小狗阅读会员会员
有解析的医学SCI阅读工具

扫码登录小狗阅读

阅读SCI医学文献

Monocytes as potential mediators of pathogen-induced Th17 differentiation in patients with primary sclerosing cholangitis (PSC).

单核细胞作为原发性硬化性胆管炎 (PSC) 患者病原体诱导 Th17 分化的潜在介质。

  • 影响因子:6.87
  • DOI:10.1002/hep.31140
  • 作者列表:"Kunzmann LK","Schoknecht T","Poch T","Henze L","Stein S","Kriz M","Grewe I","Preti M","Hartl J","Pannicke N","Peiseler M","Sebode M","Zenouzi R","Horvatits T","Böttcher M","Petersen BS","Weiler-Normann C","Hess LU","Elise Ahrenstorf A","Lunemann S","Martrus G","Fischer L","Li J","Carambia A","Kluwe J","Huber S","Lohse AW","Franke A","Herkel J","Schramm C","Schwinge D
  • 发表时间:2020-01-23
Abstract

:T cells from patients with primary sclerosing cholangitis (PSC) show a prominent IL-17 response upon stimulation with bacteria or fungi, yet the reasons for this dominant TH17 response in PSC are not clear. Here, we analyzed the potential role of monocytes in microbial recognition and in skewing the T cell response towards Th17. Monocytes and T cells from blood and livers of PSC patients and controls were analyzed ex vivo and in vitro using trans-well experiments with cholangiocytes. Cytokine production was measured using flow cytometry, ELISA, RNA in situ hybridization and quantitative real time PCR. Genetic polymorphisms were obtained from Immunochip analysis. Following ex vivo stimulation with PMA/Ionomycin, PSC patients showed significantly increased numbers of IL-17A-producing peripheral blood CD4+ T cells compared to PBC patients and healthy controls, indicating increased Th17 differentiation in vivo. Upon stimulation with microbes, monocytes from PSC patients produced significantly more IL-1β and IL-6, cytokines known to drive Th17 cell differentiation. Moreover, microbe-activated monocytes induced the secretion of Th17 and monocyte-recruiting chemokines CCL-20 and CCL-2 in human primary cholangiocytes. In livers of patients with PSC cirrhosis, CD14hi CD16int and CD14lo CD16hi monocytes/macrophages were increased compared to alcoholic cirrhosis and monocytes were found to be located around bile ducts. Conclusion: PSC patients show increased Th17 differentiation already in vivo. Microbe-stimulated monocytes drive Th17 differentiation in vitro and induce cholangiocytes to produce chemokines mediating recruitment of Th17 cells and more monocytes into portal tracts. Taken together, these results point to a pathogenic role of monocytes in patients with PSC.

摘要

: 来自原发性硬化性胆管炎 (PSC) 患者的 T 细胞在受到细菌或真菌刺激后显示出突出的 IL-17 反应,然而 PSC 中这种优势 TH17 反应的原因尚不清楚。在此,我们分析了单核细胞在微生物识别和倾斜 T 细胞对 th17 的反应中的潜在作用。使用胆管细胞的跨孔实验,对 PSC 患者和对照组的血液和肝脏中的单核细胞和 T 细胞进行离体和体外分析。使用流式细胞术、 ELISA 、 RNA 原位杂交和定量实时 PCR 检测细胞因子的产生。遗传多态性从免疫芯片分析获得。PMA/离子霉素体外刺激后,与 PBC 患者和健康对照组相比,PSC 患者的 IL-17A-producing 外周血 CD4 + T 细胞数量显著增加,表明体内 Th17 分化增加。在微生物的刺激下,PSC 患者的单核细胞产生显著更多的 il-1 β 和 IL-6,这是已知的驱动 Th17 细胞分化的细胞因子。此外,微生物激活的单核细胞诱导人原代胆管细胞分泌 Th17 和单核细胞募集趋化因子 CCL-20 和 CCL-2。在 PSC 肝硬化患者的肝脏中,与酒精性肝硬化相比,CD14hi CD16int 和 CD14lo CD16hi 单核/巨噬细胞增加,单核细胞位于胆管周围。结论: PSC 患者体内已出现 Th17 分化增加。微生物刺激的单核细胞在体外驱动 Th17 分化,诱导胆管细胞产生趋化因子,介导 Th17 细胞和更多单核细胞募集到门脉区。总之,这些结果指出了单核细胞在 PSC 患者中的致病作用。

阅读人数:1人
下载该文献
小狗阅读

帮助医生、学生、科研工作者解决SCI文献找不到、看不懂、阅读效率低的问题。提供领域精准的SCI文献,通过多角度解析提高文献阅读效率,从而使用户获得有价值研究思路。

相关文献
影响因子:6.87
发表时间:2020-01-10
DOI:10.1002/hep.31110
作者列表:["Goeppert B","Folseraas T","Roessler S","Kloor M","Volckmar AL","Endris V","Buchhalter I","Stenzinger A","Grzyb K","Grimsrud MM","Gornicka B","von Seth E","Reynolds GM","Franke A","Gotthardt DN","Mehrabi A","Cheung A","Verheij J","Arola J","Mäkisalo H","Eide TJ","Weidemann S","Cheville JC","Mazza G","Hirschfield GM","Ponsioen CY","Bergquist A","Milkiewicz P","Lazaridis KN","Schramm C","Manns MP","Färkkilä M","Vogel A","International PSC study group.","Boberg KM","Schirmacher P","Karlsen TH"]

METHODS:BACKGROUND & AIMS:Lifetime risk of biliary tract cancer (BTC) in primary sclerosing cholangitis (PSC) exceeds 20% and BTC is currently the leading cause of death in PSC patients. To open new avenues for management, we aimed to delineate novel and clinically relevant genomic and pathological features of a large panel of PSC-associated BTC (PSC-BTC). APPROACH & RESULTS:We analysed formalin fixed, paraffin embedded tumor tissue from 186 PSC-BTC patients from 11 centers in eight countries with all anatomical locations included. We performed tumor DNA sequencing at 42 clinically relevant genetic loci to detect mutations, translocations and copy number variations, along with histomorphological and immunohistochemical characterization. Irrespective of the anatomical localization, PSC-BTC exhibited a uniform molecular and histological characteristic similar to extrahepatic cholangiocarcinoma. We detected a high frequency of genomic alterations typical of extrahepatic cholangiocarcinoma, e.g. TP53 (35.5%), KRAS (28.0%), CDKN2A (14.5%), and SMAD4 (11.3%), as well as potentially druggable mutations (e.g. HER2/ERBB2). We found a high frequency of non-typical/non-ductal histomorphological subtypes (55.2%) and of the usually rare BTC precursor lesion, intraductal papillary neoplasia (18.3%) CONCLUSION: Genomic alterations in PSC-BTC include a significant number of putative actionable therapeutic targets. Notably, PSC-BTC show a distinct extrahepatic morpho-molecular phenotype, independent of the anatomical location of the tumor. These findings advance our understanding of PSC-associated cholangiocarcinogenesis and provide strong incentives for clinical trials to test genome-based personalized treatment strategies in PSC-BTC.

翻译标题与摘要 下载文献
影响因子:3.72
发表时间:2020-01-16
DOI:10.1093/ibd/izz325
作者列表:["Peverelle M","Paleri S","Hughes J","De Cruz P","Gow PJ"]

METHODS:BACKGROUND:The impact of inflammatory bowel disease (IBD) activity on long-term outcomes after liver transplantation (LT) for primary sclerosing cholangitis (PSC) is unknown. We examined the impact of post-LT IBD activity on clinically significant outcomes. METHODS:One hundred twelve patients undergoing LT for PSC from 2 centers were studied for a median of 7 years. Patients were divided into 3 groups according to their IBD activity after LT: no IBD, mild IBD, and moderate to severe IBD. Patients were classified as having moderate to severe IBD if they met at least 1 of 3 criteria: (i) Mayo 2 or 3 colitis or Simple Endoscopic Score-Crohn's Disease ≥7 on endoscopy; (ii) acute flare of IBD necessitating steroid rescue therapy; or (iii) post-LT colectomy for medically refractory IBD. RESULTS:Moderate to severe IBD at any time post-transplant was associated with a higher risk of Clostridium difficile infection (27% vs 8% mild IBD vs 8% no IBD; P = 0.02), colorectal cancer/high-grade dysplasia (21% vs 3% both groups; P = 0.004), post-LT colectomy (33% vs 3% vs 0%) and rPSC (64% vs 18% vs 20%; P < 0.001). Multivariate analysis revealed that moderate to severe IBD increased the risk of both rPSC (relative risk [RR], 8.80; 95% confidence interval [CI], 2.81-27.59; P < 0.001) and colorectal cancer/high-grade dysplasia (RR, 10.45; 95% CI, 3.55-22.74; P < 0.001). CONCLUSIONS:Moderate to severe IBD at any time post-LT is associated with a higher risk of rPSC and colorectal neoplasia compared with mild IBD and no IBD. Patients with no IBD and mild IBD have similar post-LT outcomes. Future prospective studies are needed to determine if more intensive treatment of moderate to severe IBD improves long-term outcomes in patients undergoing LT for PSC.

翻译标题与摘要 下载文献
影响因子:6.87
发表时间:2020-01-23
DOI:10.1002/hep.31140
作者列表:["Kunzmann LK","Schoknecht T","Poch T","Henze L","Stein S","Kriz M","Grewe I","Preti M","Hartl J","Pannicke N","Peiseler M","Sebode M","Zenouzi R","Horvatits T","Böttcher M","Petersen BS","Weiler-Normann C","Hess LU","Elise Ahrenstorf A","Lunemann S","Martrus G","Fischer L","Li J","Carambia A","Kluwe J","Huber S","Lohse AW","Franke A","Herkel J","Schramm C","Schwinge D"]

METHODS::T cells from patients with primary sclerosing cholangitis (PSC) show a prominent IL-17 response upon stimulation with bacteria or fungi, yet the reasons for this dominant TH17 response in PSC are not clear. Here, we analyzed the potential role of monocytes in microbial recognition and in skewing the T cell response towards Th17. Monocytes and T cells from blood and livers of PSC patients and controls were analyzed ex vivo and in vitro using trans-well experiments with cholangiocytes. Cytokine production was measured using flow cytometry, ELISA, RNA in situ hybridization and quantitative real time PCR. Genetic polymorphisms were obtained from Immunochip analysis. Following ex vivo stimulation with PMA/Ionomycin, PSC patients showed significantly increased numbers of IL-17A-producing peripheral blood CD4+ T cells compared to PBC patients and healthy controls, indicating increased Th17 differentiation in vivo. Upon stimulation with microbes, monocytes from PSC patients produced significantly more IL-1β and IL-6, cytokines known to drive Th17 cell differentiation. Moreover, microbe-activated monocytes induced the secretion of Th17 and monocyte-recruiting chemokines CCL-20 and CCL-2 in human primary cholangiocytes. In livers of patients with PSC cirrhosis, CD14hi CD16int and CD14lo CD16hi monocytes/macrophages were increased compared to alcoholic cirrhosis and monocytes were found to be located around bile ducts. Conclusion: PSC patients show increased Th17 differentiation already in vivo. Microbe-stimulated monocytes drive Th17 differentiation in vitro and induce cholangiocytes to produce chemokines mediating recruitment of Th17 cells and more monocytes into portal tracts. Taken together, these results point to a pathogenic role of monocytes in patients with PSC.

翻译标题与摘要 下载文献
方向

复制标题
发送后即可在该邮箱或我的下载查看该文献
发送
该文献默认存储到我的下载

科研福利

报名咨询

建议反馈
问题标题:
联系方式:
电子邮件:
您的需求: