layla, Shen, Yue, Zeglinski, Matthew R., Zhao, Hongyan, Oram, Cameron P., Lennox, Peter A., Van Laeken, Nancy, Carr, Nick J., Crawford, Richard I., Franzke, Claus-Werner, Overall, Christopher M., Granville, David J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018769/
https://www.ncbi.nlm.nih.gov/pubmed/29946113
http://dx.doi.org/10.1038/s41598-018-28070-0
_version_ 1783335018246963200
author Russo, Valerio
Klein, Theo
Lim, Darielle J.
Solis, Nestor
Machado, Yoan
Hiroyasu, Sho
Nabai, Layla
Shen, Yue
Zeglinski, Matthew R.
Zhao, Hongyan
Oram, Cameron P.
Lennox, Peter A.
Van Laeken, Nancy
Carr, Nick J.
Crawford, Richard I.
Franzke, Claus-Werner
Overall, Christopher M.
Granville, David J.
author_facet Russo, Valerio
Klein, Theo
Lim, Darielle J.
Solis, Nestor
Machado, Yoan
Hiroyasu, Sho
Nabai, Layla
Shen, Yue
Zeglinski, Matthew R.
Zhao, Hongyan
Oram, Cameron P.
Lennox, Peter A.
Van Laeken, Nancy
Carr, Nick J.
Crawford, Richard I.
Franzke, Claus-Werner
Overall, Christopher M.
Granville, David J.
author_sort Russo, Valerio
collection PubMed
description In healthy skin, epidermis and dermis are anchored together at the dermal-epidermal junction (DEJ), a specialized basement membrane pivotal for skin integrity and function. However, increased inflammation in the DEJ is associated with the disruption and separation of this junction and sub-epidermal blistering. Granzyme B (GzmB) is a serine protease secreted by immune cells. Dysregulated inflammation may lead to increased GzmB accumulation and proteolysis in the extracellular milieu. Although elevated GzmB is observed at the level of the DEJ in inflammatory and blistering skin conditions, the present study is the first to explore GzmB in the context of DEJ degradation in autoimmune sub-epidermal blistering. In the present study, GzmB induced separation of the DEJ in healthy human skin. Subsequently, α6/β4 integrin, collagen VII, and collagen XVII were identified as extracellular substrates for GzmB through western blot, and specific cleavage sites were identified by mass spectrometry. In human bullous pemphigoid, dermatitis herpetiformis, and epidermolysis bullosa acquisita, GzmB was elevated at the DEJ when compared to healthy samples, while α6/β4 integrin, collagen VII, and collagen XVII were reduced or absent in the area of blistering. In summary, our results suggest that regardless of the initial causation of sub-epidermal blistering, GzmB activity is a common final pathway that could be amenable to a single targeted treatment approach.
format Online
Article
Text
id pubmed-6018769
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-60187692018-07-06 Granzyme B is elevated in autoimmune blistering diseases and cleaves key anchoring proteins of the dermal-epidermal junction Russo, Valerio Klein, Theo Lim, Darielle J. Solis, Nestor Machado, Yoan Hiroyasu, Sho Nabai, Layla Shen, Yue Zeglinski, Matthew R. Zhao, Hongyan Oram, Cameron P. Lennox, Peter A. Van Laeken, Nancy Carr, Nick J. Crawford, Richard I. Franzke, Claus-Werner Overall, Christopher M. Granville, David J. Sci Rep Article In healthy skin, epidermis and dermis are anchored together at the dermal-epidermal junction (DEJ), a specialized basement membrane pivotal for skin integrity and function. However, increased inflammation in the DEJ is associated with the disruption and separation of this junction and sub-epidermal blistering. Granzyme B (GzmB) is a serine protease secreted by immune cells. Dysregulated inflammation may lead to increased GzmB accumulation and proteolysis in the extracellular milieu. Although elevated GzmB is observed at the level of the DEJ in inflammatory and blistering skin conditions, the present study is the first to explore GzmB in the context of DEJ degradation in autoimmune sub-epidermal blistering. In the present study, GzmB induced separation of the DEJ in healthy human skin. Subsequently, α6/β4 integrin, collagen VII, and collagen XVII were identified as extracellular substrates for GzmB through western blot, and specific cleavage sites were identified by mass spectrometry. In human bullous pemphigoid, dermatitis herpetiformis, and epidermolysis bullosa acquisita, GzmB was elevated at the DEJ when compared to healthy samples, while α6/β4 integrin, collagen VII, and collagen XVII were reduced or absent in the area of blistering. In summary, our results suggest that regardless of the initial causation of sub-epidermal blistering, GzmB activity is a common final pathway that could be amenable to a single targeted treatment approach. Nature Publishing Group UK 2018-06-26 /pmc/articles/PMC6018769/ /pubmed/29946113 http://dx.doi.org/10.1038/s41598-018-28070-0 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Russo, Valerio
Klein, Theo
Lim, Darielle J.
Solis, Nestor
Machado, Yoan
Hiroyasu, Sho
Nabai, Layla
Shen, Yue
Zeglinski, Matthew R.
Zhao, Hongyan
Oram, Cameron P.
Lennox, Peter A.
Van Laeken, Nancy
Carr, Nick J.
Crawford, Richard I.
Franzke, Claus-Werner
Overall, Christopher M.
Granville, David J.
Granzyme B is elevated in autoimmune blistering diseases and cleaves key anchoring proteins of the dermal-epidermal junction
title Granzyme B is elevated in autoimmune blistering diseases and cleaves key anchoring proteins of the dermal-epidermal junction
title_full Granzyme B is elevated in autoimmune blistering diseases and cleaves key anchoring proteins of the dermal-epidermal junction
title_fullStr Granzyme B is elevated in autoimmune blistering diseases and cleaves key anchoring proteins of the dermal-epidermal junction
title_full_unstemmed Granzyme B is elevated in autoimmune blistering diseases and cleaves key anchoring proteins of the dermal-epidermal junction
title_short Granzyme B is elevated in autoimmune blistering diseases and cleaves key anchoring proteins of the dermal-epidermal junction
title_sort granzyme b is elevated in autoimmune blistering diseases and cleaves key anchoring proteins of the dermal-epidermal junction
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018769/
https://www.ncbi.nlm.nih.gov/pubmed/29946113
http://dx.doi.org/10.1038/s41598-018-28070-0
work_keys_str_mv AT russovalerio granzymebiselevatedinautoimmuneblisteringdiseasesandcleaveskeyanchoringproteinsofthedermalepidermaljunction
AT kleintheo granzymebiselevatedinautoimmuneblisteringdiseasesandcleaveskeyanchoringproteinsofthedermalepidermaljunction
AT limdariellej granzymebiselevatedinautoimmuneblisteringdiseasesandcleaveskeyanchoringproteinsofthedermalepidermaljunction
AT solisnestor granzymebiselevatedinautoimmuneblisteringdiseasesandcleaveskeyanchoringproteinsofthedermalepidermaljunction
AT machadoyoan granzymebiselevatedinautoimmuneblisteringdiseasesandcleaveskeyanchoringproteinsofthedermalepidermaljunction
AT hiroyasusho granzymebiselevatedinautoimmuneblisteringdiseasesandcleaveskeyanchoringproteinsofthedermalepidermaljunction
AT nabailayla granzymebiselevatedinautoimmuneblisteringdiseasesandcleaveskeyanchoringproteinsofthedermalepidermaljunction
AT shenyue granzymebiselevatedinautoimmuneblisteringdiseasesandcleaveskeyanchoringproteinsofthedermalepidermaljunction
AT zeglinskimatthewr granzymebiselevatedinautoimmuneblisteringdiseasesandcleaveskeyanchoringproteinsofthedermalepidermaljunction
AT zhaohongyan granzymebiselevatedinautoimmuneblisteringdiseasesandcleaveskeyanchoringproteinsofthedermalepidermaljunction
AT oramcameronp granzymebiselevatedinautoimmuneblisteringdiseasesandcleaveskeyanchoringproteinsofthedermalepidermaljunction
AT lennoxpetera granzymebiselevatedinautoimmuneblisteringdiseasesandcleaveskeyanchoringproteinsofthedermalepidermaljunction
AT vanlaekennancy granzymebiselevatedinautoimmuneblisteringdiseasesandcleaveskeyanchoringproteinsofthedermalepidermaljunction
AT carrnickj granzymebiselevatedinautoimmuneblisteringdiseasesandcleaveskeyanchoringproteinsofthedermalepidermaljunction
AT crawfordrichardi granzymebiselevatedinautoimmuneblisteringdiseasesandcleaveskeyanchoringproteinsofthedermalepidermaljunction
AT franzkeclauswerner granzymebiselevatedinautoimmuneblisteringdiseasesandcleaveskeyanchoringproteinsofthedermalepidermaljunction
AT overallchristopherm granzymebiselevatedinautoimmuneblisteringdiseasesandcleaveskeyanchoringproteinsofthedermalepidermaljunction
AT granvilledavidj granzymebiselevatedinautoimmuneblisteringdiseasesandcleaveskeyanchoringproteinsofthedermalepidermaljunction