Sarcoidosis activates diverse transcriptional programs in bronchoalveolar lavage cells.
Sarcoidosis activates diverse transcriptional programs in bronchoalveolar lavage cells.
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DOI：
10.1186/s12931-016-0411-y
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发表时间：
2016-07-26
影响因子：
5.8
通讯作者：
Thomassen MJ
中科院分区：
文献类型：
--
作者：
Gharib SA;Malur A;Huizar I;Barna BP;Kavuru MS;Schnapp LM;Thomassen MJ
结节病是一种病因不明的多系统免疫炎症性疾病，最常见的是累及肺部。我们假设，一个公正的方法来确定激活的途径，在支气管肺泡灌洗（BAL）细胞可以揭示这种复杂的疾病的发病机制。我们招募了15名不同阶段的结节病患者和12名健康对照。所有受试者均接受支气管镜检查和灌洗。对于每个受试者，从BAL细胞中提取总RNA并与Affyellow U133 A微阵列杂交。应用严格的统计学方法来鉴定结节病受试者与对照组之间的差异基因表达。为了更好地阐明这些群体之间的差异激活途径，我们整合了网络和基因集富集分析BAL细胞转录谱。结节病患者为非吸烟者或既往吸烟者，均累及肺部，仅2例接受全身性泼尼松治疗。健康对照组均为非吸烟者。比较结节病和健康受试者之间的BAL细胞基因表达，发现超过1500个差异表达基因。几个先前描述的免疫介质，如干扰素γ，上调结节病的主题。使用综合计算方法，我们构建了一个模块化网络的80多个基因集，高度富集在结节病患者。这些途径中的许多被映射到炎症和免疫相关过程，包括适应性免疫、T细胞信号传导、移植物抗宿主病、白细胞介素12、23和17信号传导。此外，我们发现了蛋白酶体机制和适应性免疫之间的密切联系，突出了结节病病理生物学中潜在的重要和可靶向的关系。结节病中的BAL细胞的特征在于参与免疫和蛋白酶体过程的不同转录程序的富集。我们的研究结果增加了越来越多的证据表明，肺泡驻留免疫效应细胞在结节病的发病机制，并确定特定的途径，其激活可能会调节疾病的进展。本文的在线版本（doi：10.1186/s12931-016-0411-y）包含补充材料，可供授权用户使用。
Sarcoidosis is a multisystem immuno-inflammatory disorder of unknown etiology that most commonly involves the lungs. We hypothesized that an unbiased approach to identify pathways activated in bronchoalveolar lavage (BAL) cells can shed light on the pathogenesis of this complex disease. We recruited 15 patients with various stages of sarcoidosis and 12 healthy controls. All subjects underwent bronchoscopy with lavage. For each subject, total RNA was extracted from BAL cells and hybridized to an Affymetrix U133A microarray. Rigorous statistical methods were applied to identify differential gene expression between subjects with sarcoidosis vs. controls. To better elucidate pathways differentially activated between these groups, we integrated network and gene set enrichment analyses of BAL cell transcriptional profiles. Sarcoidosis patients were either non-smokers or former smokers, all had lung involvement and only two were on systemic prednisone. Healthy controls were all non-smokers. Comparison of BAL cell gene expression between sarcoidosis and healthy subjects revealed over 1500 differentially expressed genes. Several previously described immune mediators, such as interferon gamma, were upregulated in the sarcoidosis subjects. Using an integrative computational approach we constructed a modular network of over 80 gene sets that were highly enriched in patients with sarcoidosis. Many of these pathways mapped to inflammatory and immune-related processes including adaptive immunity, T-cell signaling, graft vs. host disease, interleukin 12, 23 and 17 signaling. Additionally, we uncovered a close association between the proteasome machinery and adaptive immunity, highlighting a potentially important and targetable relationship in the pathobiology of sarcoidosis. BAL cells in sarcoidosis are characterized by enrichment of distinct transcriptional programs involved in immunity and proteasomal processes. Our findings add to the growing evidence implicating alveolar resident immune effector cells in the pathogenesis of sarcoidosis and identify specific pathways whose activation may modulate disease progression. The online version of this article (doi:10.1186/s12931-016-0411-y) contains supplementary material, which is available to authorized users.