Granzyme B inhibition reduces disease severity in autoimmune blistering diseases

Sho Hiroyasu; Matthew R. Zeglinski; Hongyan Zhao; Megan A. Pawluk; Christopher T. Turner; Anika Kasprick; Chiharu Tateishi; Wataru Nishie; Angela Burleigh; Peter A. Lennox; Nancy Van Laeken; Nick J. Carr; Frank Petersen; Richard I. Crawford; Hiroshi Shimizu; Daisuke Tsuruta; Ralf J. Ludwig; David J. Granville

doi:10.1038/s41467-020-20604-3

Granzyme B inhibition reduces disease severity in autoimmune blistering diseases

Sho Hiroyasu, Matthew R. Zeglinski, Hongyan Zhao, Megan A. Pawluk, Christopher T. Turner, Anika Kasprick, Chiharu Tateishi, Wataru Nishie, Angela Burleigh, Peter A. Lennox, Nancy Van Laeken, Nick J. Carr, Frank Petersen, Richard I. Crawford, Hiroshi Shimizu, Daisuke Tsuruta, Ralf J. Ludwig, David J. Granville^*

^*Corresponding author for this work

1 Citation (Scopus)

Abstract

Pemphigoid diseases refer to a group of severe autoimmune skin blistering diseases characterized by subepidermal blistering and loss of dermal-epidermal adhesion induced by autoantibody and immune cell infiltrate at the dermal-epidermal junction and upper dermis. Here, we explore the role of the immune cell-secreted serine protease, granzyme B, in pemphigoid disease pathogenesis using three independent murine models. In all models, granzyme B knockout or topical pharmacological inhibition significantly reduces total blistering area compared to controls. In vivo and in vitro studies show that granzyme B contributes to blistering by degrading key anchoring proteins in the dermal-epidermal junction that are necessary for dermal-epidermal adhesion. Further, granzyme B mediates IL-8/macrophage inflammatory protein-2 secretion, lesional neutrophil infiltration, and lesional neutrophil elastase activity. Clinically, granzyme B is elevated and abundant in human pemphigoid disease blister fluids and lesional skin. Collectively, granzyme B is a potential therapeutic target in pemphigoid diseases.

Original language	English
Article number	302
Journal	Nature Communications
Volume	12
Issue number	1
Pages (from-to)	302
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-020-20604-3
Publication status	Published - 01.12.2021

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)
Centers: Center for Research on Inflammation of the Skin (CRIS)

DFG Research Classification Scheme

2.21-05 Immunology
2.22-19 Dermatology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-020-20604-3

Cite this

Hiroyasu, S., Zeglinski, M. R., Zhao, H., Pawluk, M. A., Turner, C. T., Kasprick, A., Tateishi, C., Nishie, W., Burleigh, A., Lennox, P. A., Van Laeken, N., Carr, N. J., Petersen, F., Crawford, R. I., Shimizu, H., Tsuruta, D., Ludwig, R. J., & Granville, D. J. (2021). Granzyme B inhibition reduces disease severity in autoimmune blistering diseases. Nature Communications, 12(1), 302. Article 302. https://doi.org/10.1038/s41467-020-20604-3

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title = "Granzyme B inhibition reduces disease severity in autoimmune blistering diseases",

abstract = "Pemphigoid diseases refer to a group of severe autoimmune skin blistering diseases characterized by subepidermal blistering and loss of dermal-epidermal adhesion induced by autoantibody and immune cell infiltrate at the dermal-epidermal junction and upper dermis. Here, we explore the role of the immune cell-secreted serine protease, granzyme B, in pemphigoid disease pathogenesis using three independent murine models. In all models, granzyme B knockout or topical pharmacological inhibition significantly reduces total blistering area compared to controls. In vivo and in vitro studies show that granzyme B contributes to blistering by degrading key anchoring proteins in the dermal-epidermal junction that are necessary for dermal-epidermal adhesion. Further, granzyme B mediates IL-8/macrophage inflammatory protein-2 secretion, lesional neutrophil infiltration, and lesional neutrophil elastase activity. Clinically, granzyme B is elevated and abundant in human pemphigoid disease blister fluids and lesional skin. Collectively, granzyme B is a potential therapeutic target in pemphigoid diseases.",

author = "Sho Hiroyasu and Zeglinski, {Matthew R.} and Hongyan Zhao and Pawluk, {Megan A.} and Turner, {Christopher T.} and Anika Kasprick and Chiharu Tateishi and Wataru Nishie and Angela Burleigh and Lennox, {Peter A.} and {Van Laeken}, Nancy and Carr, {Nick J.} and Frank Petersen and Crawford, {Richard I.} and Hiroshi Shimizu and Daisuke Tsuruta and Ludwig, {Ralf J.} and Granville, {David J.}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

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doi = "10.1038/s41467-020-20604-3",

language = "English",

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Hiroyasu, S, Zeglinski, MR, Zhao, H, Pawluk, MA, Turner, CT, Kasprick, A, Tateishi, C, Nishie, W, Burleigh, A, Lennox, PA, Van Laeken, N, Carr, NJ, Petersen, F, Crawford, RI, Shimizu, H, Tsuruta, D, Ludwig, RJ & Granville, DJ 2021, 'Granzyme B inhibition reduces disease severity in autoimmune blistering diseases', Nature Communications, vol. 12, no. 1, 302, pp. 302. https://doi.org/10.1038/s41467-020-20604-3

TY - JOUR

T1 - Granzyme B inhibition reduces disease severity in autoimmune blistering diseases

AU - Hiroyasu, Sho

AU - Zeglinski, Matthew R.

AU - Zhao, Hongyan

AU - Pawluk, Megan A.

AU - Turner, Christopher T.

AU - Kasprick, Anika

AU - Tateishi, Chiharu

AU - Nishie, Wataru

AU - Burleigh, Angela

AU - Lennox, Peter A.

AU - Van Laeken, Nancy

AU - Carr, Nick J.

AU - Petersen, Frank

AU - Crawford, Richard I.

AU - Shimizu, Hiroshi

AU - Tsuruta, Daisuke

AU - Ludwig, Ralf J.

AU - Granville, David J.

PY - 2021/12/1

Y1 - 2021/12/1

N2 - Pemphigoid diseases refer to a group of severe autoimmune skin blistering diseases characterized by subepidermal blistering and loss of dermal-epidermal adhesion induced by autoantibody and immune cell infiltrate at the dermal-epidermal junction and upper dermis. Here, we explore the role of the immune cell-secreted serine protease, granzyme B, in pemphigoid disease pathogenesis using three independent murine models. In all models, granzyme B knockout or topical pharmacological inhibition significantly reduces total blistering area compared to controls. In vivo and in vitro studies show that granzyme B contributes to blistering by degrading key anchoring proteins in the dermal-epidermal junction that are necessary for dermal-epidermal adhesion. Further, granzyme B mediates IL-8/macrophage inflammatory protein-2 secretion, lesional neutrophil infiltration, and lesional neutrophil elastase activity. Clinically, granzyme B is elevated and abundant in human pemphigoid disease blister fluids and lesional skin. Collectively, granzyme B is a potential therapeutic target in pemphigoid diseases.

AB - Pemphigoid diseases refer to a group of severe autoimmune skin blistering diseases characterized by subepidermal blistering and loss of dermal-epidermal adhesion induced by autoantibody and immune cell infiltrate at the dermal-epidermal junction and upper dermis. Here, we explore the role of the immune cell-secreted serine protease, granzyme B, in pemphigoid disease pathogenesis using three independent murine models. In all models, granzyme B knockout or topical pharmacological inhibition significantly reduces total blistering area compared to controls. In vivo and in vitro studies show that granzyme B contributes to blistering by degrading key anchoring proteins in the dermal-epidermal junction that are necessary for dermal-epidermal adhesion. Further, granzyme B mediates IL-8/macrophage inflammatory protein-2 secretion, lesional neutrophil infiltration, and lesional neutrophil elastase activity. Clinically, granzyme B is elevated and abundant in human pemphigoid disease blister fluids and lesional skin. Collectively, granzyme B is a potential therapeutic target in pemphigoid diseases.

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JF - Nature Communications

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ER -

Granzyme B inhibition reduces disease severity in autoimmune blistering diseases

Abstract

Research Areas and Centers

DFG Research Classification Scheme

UN SDGs

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CRU 303: Pemphigoid Diseases - Molecular Pathways and their Therapeutic Potential

Cite this

Granzyme B inhibition reduces disease severity in autoimmune blistering diseases

Abstract

Research Areas and Centers

DFG Research Classification Scheme

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

CRU 303: Pemphigoid Diseases - Molecular Pathways and their Therapeutic Potential

Cite this