International Collaboration On Repair Discoveries (ICORD) Centre, Vancouver Coastal Health Research Institute (VCHRI), Vancouver, BC, Canada.
Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, BC, Canada.
Nat Commun. 2021 Jan 12;12(1):302. doi: 10.1038/s41467-020-20604-3.
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.
天疱疮病是一组严重的自身免疫性皮肤水疱病，其特征为表皮下水疱和真皮-表皮连接部及上部真皮内的自身抗体和免疫细胞浸润导致的真皮-表皮黏附丧失。在这里，我们使用三种独立的小鼠模型探讨了免疫细胞分泌的丝氨酸蛋白酶颗粒酶 B 在天疱疮病发病机制中的作用。在所有模型中，与对照组相比，颗粒酶 B 敲除或局部药理抑制均显著减少总水疱面积。体内和体外研究表明，颗粒酶 B 通过降解真皮-表皮连接部中对真皮-表皮黏附至关重要的关键锚定蛋白而导致水疱形成。此外，颗粒酶 B 介导白细胞介素-8/巨噬细胞炎性蛋白-2 的分泌、病变处中性粒细胞浸润和病变处中性粒细胞弹性蛋白酶活性。临床上，颗粒酶 B 在人天疱疮病水疱液和病变皮肤中升高且大量存在。综上所述，颗粒酶 B 是天疱疮病的一个潜在治疗靶点。
