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.
- 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.
