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 and David J. Granville ()
Additional contact information
Sho Hiroyasu: Vancouver Coastal Health Research Institute (VCHRI)
Matthew R. Zeglinski: Vancouver Coastal Health Research Institute (VCHRI)
Hongyan Zhao: Vancouver Coastal Health Research Institute (VCHRI)
Megan A. Pawluk: Vancouver Coastal Health Research Institute (VCHRI)
Christopher T. Turner: Vancouver Coastal Health Research Institute (VCHRI)
Anika Kasprick: University of Lübeck
Chiharu Tateishi: Osaka City University Graduate School of Medicine
Wataru Nishie: Hokkaido University Graduate School of Medicine
Angela Burleigh: Department of Dermatology and Skin Science, UBC
Peter A. Lennox: Department of Surgery, UBC
Nancy Van Laeken: Department of Surgery, UBC
Nick J. Carr: Department of Surgery, UBC
Frank Petersen: Members of the German Center for Lung Research, Research Center Borstel
Richard I. Crawford: University of British Columbia (UBC)
Hiroshi Shimizu: Hokkaido University Graduate School of Medicine
Daisuke Tsuruta: Osaka City University Graduate School of Medicine
Ralf J. Ludwig: University of Lübeck
David J. Granville: Vancouver Coastal Health Research Institute (VCHRI)

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20604-3

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DOI: 10.1038/s41467-020-20604-3

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