The Serum Proteome and Ursodeoxycholic Acid Response in Primary Biliary Cholangitis
The Serum Proteome and Ursodeoxycholic Acid Response in Primary Biliary Cholangitis
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DOI：
10.1002/hep.32011
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发表时间：
2021-11-02
期刊：
影响因子：
13.5
通讯作者：
Jones, David E. J.
中科院分区：
文献类型：
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作者：
Barron-Millar, Ben;Ogle, Laura;Jones, David E. J.
背景和目的分层治疗已进入原发性胆管炎（PBC）的临床实践，对熊去氧胆酸（UDCA）一线治疗无反应的患者常规使用二线治疗。然而，UDCA无应答的机制仍然不清楚，我们缺乏机制血清标记物。建立UK-PBC研究是为了探索PBC中UDCA无反应的生物学基础，并确定标志物以加强治疗。方法和结果发现血清蛋白质组学（Olink）在526名UK-PBC患者和97名健康对照者中进行了靶向多重验证。在发现阶段，未经治疗的PBC患者（n = 68）表现出炎症蛋白组，UDCA治疗通常会减少炎症蛋白组的规模，但未解决（n = 416）。在udca治疗的患者中，有19种蛋白保持显著的表达水平（使用严格的标准定义），其中6种蛋白代表了紧密相关的趋化因子（包括CCL20，已知由PBC中胆道上皮细胞（BECs）在衰老过程中释放）。在发现和验证队列中，所有的UDCA应答者和无应答者之间的表达都有显著差异。采用血清C-X-C基序趋化因子配体11和C-C基序趋化因子配体20的水平作为应答状态的标记进行线性判别分析，表明判别水平很高，AUC为0.91 （CI, 0.83-0.91）。结论：UDCA在PBC中的低反应表现为可能与细胞衰老相关的血清趋化因子升高，并且先前被证明在PBC中由BECs释放，提示在高危疾病的发病机制中可能起作用。这些生物标志物也有潜力发展为识别高风险疾病的生物标志物，它们作为生物标志物的临床应用应在前瞻性研究中进一步评估。
Background and Aims Stratified therapy has entered clinical practice in primary biliary cholangitis (PBC), with routine use of second-line therapy in nonresponders to first-line therapy with ursodeoxycholic acid (UDCA). The mechanism for nonresponse to UDCA remains, however, unclear and we lack mechanistic serum markers. The UK-PBC study was established to explore the biological basis of UDCA nonresponse in PBC and identify markers to enhance treatment. Approach and Results Discovery serum proteomics (Olink) with targeted multiplex validation were carried out in 526 subjects from the UK-PBC cohort and 97 healthy controls. In the discovery phase, untreated PBC patients (n = 68) exhibited an inflammatory proteome that is typically reduced in scale, but not resolved, with UDCA therapy (n = 416 treated patients). Nineteen proteins remained at a significant expression level (defined using stringent criteria) in UDCA-treated patients, six of them representing a tightly linked profile of chemokines (including CCL20, known to be released by biliary epithelial cells (BECs) undergoing senescence in PBC). All showed significant differential expression between UDCA responders and nonresponders in both the discovery and validation cohorts. A linear discriminant analysis, using serum levels of C-X-C motif chemokine ligand 11 and C-C motif chemokine ligand 20 as markers of responder status, indicated a high level of discrimination with an AUC of 0.91 (CI, 0.83-0.91). Conclusions UDCA under-response in PBC is characterized by elevation of serum chemokines potentially related to cellular senescence and was previously shown to be released by BECs in PBC, suggesting a potential role in the pathogenesis of high-risk disease. These also have potential for development as biomarkers for identification of high-risk disease, and their clinical utility as biomarkers should be evaluated further in prospective studies.