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 - Publisher Copyright:
© 2021, The Author(s).
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.
UR - http://www.scopus.com/inward/record.url?scp=85099245906&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/b591b6c5-5c6d-3dcd-b7d4-57817884f46f/
U2 - 10.1038/s41467-020-20604-3
DO - 10.1038/s41467-020-20604-3
M3 - Journal articles
C2 - 33436591
AN - SCOPUS:85099245906
VL - 12
SP - 302
JO - Nature Communications
JF - Nature Communications
SN - 1751-8628
IS - 1
M1 - 302
ER -