Regulation of immune responses in primary biliary cholangitis: a transcriptomic analysis of peripheral immune cells.
Regulation of immune responses in primary biliary cholangitis: a transcriptomic analysis of peripheral immune cells.
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DOI：
10.1097/hc9.0000000000000110
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发表时间：
2023-04-01
影响因子：
5.1
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在原发性胆汁性胆管炎（PBC）患者中，熊去氧胆酸治疗期间测量的血清肝脏生化（UDCA反应）可准确预测长期结局。根据UDCA反应分层的患者的分子特征可以提高对高风险疾病的生物学理解，从而有助于确定疾病修饰治疗的替代方法。在本研究中，我们试图使用外周血单核细胞亚群的转录谱来表征UDCA应答的免疫生物学。我们对从15名UDCA应答充分的PBC患者（“应答者”）、16名UDCA应答不足的PBC患者（“无应答者”）和15名匹配对照的外周血中分离的单核细胞和TH 1、TH 17、TREG和B细胞进行了批量RNA测序。我们使用加权基因共表达网络分析来识别与反应状态相关的共表达基因（“模块”）网络以及其中最高度连接的基因（“枢纽基因”）。最后，我们对加权基因共表达网络分析模块进行了多组学因子分析，以确定所有外周血单核细胞亚群中生物变异的主轴（“潜在因子”）。使用加权基因共表达网络分析，我们在每个外周血单核细胞亚群中鉴定了与反应和/或疾病状态相关的模块（q<0.05）。Hub基因和功能注释表明，单核细胞在无应答者中是促炎性的，但在应答者中是促炎性的; TH 1和TH 17细胞在所有PBC病例中被激活，但在应答者中被更好地调节; TREG细胞被激活，但也被保留在登记应答者中。使用多组学因子分析，我们发现单核细胞中的活化活性、TH 1细胞的调节和Treg细胞的激活是相互关联的，并且在应答者中更突出。我们提供的证据表明，在具有充分UDCA应答的PBC患者中，适应性免疫应答得到更好的调节。
In patients with primary biliary cholangitis (PBC), the serum liver biochemistry measured during treatment with ursodeoxycholic acid—the UDCA response—accurately predicts long-term outcome. Molecular characterization of patients stratified by UDCA response can improve biological understanding of the high-risk disease, thereby helping to identify alternative approaches to disease-modifying therapy. In this study, we sought to characterize the immunobiology of the UDCA response using transcriptional profiling of peripheral blood mononuclear cell subsets. We performed bulk RNA-sequencing of monocytes and TH1, TH17, TREG, and B cells isolated from the peripheral blood of 15 PBC patients with adequate UDCA response (“responders”), 16 PBC patients with inadequate UDCA response (“nonresponders”), and 15 matched controls. We used the Weighted Gene Co-expression Network Analysis to identify networks of co-expressed genes (“modules”) associated with response status and the most highly connected genes (“hub genes”) within them. Finally, we performed a Multi-Omics Factor Analysis of the Weighted Gene Co-expression Network Analysis modules to identify the principal axes of biological variation (“latent factors”) across all peripheral blood mononuclear cell subsets. Using the Weighted Gene Co-expression Network Analysis, we identified modules associated with response and/or disease status (q<0.05) in each peripheral blood mononuclear cell subset. Hub genes and functional annotations suggested that monocytes are proinflammatory in nonresponders, but antiinflammatory in responders; TH1 and TH17 cells are activated in all PBC cases but better regulated in responders; and TREG cells are activated—but also kept in check—in responders. Using the Multi-Omics Factor Analysis, we found that antiinflammatory activity in monocytes, regulation of TH1 cells, and activation of TREG cells are interrelated and more prominent in responders. We provide evidence that adaptive immune responses are better regulated in patients with PBC with adequate UDCA response.