Declining Pulmonary Function in Interstitial Lung Disease Linked to Lymphocyte Dysfunction.
Declining Pulmonary Function in Interstitial Lung Disease Linked to Lymphocyte Dysfunction.
复制标题
间质性肺病肺功能下降与淋巴细胞功能障碍有关。
DOI：
10.1164/rccm.201910-1909le
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发表时间：
2020
影响因子：
24.7
通讯作者：
Finn,PatriciaW
中科院分区：
文献类型：
--
作者：
Schott,CodyA;Ascoli,Christian;Huang,Yue;Perkins,DavidL;Finn,PatriciaW
结节病和特发性肺纤维化（IPF）的病因可能不同，但它们有一个共同的结局：终末期纤维化肺病。结节病患者和IPF患者出现终末期纤维化改变，需要肺移植，其死亡率相似（1）。先天免疫和适应性免疫是这两种疾病的已知驱动因素，但对纤维化变化的机制仍知之甚少。我们之前观察到结节病患者外周血microRNA的减少与淋巴细胞减少和肺功能下降有关，表明外周免疫调节在疾病进展中的作用（2）。最近，在结节病患者和IPF患者的外周血中发现了表达阴性共刺激分子PD-1的T辅助细胞17型（Th 17）淋巴细胞（3）。这些细胞产生TGF-B（转化生长因子B）并在共培养系统中诱导成纤维细胞的胶原沉积。这些发现表明免疫反应在结节病和特发性肺纤维化的维持、消退和纤维化进展中发挥着不可或缺的作用。我们假设共同的免疫调节机制控制全身反应，并促进结节病和IPF的纤维化进展。我们进行了一项荟萃分析，以确定IPF或结节病患者与健康对照受试者相比的常见淋巴细胞表达模式。对来自基因表达综合数据库（国家生物技术信息中心）的公开可用外周血单核细胞表达数据进行系统检索，确定了两项具有严重程度指标的病例对照研究：GSE 37912（结节病队列）和GSE 38958（IPF队列）。GSE 37912中的重度疾病定义为“FVC%预测值，50%或心脏或神经系统受累”（4）。GSE 38958未定义严重程度，但使用了“FVC%预测值，55%和肺一氧化碳弥散量（DLCO）%预测值，40%”的临界值（5）。为了识别数据集中的基因表达模块，我们进行了共识加权基因相关网络分析（6）。在构建的八个模块中，我们鉴定了淋巴细胞免疫模块（LIM），其与免疫应答和淋巴细胞活化基因具有显著关联（图1A）。与对照受试者相比，在IPF患者和结节病患者中鉴定到LIM的表达显著降低（图1B和1C）。在组成该模块的442个成员基因中，与对照受试者相比，两个患者队列中有263个基因的表达显著降低。LIM中最重要的基因包括共刺激分子CD 40 LG（分化簇40配体）和ICOS（诱导型T细胞共刺激分子和CD 28）。其他LIM成员包括淋巴细胞表面标志物、趋化因子受体CCR 4（CC趋化因子受体4型）、CCR 6、CCR 7和淋巴细胞分化因子RORA（RAR相关孤儿受体α）、GATA 3（加塔结合蛋白3）、EOMES（原中胚层蛋白）和IKZF 3（ikaros家族锌指蛋白3）。这些结果表明，效应相关因子的泛淋巴细胞抑制在结节病或IPF患者的全身免疫应答中发挥作用。有趣的是，Th 1转录因子TBX 21（T-box转录因子21）并没有被分配到LIM，但在结节病患者中显著降低。我们使用来自其他IPF和结节病数据集的表达数据（来自GSE 28042的微阵列数据和来自ACCESS的RNA测序数据[A Case...
Sarcoidosis and idiopathic pulmonary fibrosis (IPF) may differ in etiology but they share a common outcome: end-stage fibrotic lung disease. Patients with sarcoidosis and patients with IPF who exhibit end-stage fibrotic changes requiring lung transplant have similarly high mortality rates (1). Innate and adaptive immunity are known drivers of both diseases, but the mechanisms underpinning the fibrotic changes remain poorly understood. We previously observed that a decrease in peripheral blood microRNAs in patients with sarcoidosis was linked to lymphopenia and declining pulmonary function, suggesting a role for peripheral immune regulation in disease progression (2). Recently, T-helper cell type 17 (Th17) lymphocytes expressing the negative costimulatory molecule PD-1 were identified in the peripheral blood of patients with sarcoidosis and patients with IPF (3). These cells produced TGF-b (transforming growth factor b) and induced collagen deposition from fibroblasts in a coculture system. These findings suggest an integral role for the immune response in the maintenance, resolution, and fibrotic progression of both sarcoidosis and IPF. We hypothesized that common immuneregulatory mechanisms govern systemic responses and contribute to fibrotic progression in sarcoidosis and IPF. We performed a meta-analysis to identify common lymphocyte expression patterns in patients with IPF or sarcoidosis compared with healthy control subjects. A systematic search of publicly available peripheral blood mononuclear cell expression data from the Gene Expression Omnibus (National Center for Biotechnology Information) identified two case–control studies with severity metrics: GSE37912 (sarcoidosis cohort) and GSE38958 (IPF cohort). Severe disease in GSE37912 was defined as “FVC% predicted, 50% OR cardiac OR neurological involvement”(4). GSE38958 did not define severity, but a cutoff of “FVC% predicted, 55% AND diffusion capacity of the lung for carbon monoxide (DLCO)% predicted, 40%” was used (5). To identify modules of gene expression in our datasets, we performed a consensus weighted gene correlation network analysis (6). Among the eight modules constructed, we identified the lymphocyte immunity module (LIM), which had significant associations with immune response and lymphocyte activation genes (Figure 1A). Significantly reduced expression of LIM was identified in patients with IPF and patients with sarcoidosis compared with control subjects (Figures 1B and 1C). Of the 442 member genes that made up this module, 263 had significantly decreased expression in both patient cohorts compared with control subjects. The most significant genes within the LIM included the costimulatory molecules CD40LG (cluster of differentiation 40 ligand) and ICOS (inducible T cell costimulator, and CD28). Other LIM members included lymphocyte surface markers, the chemokine receptors CCR4 (CC chemokine receptor type 4), CCR6, CCR7, and lymphocyte differentiation factors RORA (RAR-related orphan receptor a), GATA3 (GATA binding protein 3), EOMES (eomesodermin), and IKZF3 (ikaros family zinc finger protein 3). These findings suggest that pan-lymphocyte depression of effector-related factors plays a role in the systemic immune response of patients with sarcoidosis or IPF. Interestingly, the Th1 transcription factor TBX21 (T-box transcription factor 21) was not assigned to the LIM but was significantly decreased in patients with sarcoidosis. We validated LIM expression using expression data from additional IPF and sarcoidosis datasets (microarray data from GSE28042 and RNA sequencing data from ACCESS [A Case …