OBJECTIVE:Alveolar echinococcosis (AE) is a zoonosis caused by the larval stage of the metacestode Echinococcosis multilocularis with a tumor-like behavior in the targeted organ, especially in the liver. Surgery with albendazole is first-line modality for AE. Drug discontinuation is usually based upon the parasitic viability shown by the positron emission tomography (PET) scan. However, as a demanding and expensive method, it is not widely practiced in majority of the endemic regions. Further understanding on the cytokine and chemokine response profiles in AE patients may provide an interesting insight for potential markers in viability assessment. METHODS:Mice were inoculated with Echinococcus multilocularis intrahepatically to develop the hepatic AE murine model. Oral albendazole administration was then applied for three months after the first inoculation, and peripheral and regional immune cells including type 1 T helper cells (Th), Th2, Th17, regulatory T (Treg) cells, related cytokines, and chemokines were examined. RESULTS:The hepatic AE lesion was confirmed by ultrasound examination resulting in a successful rate of 70%. Among the 17 cytokines and chemokines detected, plasma levels of IL-23 were significantly higher in E. multilocularis-infected mice when compared to the control group; furthermore, more obvious increasing levels were found after albendazole treatment (p < 0.05). All chemokine levels other than eotaxin and MCP-3 were slightly higher in E. multilocularis-infected mice compared to the control group (p > 0.05). Eotaxin levels were significantly decreased in mice with E. multilocularis infection followed by albendazole treatment (p < 0.05). Both IL-17A and IL-23 expressions in hepatic AE lesions were significantly higher and related with disease activity. CONCLUSION:Albendazole administration influenced the balance of immune response and promotes the secretion of proinflammatory factors which is beneficial to parasite clearance. IL-23 seems to be associated with the successful albendazole treatment in mice with E. multilocularis infection; such a change could be translated into clinical application in the near future.

目的:评估血清生长和分化因子15(GDF-15)与营养状态的相关性,为胃癌术后患者发生营养不良的临床诊疗提供新的临床思路和治疗靶点.方法:收集2019年3月—2020年3月收治的胃癌患者78例,根据TNM分期分为早期胃癌组和进展期胃癌组,分别在术前、术后14 d、术后30 d时收集两组患者的营养状态指标及GDF-15水平.用NRS-2002评分和PG-SGA评分评估患者的营养状态.结果:术后14 d时两组总白蛋白、白蛋白、前白蛋白均较术前降低(<0.05),而GDF-15、NRS-2002评分和PG-SGA评分均显著高于术前(<0.05).术后30 d时早期胃癌组的营养状态较术后14 d有所恢复,但进展期胃癌组总白蛋白、白蛋白、前白蛋白仍低于术后14 d(<0.05),GDF-15、NRS-2002评分和PG-SGA评分均显著高于术后14 d(<0.05).相关性分析结果显示术后14 d和术后30 d的GDF-15与前白蛋白显著负相关(=-0.872、-0.895,<0.05),与NRS-2002评分、PG-SGA评分正相关(=0.262、0.401和0.551、0.436,<0.05),在术后30 d时GDF-15与总蛋白质和白蛋白也表现出负相关性(=-0.598、-0.503,<0.05).结论:胃癌术后患者GDF-15水平与前白蛋白和PG-SGA评分密切相关,营养状态越差,GDF-15水平越高,因此GDF-15可以作为评估胃癌患者术后营养状态的潜在生物标志物.

ObjectivesTo investigate potential biomarkers for distinguishing biological viability of hepatic cystic echinococcosis.MethodsUsing Luminex assay we measured plasma concentrations of cytokine and chemokine in patients with active and non-active cysts (hepatic cystic echinococcosis (HCE), n = 47) and stable/progressive hepatic alveolar echinococcosis (HAE, n = 38), and in comparable infection-free volunteers (n = 48). Disease progression was staged according to the classification standard.ResultsCompared with healthy controls, enhanced elevation was found of T helper 22 type cytokine interleukin (IL)-22 and chemokines Eotaxin, interferon-γ inducible protein-10, monocyte chemoattractant protein-1, and stromal cell-derived factor-1α concentrations in HAE patients, and IL-22, growth-related oncogene α, monocyte chemoattractant protein-1, regulated on activation normal T-expressed and secreted, and stromal cell-derived factor-1α concentrations in HCE patients (P < 0.05–0.001). For HCE patients, only IL-27 concentrations in non-active HCE were significantly lower than in active HCE. In logistic regression analysis, IL-27 <20.79 pg/mL was an independent risk factor for HCE biological viability with receiver operating characteristic analysis at a 44.23 pg/mL cut-off resulting in 0.72 area under the curve.ConclusionsOur findings correlate multiple cytokine and chemokine secretion patterns in HAE and HCE patients with different disease progression stages. IL-27 could serve as a referring biomarker for distinguishing HCE biological viability and provide a preliminary foundation for clinical decision-making.

肝移植是目前治疗肝脏终末期疾病的最佳治疗手段[1-2].在世界范围内人类器官捐献者远远不能满足对器官日益增长的需求,导致许多患者在等待移植的过程中死亡.为扩大捐献器官库移植医师们不断尝试扩大标准,使用边缘肝脏、活体肝脏捐献、离体肝切除自体肝移植、劈离式肝移植等[3-6].目前,异种移植虽然具有很强的吸引力,但伦理和临床研究未能克服,从而未得以顺利实施[7].由于器官短缺持续存在,患有相关病毒感染的供体器官的移植已经通过改进的治疗手段得以实施,使用人类免疫缺陷病毒(human immunodeficiency virus,HIV)、乙型肝炎病毒(hepatitis B virus,HBV)、丙型肝炎病毒(hepatitis C virus,HCV)等慢性病毒感染的活体或死者供体器官已成为可能.如直接作用的抗病毒剂(direct acting antiviral agents,DAAs)用于HCV的感染患者,三重组合抗逆转录病毒(antiretroviral thera-py,ART)的治疗方法应对HIV的感染患者[8-10].目前,来自3种病毒阳性死亡捐献者的大多数器官已被植入特定终末期患病人群.本文主要对 HIV、HBV、HCV 3种病毒感染的供体肝脏使用情况和临床应对方法做一综述.

Fluorodeoxyglucose (FDG) uptake by alveolar echinococcosis (AE) liver lesions is a signal of their metabolic activity and of disease progression. In order to find a surrogate marker for this status, we investigated whether parameters of the peripheral and/or periparasitic immune responses were associated with metabolic activity in a prospective case-control study of 30 AE patients and 22 healthy controls. Levels of 18 cytokines and chemokines, representative of innate and adaptive immune responses, were assessed in plasma and peripheral cells of two groups of patients with (MAAE) and without (MIAE) metabolically active lesions, and in the liver of MAAE patients. Mixed cytokine profile was observed in the peripheral blood of AE patients, with a predominance of Th2, Th17 and Treg responses. Among the detected markers only plasma IL-5 and IL-23, more elevated in MAAE patients, were found discriminant. Discrimination between MAAE and MIAE patients obtained by using IL-23 was improved when IL-5 was used in combination. The combination of elevated levels of IL-5 and IL-23 is significantly associated with FDG uptake at PET scan. It offers a new tool for the follow-up of AE patients which could substitute to FDG-PET whenever non-available to assess disease progression.

Immune response pattern between host and Echinococcus multilocularis (E. multilocularis) is considered as a crucial point in development of alveolar echinococcosis (AE). In this study, we are aiming to study the expression patterns of TLR2 and TLR4 with related cytokines and transcription factors in secondary E. multilocularis infected murine model. The murine model of AE was developed by using intraperitoneal inoculation of E. multilocularis protoscolexes and albendazole (E. m+ABZ group) or carboxy methyle cellulose (CMC; E. m+CMC group) administration via gastric tube was initiated in the third month and continued for one month. Mice with CMC administration served as negative controls (C+CMC group). The splenic cells and peritoneal exudates cells (PECs) were prepared and the levels of IFN-γ, IL-10, and IL-5 in splenic cells and PECs culture supernatants were detected using enzyme linked immune-sorbent assay (ELISA). Besides, the mRNA expression levels of TLR2, 4, transcription factors and cytokines were detected by using real-time fluorescent quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The concentration levels of IFN-γ, IL-10, and IL-5 in PECs and splenic cell supernatants were extremely lower, however, significantly elevated after stimulated with Concanavalin A (ConA) for 36 h with higher concentrations in E. m+CMC group comparing to both E. m+ABZ and C+CMC group. The mRNA levels of TLR2, 4 and GATA3, IFN-γ, IL-10 in splenic cells were significantly increased in E. m+CMC group comparing with other groups. Simultaneously, T-bet mRNA expressions were elevated in E. m+ABZ and C+CMC group compared to E. m+CMC group. In addition, T-bet/GATA3 ratios was higher in E. m+ABZ group compared to E. m+CMC group and were higher in C+CMC group than those in E. m+CMC group. TLR2 mRNA expression in splenic cells showed a positive correlation with IL-10 concentration levels in splenic cell culture supernatants. The present study provides evidence on the possible role of TLR2 in the process of immune tolerance during E. multilocularis infection and suggests albendazole treatment might reverse the immune tolerance situation and improve parasite clearance process.

目的 探讨多房棘球幼(E.m)感染所致的免疫应答偏倚对实验性类风湿性关节炎(CIA)的免疫调节作用.方法 分别建立雌性C57小鼠胶原性关节炎模型(CIA组)、多房棘球蚴感染模型(E.m组)和多房棘球蚴感染后类风湿性关节炎诱导模型(E.m+CIA组),利用实时荧光定量RT-PCR和酶联免疫吸附试验(ELISA)检测小鼠足爪组织、外周血及脾脏细胞中Th17细胞相关因子及转录因子水平,实验设阴性对照组(Control组).组间比较采用非参数秩和检验两个独立样本比较法(M-W法);采用Spearman线性相关性分析方法分析细胞因子及转录因子之间的相关关系.结果 外周血及脾脏细胞中IL-17A、IL-1β、IFN-γ水平在E.m+CIA组18.93(14.90～20.53) pg/ml、18.93(14.90～20.53)pg/ml,4.18(1.79～4.45)pg/ml、4.182(1.794～4.446)pg/ml,14.79(0.64～29.38)pg/ml、14.79(0.64～29.38)pg/ml,显著低于CIA组16.47(15.41-19.46)pg/ml、16.47(15.41～19.46) pg/ml,161.60(125.40～222.20) pg/ml、367.2(240.4～550.3)pg/ml,29.89(19.93～58.95) pg/ml、29.89(19.93～58.95) pg/ml(P＜0.05或P＜0.01);E.m+CIA组IL-4、IL-6等抗炎相关因子水平11.68(11.00～12.85) pg/ml、11.68(11.00～12.85) pg/ml,450.40(292.80～697.50) pg/ml、450.40(292.80～645.60)pg/ml,较其他组显著升高(P＜0.05或P＜0.01).小鼠足爪中IL-17A及RORrt mRNA相对表达量在E.m+CIA组13.29(5.38～18.93),1.07(0.78～6.99)较其他组降低.结论 E.m感染诱导的Th2优势应答可使CIA不能有效启动致病性Th1免疫应答,抑制CIA小鼠过度的Th17应答,从而减轻RA炎症损伤.

Parasites, which are a recently discovered yet ancient dweller in human hosts, remain a great public health burden in underdeveloped countries, despite preventative efforts. Rheumatoid arthritis is a predominantly cosmopolitan health problem with drastic morbidity rates, although encouraging progress has been achieved regarding treatment. However, although various types of methods and agents have been applied clinically, their broad usage has been limited by their adverse effects and/or high costs. Sustained efforts have been exerted on the 'hygiene hypothesis' since the 1870s. The immunosuppressive nature of parasitic infections may offer potential insight into therapeutic strategies for rheumatoid arthritis, in which the immune system is overactivated. An increasing number of published papers are focusing on the preventive and/or curative effect of various parasitic infection on rheumatoid arthritis from experimental studies to large-scale epidemiological studies and clinical trials. Therefore, the present review aimed to provide a general literature review on the possible beneficial role of parasitic infection on rheumatoid arthritis.

There are increases in TLR2 and TLR4 mNRA expression in PBMCs and in HAE lesions in HAE patients. The TLR2 mNRA expression in PBMCs positively correlates with plasma IL-23 level and peripheral Eo%.

目的:探讨Foxp3和RORγt在肝泡型包虫病患者肝脏组织中的表达及意义.方法:将手术治疗的14位肝泡型包虫病患者的肝脏组织分为3组:病灶组织组(L组)14例,病灶旁组织组(P组)14例,正常肝组织组(N组)14例.应用实时荧光定量PCR(qRT-PCR)法检测各肝脏组织中Foxp3和RORγt mRNA的表达,分析其结果.结果:Foxp3mRNA在L组中的表达明显高于P组(P=0.005)和N组(P=0.004),P组中的表达高于N组(P=0.246).RORγtmRNA在L组中的表达高于P组和N组(L组vsP组,P=0.187);L组vsN组,P=0.044),在P组中的表达高于N组(P=0.027).肝脏不同组织中,RORγt与Foxp3的表达量呈正相关.结论:Th17细胞转录因子Foxp3和Treg细胞转录因子ROR γ t在肝脏病灶组织中mRNA的表达升高,这些变化可能与泡型包虫病发病过程中寄生虫肉芽肿的形成有关.

目的探讨辅助性T细胞9（Th9）相关细胞因子IL-9及转录因子PU.1和IRF-4mRNA在肝脏泡型包虫病患者外周血单个核细胞中的表达及其作用。方法 2012年10月—2014年3月新疆医科大学第一附属医院收治的肝脏泡型包虫病患者（AE组）14例,健康志愿者（HC组）14例,应用实时荧光定量PCR法检测两组受试者外周血单个核细胞中IL-9、PU.1和IRF-4 mRNA的相对表达量,数据分析采用非参数秩和检验两独立样本比较法（M-W法）,用Spearman线性相关性检验分析细胞因子和转录因子之间的相关关系。结果肝泡型包虫病组和健康对照组受试者外周血单个核细胞IL-9 mRNA相对表达量分别为2.44911（IQR:0.69268-5.70628）和0.00316（IQR:0.0198-0.00815）,差异有统计学意义（P=0.000）;PU.1 mRNA相对表达量分别为313.105（IQR:94.80556-548.13140）和0.77147（IQR:0.28829-1.59077）,差异有统计学意义（P=0.009）;IRF-4 mRNA相对表达量分别为0.04126（IQR:0.01957-0.08204）和21.58347（IQR:8.95431-52.31027）,差异有统计学意义（P=0.000）,单个核细胞中IL-9mRNA水平与PU.1mRNA呈正相关（r=0.8228,P=0.000）,与IRF-4mRNA也呈正相关（r=0.9332,P=0.000）。结论 Th9细胞功能性细胞因子IL-9以及转录因子PU.1和IRF-4参与泡型包虫病发生发展过程,其表达水平上调有利于虫体继续寄生于宿主体内,同时可能与形成泡型包虫慢性肉芽肿有关。

Human alveolar echinococcosis (AE) is a lethal parasitic infectious disease which may lead to liver failure if left untreated. It is caused by the larval stage of the fox tapeworm Echinococcus multilocularis and usually develops a substantial infiltrative occupation in solid organs. During the infection, T helper subsets are known to play crucial role in crosstalk between the parasite and human host. Th9 cells, a new member of CD4+ T cell family which is characterized by its specific cytokine IL-9 and transcription factors PU.1 and IRF-4, have been known recently to have a critical role in allergic diseases, and cancers as well as the parasitic infection. To assess the potential role of Th9 cells during the infection, the mRNA levels of IL-9, PU.1, and IRF-4 both in peripheral blood mononuclear cells and in liver tissues were, respectively, detected by using real-time PCR. The plasma concentration levels of IL-9 were detected by using enzyme linked immunosorbent assay (ELISA). Th9 related cytokine IL-9 and transcription factors PU.1 and IRF-4 mRNA levels elevated both in PBMCs, and in hepatic lesion and paralesion tissues in AE patients. This may facilitate the infiltrative growth of the parasite and its persistence in human host.

目的:通过定量检测感染泡型包虫病患者肝脏组织中IL-9、PU.1和IRF-4 mRNA的表达水平,初步探讨Th9相关细胞因子和转录因子在该疾病感染中所起的可能的作用.方法:将14例经手术确诊的肝脏泡型包虫病患者肝脏组织标本根据病灶分布部位分为病灶组织(L)、病灶邻近组织(PL)和正常肝脏组织(N),应用实时荧光定量PCR技术检测各组标本中IL-9、PU.1和IRF-4 mRNA表达水平,并将数据采用非参数配伍设计Wilcoxon秩和检验和Spearman直线相关性分析的统计学方法进行分析.结果:L组IL-9 mRNA的表达水平明显高于PL组和N组(P=0.002和0.000 9),而PL组较N组轻微升高(P＞ 0.05/3);PU.1 mRNA的表达在L组较PL组和N组显著升高(P=0.013和0.000 8),而N组较PL组轻度降低(P＞ 0.05/3);L组IRF-4 mRNA的表达较N组显著升高(P=0.008 1),而PL组较N组、L组较PL组均轻微升高(P＞ 0.05/3).各组肝脏组织IL-9 mRNA表达水平分别与PU.1和IRF-4mRNA表达水平呈正相关(r=0.872 6和0.924 8,P均＜0.000 1).与N组和PL组相比,IL-9、PU.1和IRF-4 mRNA在L组有显著的高水平的表达.结论:Th9相关细胞因子IL-9及特异性转录因子PU.1和IRF-4可能参与泡型包虫病感染后的免疫应答过程,并有利于多房棘球绦虫在宿主体内继续寄生存活.

Several studies have demonstrated the important role of Toll-like receptors in various parasitic infections. This study aims to explore expression of Toll-like receptors (TLRs) and related cytokines in patients with human cystic echinococcosis (CE) and alveolar echinococcosis (AE). 78 subjects including AE group (N = 28), CE group (N = 22), and healthy controls (HC, N = 28) were enrolled in this study. The mRNA expression levels of TLR2 and TLR4 in blood and hepatic tissue and plasma levels related cytokines were detected by using ELISA. Median levels of TLR2 mRNA in AE and CE groups were significantly elevated as compared with that in healthy control group. Median levels of TLR4 expression were increased in AE and CE. Plasma concentration levels of IL-5, IL-6, and IL-10 were slightly increased in AE and CE groups compared with those in HC group with no statistical differences (p > 0.05). The IL-23 concentration levels were significantly higher in AE and CE groups than that in HC subjects with statistical significance. The increased expression of TLR2 and IL-23 might play a potential role in modulating tissue infiltrative growth of the parasite and its persistence in the human host.