Occurrence of an activated, profibrotic pattern of gene expression in lung CD8+T cells from scleroderma patients
Occurrence of an activated, profibrotic pattern of gene expression in lung CD8+T cells from scleroderma patients
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DOI：
10.1002/art.11080
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发表时间：
2003-08-01
影响因子：
--
通讯作者：
White, B
中科院分区：
文献类型：
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作者：
Luzina, IG;Atamas, SP;White, B
Objective.肺纤维化是硬皮病患者死亡的主要原因。先前的研究表明硬皮病患者肺部的CD 8 + T细胞增加。在本研究中，我们试图确定活化的CD 8 + T细胞是否通过促纤维化介质的产生和活化而促进硬皮病患者的肺纤维化。从19名硬皮病患者和7名健康受试者的支气管肺泡灌洗液中分离CD 8+细胞。使用DNA阵列技术确定这些细胞的表型。所选基因的表达在实时聚合酶链反应和酶联免疫吸附试验中得到证实。基因表达谱的层次聚类显示2组受试者。第1组包括11例患者（8例有肺部炎症，3例无肺部炎症）。第2组包括15名受试者（7名健康对照和2名肺部炎症患者和6名无肺部炎症患者）。第1组中的基因表达表明T细胞活化（2型表型）、促纤维化因子和基质金属蛋白酶的产生以及活化诱导的细胞死亡减少。第1组中CD 8 + T细胞136整合素mRNA表达的增加提示这些T细胞可能诱导潜在转化生长因子β（TGF β）的细胞接触依赖性活化。一部分硬皮病患者在其肺部具有活化的、长寿命的CD 8 + T细胞，其可通过产生促纤维化因子（如白细胞介素-4和制瘤素M）直接促进纤维化，以及通过活化TGF β间接促进纤维化。
Objective. Pulmonary fibrosis is a major cause of death in scleroderma patients. Previous studies have shown an increase in CD8+ T cells in the lungs of scleroderma patients. In the present study, we sought to determine whether activated CD8+ T cells contribute to pulmonary fibrosis in scleroderma patients through the production and activation of profibrotic mediators.Methods. CD8+ cells were isolated from bronchoalveolar lavage fluid obtained from 19 scleroderma patients and 7 healthy subjects. The phenotype of these cells was determined using DNA array technology. Expression of selected genes was confirmed in real-time polymerase chain reaction and enzyme-linked immunosorbent assay experiments.Results. Hierarchical clustering of gene expression profiles revealed 2 groups of subjects. Group 1 consisted of 11 patients (8 with and 3 without lung inflammation). Group 2 consisted of 15 subjects (7 healthy controls and 2 patients with and 6 without lung inflammation). Gene expression in group 1 indicated T cell activation, a type 2 phenotype, production of profibrotic factors and matrix metalloproteinases, and reduced activation-induced cell death. Increased expression of 136 integrin messenger RNA by CD8+ T cells in group 1 suggested the possibility that these T cells might induce cell-contact-dependent activation of latent transforming growth factor beta (TGFbeta).Conclusion. A subset of scleroderma patients at higher risk of progressive lung disease have activated, long-lived CD8+ T cells in their lungs that could promote fibrosis directly, through production of profibrotic factors such as interleukin-4 and oncostatin M, as well as indirectly, through activation of TGFbeta.