Matsushita Hiroshi, Miyake Yasuhiro, Takaki Akinobu, Yasunaka Tetsuya, Koike Kazuko, Ikeda Fusao, Shiraha Hidenori, Nouso Kazuhiro, Yamamoto Kazuhide
Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
J Gastroenterol Hepatol. 2015 Mar;30(3):600-8. doi: 10.1111/jgh.12711.
Inappropriate innate immune responses have been suggested to contribute to the pathogenesis of primary sclerosing cholangitis (PSC). We evaluated the associations of expressions of toll-like receptor (TLR) 4, TLR9, and nucleotide-binding oligomerization domain-containing protein (NOD)-like receptor family pyrin domain containing 3 (NLRP3) in the biliary epithelial cells (BECs) with clinical features of PSC patients.
We retrospectively evaluated the expressions of TLR4, TLR9, and NLRP3 in the intrahepatic BECs by immunohistochemical staining in 21 PSC patients and 10 normal controls. In PSC, 17 patients underwent liver biopsy, and, in the other four patients, liver specimens were obtained at the time of liver transplantation.
TLR9 expressions in BECs were higher in PSC patients than in normal controls. TLR9 expressions were correlated with Ludwig fibrosis scores in PSC patients. TLR4 and NLRP3 expressions were similar between PSC patients and normal controls. Seventeen PSC patients undergoing liver biopsy were followed up during a median period of 55.7 months. Four reached to liver transplantation and four developed cholangiocarcinoma. Patients developing cholangiocarcinoma showed lower NLRP3 expressions than the others. Patients reaching to liver transplantation showed higher TLR9 expressions. Expression levels of TLR9 and NLRP3 were not correlated with liver biochemical tests and Mayo risk scores.
In PSC, excessive immune responses through TLR9 signaling may be associated with the disease progression. Insufficient immune response through NLRP3 signaling may be associated with the development of cholangiocarcinoma. Evaluation of TLR9 and NLRP3 expressions in BECs may be useful for predicting the prognosis as an auxiliary marker.
有研究表明不适当的先天性免疫反应参与原发性硬化性胆管炎（PSC）的发病机制。我们评估了胆管上皮细胞（BECs）中Toll样受体（TLR）4、TLR9和含核苷酸结合寡聚化结构域蛋白（NOD）样受体家族含pyrin结构域蛋白3（NLRP3）的表达与PSC患者临床特征之间的关联。
我们回顾性评估了21例PSC患者和10例正常对照者肝内BECs中TLR4、TLR9和NLRP3的表达，采用免疫组织化学染色法。在PSC患者中，17例行肝活检，另外4例在肝移植时获取肝组织标本。
PSC患者BECs中TLR9的表达高于正常对照者。PSC患者中TLR9的表达与Ludwig纤维化评分相关。PSC患者和正常对照者之间TLR4和NLRP3的表达相似。17例行肝活检的PSC患者接受了中位时间为55.7个月的随访。4例接受了肝移植，4例发生了胆管癌。发生胆管癌的患者NLRP3表达低于其他患者。接受肝移植的患者TLR9表达较高。TLR9和NLRP3的表达水平与肝脏生化检查及Mayo风险评分无关。
在PSC中，通过TLR9信号通路的过度免疫反应可能与疾病进展相关。通过NLRP3信号通路的免疫反应不足可能与胆管癌的发生相关。评估BECs中TLR9和NLRP3的表达作为辅助标志物可能有助于预测预后。
