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.
N1 - Funding Information:
We express our thanks to Dr. Karen Jung and Aoi Hiroyasu from the Granville laboratory, ICORD, UBC, and Tatjana Bozin from the Centre for Heart Lung Innovation, St. Paul’s Hospital, UBC, for their assistance with manuscript editing, experiments, and animal husbandry, respectively. This research was supported by funding from the Canadian Institutes for Health Research (CIHR) (D.J.G.) and the Michael Smith Foundation for Health Research (MSFHR) (D.J.G.). S.H. and C.T.T. are supported by CIHR Post-doctoral Fellowships. M.R.Z. is supported by a CIHR Post-doctoral Fellowship and a MSFHR Post-doctoral Fellowship.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
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.
UR - https://www.scopus.com/pages/publications/85099245906
U2 - 10.1038/s41467-020-20604-3
DO - 10.1038/s41467-020-20604-3
M3 - Article
C2 - 33436591
AN - SCOPUS:85099245906
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 302
ER -
