CD14+CD163-HLA-DRlow单核细胞转录组预测特发性肺纤维化死亡率
本研究通过单细胞RNA测序分析外周血单个核细胞，探索免疫细胞特异性转录组谱与IPF死亡率的关联。来自CD14+CD163-HLA-DRlow单核细胞的230基因上调评分在独立PBMC队列预测死亡率（HR 6.58），在BAL中亦预测死亡（HR 2.20），且与肺组织FVC负相关。该转录组特征与IPF不良预后相关，值得作为精准治疗靶点研究。
要点
- CD14+CD163-HLA-DRlow单核细胞230基因评分可预测IPF死亡率。
- 该评分在PBMC和BAL中均与死亡率相关，并与肺组织FVC负相关。
- 进展性IPF中该单核细胞比例高于稳定性IPF。
核心结论
- CD14+CD163-HLA-DRlow单核细胞转录组与IPF患者死亡率增加相关。
- 逆转该转录组特征应作为IPF精准治疗方向进行研究。
研究设计与样本
- 研究采用单细胞RNA测序分析外周血单个核细胞，并在PBMC、BAL和肺组织中验证预后准确性。
- 总样本量n=1054，其中IPF n=555，其他n=499。
- 通过流式细胞术、独立scRNA-seq数据集分析和细胞去卷积验证发现。
主要发现
- 来自CD14+CD163-HLA-DRlow单核细胞的230基因上调评分（Pittsburgh PBMC队列）预测Chicago PBMC队列死亡率（HR 6.58，95%CI 2.15-20.13；p=0.001）。
- 该评分在BAL汇总分析中预测死亡率（HR 2.20，95%CI 1.44-3.37；p=0.0003），并与肺组织FVC负相关（ρ=-0.2，p=0.02）。
- 进展性IPF中CD14+CD163-HLA-DRlow单核细胞比例高于稳定性IPF（12.59%，95%CI 9.66-16.23% vs 7.61%，95%CI 6.68-10.21%；p=0.014）。
- 高危IPF患者T细胞共刺激基因表达降低（Pittsburgh和Chicago，p<0.01）。
- CD14+HLA-DRlow单核细胞较CD14+HLA-DRhi单核细胞表达更高水平的促纤维化、促血管生成和趋化因子（p<0.05）。
关键数值与推荐
- 230基因上调评分在PBMC汇总队列中预测死亡（HR 6.58，95%CI 2.15-20.13；p=0.001）。
- BAL汇总分析中预测死亡（HR 2.20，95%CI 1.44-3.37；p=0.0003）。
- 与肺组织FVC负相关（ρ=-0.2，p=0.02）。
- 进展性IPF单核细胞比例12.59%（95%CI 9.66-16.23%）vs 稳定性7.61%（95%CI 6.68-10.21%）；p=0.014。
- 六基因子集保留预测性能（PBMC汇总队列HR 4.79，95%CI 2.58-8.92；p<0.0001）。
临床怎么用
- CD14+CD163-HLA-DRlow单核细胞转录组评分可用于IPF死亡风险分层。
- 该评分在PBMC和BAL中均可评估，肺组织FVC负相关支持其临床相关性。
- Connectivity map分析识别的药物类别可能逆转该基因特征，待进一步研究。
以上解读依据论文摘要（全文未开放获取或许可不允许翻译转载）。
原文
BACKGROUND: The association between immune-cell-specific transcriptomic profiles and mortality in idiopathic pulmonary fibrosis (IPF) is unknown. METHODS: We profiled peripheral blood mononuclear cells by single-cell RNA sequencing (scRNA-seq) and investigated which immune-cell-specific transcriptomic profile predicted IPF outcomes consistently. Prognostic accuracy was investigated in peripheral blood mononuclear cells (PBMCs), bronchoalveolar lavage (BAL) and lung tissue. Findings were validated by flow cytometry, analysis of independent scRNA-seq datasets and cellular deconvolution. We investigated the function of this transcriptomic profile and its cellular source in lung tissue (overall sample size, n=1054; IPF, n=555; other, n=499). Connectivity map analysis and LASSO regression were used to identify drug candidates and a subset of genes with prognostic potential, respectively. RESULTS: A 230-gene up-score (Pittsburgh PBMC cohort) from CD14+CD163-HLA-DRlow monocytes predicted mortality in the Chicago PBMC cohort (HR 6.58, 95% CI 2.15-20.13; p=0.001), in BAL pooled analysis (HR 2.20, 95% CI 1.44-3.37; p=0.0003), and negatively correlated with forced vital capacity in lung tissues (ρ= -0.2, p=0.02). Proportions of CD14+CD163-HLA-DRlow monocytes were higher in progressive versus stable IPF (12.59%, 95% CI 9.66-16.23%, versus 7.61%, 95% CI 6.68-10.21%; p=0.014). High-risk patients with IPF had decreased expression of T-cell co-stimulatory genes (Pittsburgh and Chicago, p<0.01). CD14+HLA-DRlow monocytes had higher expression of profibrotic, proangiogenic and chemotactic factors compared to CD14+HLA-DRhi monocytes (p<0.05). The 230-gene up-score correlated with the secreted phosphoprotein 1 (SPP1)+ fibrosis-associated macrophages gene-score in lung tissues (ρ=0.19, p<2.2e-16). Connectivity map analysis identified drug categories to reverse the 230-gene signature. A subset of six genes retained predictive performance (pooled PBMC cohorts HR 4.79, 95% CI 2.58-8.92; p<0.0001). CONCLUSIONS: The transcriptome of CD14+CD163-HLA-DRlow monocytes is associated with increased mortality in patients with IPF. Its reversal should be investigated as a precision-based therapy in IPF.
引用
- Karampitsakos T, Jia M, Tourki B, et al. The transcriptome of CD14+CD163-HLA-DRlow monocytes predicts mortality in idiopathic pulmonary fibrosis. Eur Respir J. 2026. PMID: 41360505. doi:10.1183/13993003.00804-2025
供执业医师工作参考，不替代临床判断；数值与分级以指南原文为准。