Mechanisms of lysis by activated cytotoxic cells expressing perforin and granzyme-B genes and the protein TIA-1 in muscle biopsies of myositis.
Mechanisms of lysis by activated cytotoxic cells expressing perforin and granzyme-B genes and the protein TIA-1 in muscle biopsies of myositis.
复制标题
肌炎肌肉活检中表达穿孔素和颗粒酶 B 基因以及蛋白 TIA-1 的活化细胞毒性细胞的裂解机制。
作者：
P. Cherin;S. Herson;Crevon Mc;J. Hauw;P. Cervera;P. Galanaud;D. Émilie
客观化
多发性肌炎(PM)和宫颈肌炎(DM)是自身免疫性炎症性肌肉疾病。PM和DM肌肉损害周围常有慢性单核细胞浸润。在PM中，主要细胞是激活的细胞毒细胞、自然杀伤细胞和CD8+T淋巴细胞。细胞毒细胞可通过两种机制杀伤靶细胞。这两种途径都通过释放分子(颗粒胞吐作用)、TIA-1蛋白和颗粒酶-B(GZB)来诱导靶细胞死亡。穿孔素(PF)攻击靶细胞膜，导致细胞坏死。我们研究了肌炎肌肉活检中的溶解机制。
方法
我们用一组单抗检测了反应性淋巴细胞亚群的表型，用原位杂交检测了Pf和GZB基因的表达，用免疫组织化学方法检测了14例肌炎(11 PM/3 DM)肌肉活检组织中TIA-1蛋白的表达。将结果与12名肌肉无力的对照组患者的肌肉活检结果进行比较，其中包括肌肉营养不良和血管炎患者，但没有肌炎。
结果
PM的主要表型是丰富的CD8+细胞，尤其是在肌内膜部位。糖尿病患者血管周围的单个核细胞以CD4+T细胞和CD22+B细胞为主。GZB和Pf基因以及TIA-1蛋白在肌炎患者的肌肉样本中同时表达。GZB、Pf和TIA-1阳性细胞主要位于PM的肌内膜部位，在非坏死肌纤维中。在DM中，这些阳性细胞很少见。
结论
在肌炎，尤其是PM中，细胞毒细胞可能通过释放几种蛋白(Pf、GZB和TIA-1蛋白)而导致肌肉损伤和肌肉细胞坏死和/或凋亡，这些蛋白负责这些刺激靶细胞的裂解。一些药物(泼尼松和环孢素)抑制GZB和PF的释放。它们的疗效可能部分归因于这种抑制作用。
OBJECTIVE
Polymyositis (PM) and cermatomyositis (DM) are inflammatory muscle diseases of autoimmune origin. A chronic mononuclear cell infiltrate is always present around PM and DM muscle damage. In PM, the predominant cells are activated cytotoxic cells, natural killer, and CD8+ T lymphocytes. Cytotoxic cells can kill the target cells via 2 mechanisms. Both pathways induce target cell death by releasing the molecules (granule exocytosis) perforin (PF), which attacks the target cell membrane and causes cell death by necrosis, and TIA-1 protein and granzyme-B (GZB), possibly responsible for apoptosis. We studied the mechanisms of lysis in muscle biopsies of myositis.
METHODS
We used a panel of monoclonal antibodies to determine the phenotypes of reactive lymphocyte subsets, in situ hybridization to study the expression of PF and GZB genes, and immunohistochemistry to evaluate TIA-1 protein production in muscle biopsies from 14 patients with myositis (11 PM/3 DM). Results were compared to those obtained from muscle biopsies of 12 control patients with muscle weakness, including patients with muscle dystrophy and vasculitis, but without myositis.
RESULTS
Abundant CD8+ cells, especially in endomysial sites in PM, formed the predominant phenotype. The predominant mononuclear cells observed in DM were CD4+ T cells and CD22+ B lymphocytes, in perivascular sites. The GZB and PF genes and the TIA-1 protein were expressed simultaneously in muscle samples from patients with myositis. GZB, PF, and TIA-1 positive cells were predominantly located in endomysial sites of PM, in the nonnecrotic muscle fibers. In DM, these positive cells were rare.
CONCLUSION
In myositis, especially PM, cytotoxic cells may cause muscle damage and muscle cell necrosis and/or apoptosis by releasing several proteins (PF, GZB, and TIA-1 proteins) responsible for the lysis of these stimulating target cells. Some drugs (prednisone and cyclosporine) inhibit the release of GZB and PF. Their efficacy may be due in part to this inhibitory effect.