Blockade of granzyme B remarkably improves mucocutaneous diseases with keratinocyte death in interface dermatitis.
Blockade of granzyme B remarkably improves mucocutaneous diseases with keratinocyte death in interface dermatitis.
复制标题
颗粒酶 B 的阻断可显着改善界面皮炎中角质形成细胞死亡的皮肤粘膜疾病。
DOI：
10.1016/j.jid.2018.03.1507
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Fujimoto M
中科院分区：
文献类型：
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作者：
Saito A;Okiyama N;Kubota N;Nakamura Y;Fujisawa Y;Watanabe R;Ishitsuka Y;Bleackley RC;Fujimoto M
地衣样组织反应/界面皮炎（LTR/IFD）是一种皮肤炎症模式，其病理特征是自身侵袭性T细胞浸润皮肤基底膜，导致角化细胞死亡（Sontheimer和Gilliam， 1981）。广泛的皮肤疾病表现出这组组织学特征和皮肤粘膜病变，包括急性移植物抗宿主病（aGVHD）。以往LTR/IFD疾病的临床研究表明，CD8+ T细胞主要浸润于水疱表皮，其数量随疾病进展而增加。浸润的CD8+ T细胞分布在凋亡的角质形成细胞周围，表达PRF1和颗粒酶（Gzm） B （Correia et al., 2001, Jungell et al., 1989, Paller et al., 1988, Takata et al., 1993）。据报道，aGVHD患者血清中CD8+ T细胞产生的可溶性FasL水平也升高（Liem et al., 1998）。同种异体骨髓移植小鼠模型的研究也支持这些临床观察（Baker et al., 1996, Braun et al., 1996, Graubert et al., 1996）。我们特别评估了PRF1/Gzm和Fas/FasL通路对LTR/IFD的影响。我们使用了鸡卵白蛋白（OVA）转基因小鼠，其中角化细胞在角蛋白14启动子（K14-mOVA小鼠）的控制下表达膜结合的OVA。K14-mOVA小鼠发生agvhd样粘膜皮肤病（在线补充图S1），并且在转移表达ova特异性T细胞受体的转基因CD8+ T细胞（来自GFP转基因OT-I小鼠）后观察到体重减轻（Shibaki et al., 2004）。晚期体重减轻反映了皮肤粘膜病变的严重程度，导致进食困难。耳标本苏木精和伊红染色显示LTR/IFD（在线补充图S2）。抗GFP抗体免疫荧光染色显示表皮和真皮中有GFP+ OT-I细胞浸润，TUNEL实验显示有大量角质形成细胞死亡（补充图S2）。该疾病是由CD8+ T细胞介导的（补充图S3在线）。
Lichenoid tissue reaction/interface dermatitis (LTR/IFD) is a pattern of skin inflammation characterized pathologically by infiltration of the skin basement membrane by auto-aggressive T cells, causing keratinocyte death (Sontheimer and Gilliam, 1981). A wide spectrum of skin disorders exhibit this set of histological features and mucocutaneous lesions, including acute graft-versus-host disease (aGVHD). Previous clinical studies on disorders with LTR/IFD have described that CD8+ T cells mainly infiltrate the blistered epidermis and their number increases concomitantly with disease progression. The infiltrating CD8+ T cells were distributed around apoptotic keratinocytes and express PRF1 and granzyme (Gzm) B (Correia et al., 2001, Jungell et al., 1989, Paller et al., 1988, Takata et al., 1993). Serum levels of soluble FasL produced by CD8+ T cells were also reportedly increased in patients with aGVHD (Liem et al., 1998). Studies with allogeneic bone marrow transplant murine models also supported these clinical observations (Baker et al., 1996, Braun et al., 1996, Graubert et al., 1996). We particularly evaluated the impact of PRF1/Gzm and Fas/FasL pathways on LTR/IFD.We used chicken ovalbumin (OVA) transgenic mice, in which keratinocytes express membrane-bound OVA under the control of a keratin 14 promoter (K14-mOVA mice). K14-mOVA mice develop aGVHD-like mucocutaneous disease (Supplementary Figure S1 online) and weight loss was observed after transfer of transgenic CD8+ T cells expressing OVA-specific T-cell receptor (from GFP transgenic OT-I mice)(Shibaki et al., 2004). Weight loss during late-phase reflects the severity of mucocutaneous lesions causing difficulty in food intake. Hematoxylin and eosin staining of ear specimens showed LTR/IFD (Supplementary Figure S2 online). Immunofluorescence staining with anti-GFP antibodies revealed infiltration of GFP+ OT-I cells in the epidermis and dermis, which resulted in a number of dead keratinocytes revealed by TUNEL assay (Supplementary Figure S2). The disease is mediated by CD8+ T cells (Supplementary Figure S3 online).