Interleukin-28 and hepatitis C virus genotype-4:Treatment-induced clearance and liver fibrosis

AIM:To investigate the association between interleukin-28B(IL28B) genotype and response to treatment and hepatic fibrosis in patients with hepatitis C virus(HCV) genotype 4.METHODS:Two hundred and one HCV-genotype 4 patients were included.All patients were treated with Peginterferon alph2a/Ribavirin for 48 wk.End of treatment response(ETR) was defined as loss of detectable serum HCV RNA at the end of treatment.Sustained viral response(SVR) was defined as loss of detectable serum HCV RNA at the end of 24 wk follow up.Genotyping of IL28B rs12979860 was performed using the TaqMan assay.We used logistic regression to estimate the adjusted odds ratio(aOR) and 95%CI.RESULTS:The study included 201 HCV-genotype 4 patients.The majority of patients were men(89.6%),with a median age of 47 years,inter-quartile range(40-51).Approximately 62.5% of patients had ETR,and 49.6% had SVR.Individuals who achieved SVR were more likely to be younger(χ 2 = 4.91,P = 0.027),and less likely to have fibrosis(χ 2 = 15.54,P < 0.0001),or inflammation(χ 2 = 7.58,P = 0.006).The genotype distribution of rs12979860 was 36.2%,49.0% and 14.8% for genotypes CC,CT,and TT,respectively.In these participants,rs12979860 genotype distribution did not differ by gender(P = 0.466),pretreatment viral load(P = 0.600),inflammation(P = 0.435),or fibrosis(P = 0.291).The frequencies of IL28B rs12979860 genotypes were TT(14.8%),CT(49.0%),and CC(36.2%).Compared to rs12979860 genotype TT,aORs(95%CI) for ETR and SVR were:CC genotype,[17.55(5.34-57.69) and 5.92(2.09-16.76),respectively];CT genotype,[5.15(1.80-14.78) and 2.48(0.94-6.52),respectively].In the current study,the patients who did not achieve ETR or SVR had a lower prevalence of rs12979860 CC(17.4% and 23.3%,respectively) than individuals who had ETR or SVR(47.9% and 47.2%,respectively).Individuals with rs12979860 CC genotype had approximately 6 times the odds of SVR compared to individuals with TT genotype(aOR = 5.92;95%CI:2.09-16.76).Similarly,patients with CT genotype had SVR more often than patients with TT genotype(aOR = 2.48;95%CI:0.94-6.52).Carrying at least one copy of the C allele(genotypes CT and CC) had almost 8 times the probability of ETR compared to those with genotype rs12979860 TT(aOR = 7.87;95%CI:2.84-21.82),and approximately 3 times the odds of SVR compared to those with genotype rs12979860 TT(aOR = 3.46;95%CI:1.37-8.74).In addition,data were consistent with a significant gene-dose relationship(aOR = 4.05/allele;95%CI:2.27-7.22).The association between rs12979860 genotype and SVR was similar among those who achieved and those who did not achieve SVR.CONCLUSION:In HCV-genotype 4 patients,rs12979860 is a sensitive predictor of viral clearance,independent of viral load,age,gender or fibrosis,with no similar relation to severity of fibrosis.

共刺激分子CD28:CTLA4/B7及CD40/CD40L和SLE

共刺激分子CD2 8:CTLA 4/B7和CD40 /CD40L对B细胞的增殖、分化、抗体的分泌和T细胞的活化、细胞因子的分泌具有重要作用 ,其对系统性红斑狼疮的发生、发展具有重要的促进作用。本文综述了CD2 8:CTLA 4/B7和CD40 /CD40L生物学特性、功能及在系统性红斑狼疮发生、发展中的作用 ,以及免疫学治疗的临床应用前景。

CD_(28):CTLA-4/B7及CD_(40)/CD_(40)L与多发性硬化

共刺激分子CD28:CTLA-4/B7及CD40/CD40L对T细胞的活化、调节、B细胞的增殖、分化具有重要作用,共刺激分子在多发性硬化中的表达发生明显变化,它们对多发性硬化的发生、发展起着重要的促进作用,选择性阻断共刺激分子可控制疾病的发展,对多发性硬化治疗具有重要的意义。本文综述了CD28:CTLA-4/B7和CD40/CD40L生物学特性、功能,在多发性硬化的发生、发展中的作用以及相关的治疗前景。

自身反应性T细胞及共刺激分子CD28／CTLA-4／B7、CD40／CD40L和ITP

血小板抗原特异性自身反应性T细胞的活化在特发性血小板减少性紫癜(ITP)的发病机制中起着关键性作用,T细胞的活化除需要抗原递呈细胞表面MHCⅡ抗原复合物外还需要共刺激分子(第二信号),主要包括CD28／CTLA-4／B7和CD40／CD40L。本文就自身反应性T细胞和共刺激分子CD28／ CTLA-4／B7、CD40／CD40L在ITP中的作用机制及潜在的治疗价值作一综述。

CD28:CTLA4/B7及CD40/CD40L在炎症性肠病发病机制中的作用

炎症性肠病(IBD)是一组病因未明的累及肠道的免疫反应异常性疾病,T细胞功能失调与IBD发病密切相关。CD28：CTLA4/B7及CD40/CD40L是重要共刺激分子,对调节免疫具有非常重要的作用,可能在IBD发生和发展中起着关键作用。

IL28B polymorphism genotyping as predictor of rapid virologic response during interferon plus ribavirin treatment in hepatitis C virus genotype 1 patients

AIM: To clarify the association of interleukin-28B (IL28B) single nucleotide polymorphisms (SNPs) with hepatitis C virus (HCV) viremia changes for assessment of interferon (IFN) response.

Is the use of IL28B genotype justified in the era of interferon-free treatments for hepatitis C?

In 2009, several groups reported that interleukin-28B(IL28B) genotypes are associated with the response to peginterferon plus ribavirin therapy for chronic hepatitis C virus(HCV) infection in a genome-wide association study, although the mechanism of this association is not yet well understood. However, in recent years, tremendous progress has been made in the treatment of HCV infection. In Japan, some patients infected with HCV have the IL28 B major genotype, which may indicate a favorable response to interferon-including regimens; however, certain patients within this group are also interferon-intolerant or ineligible. In Japan, interferonfree 24-wk regimens of asunaprevir and daclatasvir are now available for HCV genotype 1b-infected patients who are interferon-intolerant or ineligible or previous treatment null-responders. The treatment response to interferon-free regimens appears better, regardless of IL28 B genotype. Maybe other interferon-free regimens will widely be available soon. In conclusion, although some HCV-infected individuals have IL28 B favorable alleles, importance of IL28 B will be reduced with availability of oral interferon free regimen.

The expression of Lin28B was co-regulated by H3K4me2 and Wnt5a/β-catenin/TCF7L2

Lin28A and Lin28B are homologous RNA-binding proteins that participate in the development of primordial germ cells. The mechanisms underlying expression and regulation of Lin28A have been well documented, but such information for Lin28B is limited. In this study, a fragment of the Lin28B promoter was cloned, the pEGFP-pLin28B vector was constructed. DF-1 chicken fibroblasts were transfected and the expression of green fluorescent protein (GFP) was measured. Furtherly, Lin28B promoter of different lengths fragments was cloned using the chromosome-walking method and the fragments were ligated into the PGL3-Basic vector, and transfected into DF-1 cells. Results of dual-luciferase reporter assay showed that the core of the Lin28B promoter was included in the sequence from –1 431 to –1 034 bp. The binding sites of the transcription factor TCF7L2 was showed within this sequence by bioinformatics analysis. The promoter activity of Lin28B was downregulated (P<0.05) when the TCF7L2 binding site was mutated. Further experiments suggested that Lin28B promoter activity responded to the activation or inhibition of Wnt signaling. Results of chromatin immunoprecipitation and quantitative PCR showed that β-catenin-TCF7L2 may be enriched in the Lin28B promoter core area. In vivo and in vitro activation or inhibition of Wnt signaling significantly up- or down-regulated (P<0.05) Lin28B expression. H3K4me2 enriched in the promoter of Lin28B, which affected the regulation of Wnt signaling to Lin28B. In conclusion, our results showed that H3K4me2 and Wnt5a/β-catenin/TCF7L2 were the positive regulators of Lin28B expression. Findings of this study may lay a theoretical foundation for illuminating the mechanism underlying Lin28B expression.

Polymorphisms in the IFNL3/IL28B gene and hepatitis C: From adults to children

The purpose of the present review is to summarise the current knowledge on the association between single nucleotide polymorphisms (SNPs) in the interferon L3 (IFNL3) gene and hepatitis C virus (HCV) infection in children. Many studies in adults have demonstrated that genetic variation in IFNL3 is a strong predictor of the virological response in treatment-naive patients with HCV genotype 1 who were treated with Pegylated-IFN-&#x003b1; and ribavirin. Genetic variation in IFNL3 is also associated with the spontaneous clearance of HCV. Thus far, few paediatric studies have explored the association between variations in the IFNL3 gene and either spontaneous or treatment-induced clearance of HCV. The CC genotype of the rs12979860 SNP is associated with the spontaneous clearance of HCV in children independently of HCV genotype. Four paediatric studies have shown that both the CC genotype of the rs12979860 SNP and the TT genotype of the rs8099917 SNP are associated with the treatment-induced (IFN monotherapy and Pegylated-IFN-&#x003b1; and ribavirin association) clearance of HCV, while the rs12980275 SNP did not affect the virological response. The possible role of IFNL3 gene variation as a pre-treatment and on-treatment predictor of virological response in children is highly attractive but still undetermined. Further paediatric studies are needed to evaluate if testing for SNPs in IFNL3, either alone or together with other predictors of response to treatment, could be used to direct treatment strategies, including an avoidance of unnecessary protease inhibitor therapy and the duration of treatment.

Role of IL28B genotype in older hepatitis C virus-infected patients

The average age of hepatitis C virus(HCV)-infected individuals is becoming increasingly higher in Japan and steps should be taken to treat older individuals infected with HCV. Until an interferon-free regimen becomes available, peginterferon plus ribavirin will play a critical role in the treatment. The perception that older HCVinfected patients may be at higher risk than younger patients for adverse events from peginterferon plus ribavirin treatment but may obtain less clinical benefit from it may be based on the underrepresentation of older patients in clinical trials. A recent genomewide association study revealed that interleukin-28B(IL28B) genotype closely correlates with the treatment response against HCV. The relationship of IL28 B genotype with the treatment response in older HCV-infected patients is also unknown. In this review, we focused on the treatment response in older patients infected with HCV and the effects of IL28 B genotype. IL28 B major genotype is a useful predictor of sustained virological response in the interferon-including treatment of older patients infected with HCV. It also seems useful for avoiding adverse events, although the mechanisms ofthe effects of IL28 B genotype on the treatment outcome are still poorly understood and are currently under investigation. Further studies will be needed.

Gene polymorphisms of interleukin-28, p21-activated protein kinases 4, and response to interferon-α based therapy in Chinese patients with chronic hepatitis B

Background Peg-lnterferon-a treatment is expensive and associated with considerable adverse effects, selection of patients with the highest probability of response is essential for clinical practice. The objective of this study was to assess the relationship between the gene polymorphisms of interleukin-28 （IL-28）, p21-activated protein kinase 4 （PAK4） and the response to interferon treatment in chronic hepatitis B patients. Methods Two hundred and forty interferon-naive treatment HBeAg seropositive chronic hepatitis B patients were enrolled in the present prospective nested case-control study. Peripheral blood samples were collected, including 92 with favorable response and 148 without response to the interferon treatment. Rs8099917, rs12980602, and rs9676717 SNP was genotyped using matrix assisted laser desorption/ionization time of flight mass spectrometry （MALDI-TOF MS）. Results IL-28 genotype was not associated with response to interferon treatment （OR for GT/GG vs. TT, 0.881 （95% CI 0.388-2.002）; P=0.762; OR for CT/CC vs. TT, 0.902 （95% CI 0.458-1.778）; P=-0.766）. Rs9676717 in PAK4 genotype was independently associated with the response （OR for CT/CC vs. TT, 0.524 （95% CI 0.310-0.888）; P=0.016）. When adjusting for age, gender, smoking, drinking, levels of hepatitis B virus DNA, and alanine aminotransferase （ALT）, rs9676717 genotype TT appeared to be associated with a higher probability of response for interferon treatment （OR, 0.155 （95% CI 0.034-0.700）; P=0.015）. Conclusion Genotype TTfor rs9676717 in PAK4 gene and no drinking may be predictive of the interferon-a treatment success.

Potential mechanisms of hepatitis B virus induced liver injury

Chronic active hepatitis(CAH) is acknowledged as an imperative risk factor for the development of liver injury and hepatocellular carcinoma.The histological end points of CAH are chronic inflammation,fibrosis and cirrhosis which are coupled with increased DNA synthesis in cirrhotic vs healthy normal livers.The potential mechanism involved in CAH includes a combination of processes leading to liver cell necrosis,inflammation and cytokine production and liver scaring(fibrosis).The severity of liver damage is regulated by Hepatitis B virus genotypes and viral components.The viral and cellular factors that contribute to liver injury are discussed in this article.Liver injury caused by the viral infection affects many cellular processes such as cell signaling,apoptosis,transcription,DNA repair which in turn induce radical effects on cell survival,growth,transformation and maintenance.The consequence of such perturbations is resulted in the alteration of bile secretion,gluconeogenesis,glycolysis,detoxification and metabolism of carbohydrates,proteins,fat and balance of nutrients.The identification and elucidation of the molecular pathways perturbed by the viral proteins are important in order to design effective strategy to minimize and/or restore the hepatocytes injury.

Humoral and cellular immunogenecity of DNA vaccine based on hepatitis B core gene in rhesus monkeys

INTRODUCTIONHepatitis B virus (HBV) is the most commonetiologic agent for infectious liver diseases. It isestimated that there are more than 250 millionchronic HBV carriersin the world today and thereis a significant association among persistentinfection, liver cirrhosis and hepatocellularcarcinoma[1-3].

IL-28B、IFNL4基因多态性与慢性丙型肝炎患者聚乙二醇干扰素联合利巴韦林抗病毒疗效相关性的研究

丙型肝炎病毒（HCV）感染是导致肝硬化和肝细胞癌的主要原因，有效的抗病毒治疗能延缓病情进展，降低肝硬化及肝细胞癌的发生率。直接抗病毒药物（DAAs）治疗方案大大提高了丙型肝炎的持续病毒学应答率（SVR），使难治的HCV-1基因型慢性丙型肝炎（CHC）患者的SVR率提高到80％以上，同时疗程缩短，不良反应减少。

T helper cells in patients with chronic hepatitis B virus infection

OBJECTIVE: To investigate the compositions of Th1/Th2/Th3 cells in chronic hepatitis B virus (HBV)-infected individuals by determining the expression of interleukin-4 (IL-4), inetrferon-gamma (IFN-gamma), and transform growth factor-beta (TGF-beta) in single CD4(+) T cells isolated from peripheral blood mononuclear cells (PBMCs) and the role of polarized Th cell populations in chronic HBV-infection was discussed. METHODS: PBMCs from chronically infected HBV individuals were isolated, stimulated by PMA/Ionomycin/Monensin, and IL-4, IFN-gamma and TGF-beta production by CD4(+) T cells was determined by using fluorescence activated cell sorter (FACS) analysis. RESULTS: The percentage of IFN-gamma-producing T cells, IL-4-producing T cells and TGF-beta-producing T cells ranged from 2.3% - 18.6%, 1.1% - 8.7% and 0.7% - 7.1% respectively in CD4(+) T cells from non-infected individuals. Most of CD4(+) T cells from PBMCs in chronically infected HBV individuals were Th0 cells. The proportion of Th1 cells increased significantly with hepatic inflammatory activity, and in the active period of chronic hepatitis B infection were higher than those in the non-active period (P 0.05), but were higher than that from controls (P

大叶铁线莲乙醇提取物正丁醇部位的化学成分研究

目的研究大叶铁线莲Clematis heracleifolia全草的化学成分。方法利用硅胶、Sephadex LH-20凝胶、ODS反相柱色谱和半制备高效液相色谱等分离方法进行分离纯化,结合核磁共振、质谱等波谱学技术鉴定其化学结构。结果从大叶铁线莲全草75%乙醇提取物的正丁醇萃取部位分离鉴定了10个化合物,包括三萜皂苷6个、黄酮苷1个、木栓烷型三萜2个和植物甾醇1个,分别为3,23-二羟基-齐墩果-18-烯-28-酸-O-α-L-吡喃鼠李糖基-(1→4)-β-D-吡喃葡萄糖基-(1→6)-β-D-吡喃葡萄糖苷(1)、刺楸皂苷B(2)、粗齿铁线莲皂苷B(3)、刺五加苷A1(4)、皂苷PJ3(5)、异株五加苷B(6)、金丝桃苷(7)、木栓酮(8)、表木栓醇(9)和β-谷甾醇(10)。结论化合物1是新化合物,命名为大叶铁线莲皂苷D;化合物2~9均为首次从大叶铁线莲中分离得到。