Granzyme B inhibition reduces disease severity in autoimmune blistering diseases.
Granzyme B inhibition reduces disease severity in autoimmune blistering diseases.
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DOI：
10.1038/s41467-020-20604-3
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发表时间：
2021-01-12
影响因子：
16.6
通讯作者：
Granville DJ
中科院分区：
文献类型：
--
作者：
Hiroyasu S;Zeglinski MR;Zhao H;Pawluk MA;Turner CT;Kasprick A;Tateishi C;Nishie W;Burleigh A;Lennox PA;Van Laeken N;Carr NJ;Petersen F;Crawford RI;Shimizu H;Tsuruta D;Ludwig RJ;Granville DJ
类天疱疮病是指一组严重的自身免疫性皮肤水疱病，其特征是真皮-表皮交界处和真皮上层的自身抗体和免疫细胞浸润引起的表皮下水疱和真皮-表皮粘附丧失。在这里，我们探讨的作用，免疫细胞分泌的丝氨酸蛋白酶，颗粒酶B，天疱疮疾病的发病机制，使用三个独立的小鼠模型。在所有模型中，与对照相比，颗粒酶B敲除或局部药理学抑制显著减少了总起泡面积。体内和体外研究表明，颗粒酶B通过降解真皮-表皮连接中真皮-表皮粘附所必需的关键锚定蛋白而导致起泡。此外，颗粒酶B介导IL-8/巨噬细胞炎性蛋白-2分泌、病变中性粒细胞浸润和病变中性粒细胞弹性蛋白酶活性。临床上，颗粒酶B在人类类天疱疮疾病疱液和皮损中升高且丰富。总之，颗粒酶B是类天疱疮疾病的潜在治疗靶点。类天疱疮疾病涉及自身免疫介导的起泡和上层真皮的免疫病理学。在这里，作者暗示颗粒酶B在类天疱疮疾病的多种体内模型的免疫病理学中，并利用局部颗粒酶B抑制剂，在体内减弱疾病表型。
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. Pemphigoid diseases involve autoimmune mediated blistering and immunopathology of the upper dermis. Here, the authors implicate granzyme B in the immunopathology in multiple in vivo models of pemphigoid diseases and utilise a topical granzyme B inhibitor that attenuates disease phenotypes in vivo.
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影响因子：
--
作者：
Kasprick, Anika;Bieber, Katja;Ludwig, Ralf J
通讯作者：
Ludwig, Ralf J
影响因子：
6.5
作者：
Kawasaki, Hiroshi;Tsunoda, Kazuyuki;Amagai, Masayuki
通讯作者：
Amagai, Masayuki
DOI：
10.1164/ajrccm.161.5.9908090
发表时间：
2000-05-01
影响因子：
24.7
作者：
Gauvreau, GM;Lee, JM;O'Byrne, PM
通讯作者：
O'Byrne, PM
影响因子：
4.4
作者：
Genovese, A;Borgia, G;Marone, G
通讯作者：
Marone, G
影响因子：
3.4
作者：
Hussein, Mahmoud R.;Ali, Fayed Mahammad Nagy;Omar, Abd-Elhady M. M.
通讯作者：
Omar, Abd-Elhady M. M.