DCA is formed after bacterial 7 alpha dehydroxylation of CA in the colon and is a potent natural TGR5 agonist20, 21 and a ligand activating FXR.22-24 Using mouse 3T3 cells as adipocytes, the authors could further demonstrate

that both TGR5 and FXR activation was able to induce adiponectin expression. However, it must be kept in mind that the presence of FXR in adipose tissue may be questionable25 and that in addition to adipocytes also inflammatory cells could significantly contribute to TGR5 expression within fat.21 Since TGR5 and FXR have different affinities FK506 mouse for DCA, the absolute serum concentrations would have been of interest in order to estimate which receptor may be most likely involved. Moreover, the possibility to activate TGR5 and FXR in vivo by specific ligands

and using specific knockout mice should help to decipher in the near future which receptor plays a key role in regulation of adiponectin expression. Whether such agonists regulate adiponectin in humans could be addressed in ongoing and future clinical trials with FXR and TGR5 activators. On the other hand, it is important to consider that high adiponectin levels are associated with increased cardiovascular mortality despite improved inflammatory, atherogenic, and insulin-sensitizing effects,26 which might result from adiponectin selleck chemicals llc resistance.27 It is known that DCA represses

endogenous BA synthesis MCE公司 by way of Cyp7a1, but without suppressing cholesterol synthesis, in contrast to CDCA.28 Increased hepatic cholesterol synthesis promotes progression of NAFLD.29 Therefore, a DCA increase in patients with advanced burnt-out NASH might also contribute to deterioration of the liver condition by failing to repress the endogenous cholesterol synthesis (Fig. 1). In addition, a high fat diet is known to increase DCA levels in mouse, which in turn increases the intestinal permeability and thus propagates inflammation.30 It is therefore possible that a fat-enriched diet in human favors ectopic fat storage in the liver and DCA formation, which then keeps endogenous cholesterol synthesis at a high level and promotes intestinal leakage by enhancing bacterial translocation promoting inflammation and fatty liver development. The identification of DCA as an important BA in NASH patients in the current study could also indicate a potential role of the gut flora. In the gut, FXR maintains epithelial barrier integrity by induction of multiple genes involved in intestinal mucosal defense against inflammation and microbes, which, together with direct antibacterial detergent actions, help to control the gut microbiota.

77 in Child-Pugh class A, B, and C, respectively), suggesting that this allele may also play a role in determining prognosis and clinical outcome. The rare variant rs6006460(T) reported by Romeo et al.9 was detected in both cirrhotic and control groups, but the very low frequency (0.0002) meant the study had insufficient power to detect any association with disease. No association was observed with any SNPs previously reported to be associated with hepatitis C–related cirrhosis. The authors conclude that their study, taken together with evidence from other studies, supports the view that rs738409 is an independent risk factor for liver dysfunction in fatty liver diseases. Indeed, recent

data from Day’s group, using a real-time fluorescent allele-specific system (K-Biosciences, Essex, UK), replicate these findings in a UK cohort to provide further evidence of rs738409(G) association with ALD (Table 1; C.P. Day et al., unpublished data). From what is known of the function selleck screening library of adiponutrin, Lenvatinib these data strongly suggest that altered lipid processing plays a key role in the pathogenesis of progressive liver disease and provide further support for common pathogenic pathways in ALD and NAFLD. Clearly understanding the function of adiponutrin and its role in the

pathogenesis of advanced fatty liver diseases is now the focus of considerable attention because this may lead to therapeutic advances for these common liver diseases for which there are currently no effective treatments available. For now, PNPLA3 genotyping offers the potential to identify individuals at increased risk of developing ALD and NAFLD providing the opportunity 上海皓元 for targeted interventions. “
“Astrocyte elevated gene-1 (AEG-1) and c-Myc are overexpressed in human hepatocellular carcinoma (HCC) functioning as oncogenes. AEG-1 is transcriptionally regulated by c-Myc and AEG-1 itself induces c-Myc by activating Wnt/β-catenin signaling pathway. We now document cooperation of AEG-1 and c-Myc in promoting hepatocarcinogenesis by analyzing hepatocyte-specific transgenic mice expressing either AEG-1 (Alb/AEG-1), c-Myc (Alb/c-Myc) or both (Alb/AEG-1/c-Myc). WT and Alb/AEG-1 mice did not

develop spontaneous HCC. Alb/c-Myc mice developed spontaneous HCC without distant metastasis while Alb/AEG-1/c-Myc mice developed highly aggressive HCC with frank metastasis to the lungs. Induction of carcinogenesis by N-nitrosodiethylamine (DEN) significantly accelerated the kinetics of tumor formation in all groups. However, in Alb/AEG-1/c-Myc the effect was markedly pronounced with lung metastasis. In vitro analysis showed that Alb/AEG-1/c-Myc hepatocytes acquired increased proliferation and transformative potential with sustained activation of pro-survival and epithelial-mesenchymal transition (EMT) signaling pathways. RNA-sequencing analysis identified a unique gene signature in livers of Alb/AEG-1/c-Myc mice that was not observed when either AEG-1 or c-Myc was overexpressed.

Number of TIPS revision was predictive of complete response

at 12 months (OR 0.7, 95% CI 0.5-0.9, p<0.05). Age (HR=1.05 [95% CI 1.02-1.08], p<0.01), complete response (HR=0.22 [95% CI 0.12-0.40], p<0.0001) and PTFE stents (HR=0.23 [95% CI 0.05–0.97], p<0.05) were predictive of survival. TIPS is an effective treatment for cirrhotic refractory ascites. Ascites clearance is dependent on number of TIPS revision, while survival is predicted by younger age, complete response and covered Pexidartinib clinical trial stent use, although era-effect likely contributed to improved survival with covered stent use. “
“Notch signaling and hepatocyte nuclear factor-6 (HNF-6) are two genetic factors known to affect lineage commitment in the bipotential hepatoblast progenitor cell (BHPC) population. A genetic interaction involving Notch signaling and HNF-6 in mice has been inferred through separate experiments showing that both affect BHPC specification and bile duct morphogenesis. To define the genetic interaction between HNF-6 and Notch signaling in an in vivo mouse model, we examined the effects of BHPC-specific loss of HNF-6 alone and within

the background of BHPC-specific loss of recombination signal binding protein immunoglobulin kappa J (RBP-J), the common DNA-binding partner of all Notch receptors. Isolated loss of HNF-6 in this mouse model fails to demonstrate a phenotypic variance in bile duct development compared to MCE control. However, when HNF-6 loss is combined with RBP-J loss, a phenotype consisting of selleck chemicals llc cholestasis, hepatic necrosis, and fibrosis is observed that is more severe than the

phenotype seen with Notch signaling loss alone. This phenotype is associated with significant intrahepatic biliary system abnormalities, including an early decrease in biliary epithelial cells, evolving to ductular proliferation and a decrease in the density of communicating peripheral bile duct branches. In this in vivo model, simultaneous loss of both HNF-6 and RBP-J results in down-regulation of both HNF-1β and Sox9 (sex determining region Y–related HMG box transcription factor 9). Conclusion: HNF-6 and Notch signaling interact in vivo to control expression of downstream mediators essential to the normal development of the intrahepatic biliary system. This study provides a model to investigate genetic interactions of factors important to intrahepatic bile duct development and their effect on cholestatic liver disease phenotypes. (HEPATOLOGY 2012;55:232–242) Notch signaling is an intercellular signaling pathway required throughout embryonic development and adulthood for cell specification, lineage commitment, and maintenance of progenitor cells.1 In mammals, the canonical Notch pathway includes four receptors (Notch 1 [N1], N2, N3, N4) and two families of ligands (Jagged and Delta-like).

Culture medium virion DNA was quantified by Real-time PCR assay. Results: E77K/R, D78K/R mutations fully abolished the capsid formation, viral pregenomic RNA encapsidation and DNA replication, while E77K/A, D78K/A mutations formed large aggregates with discount function still supporting replication. In addition, E77K/R, D78K/R core protein mutants were able to interact with wild type HBV core protein monomers, induced irregular core protein aggregates formation and block the correct capsid assembly, HBV replication signaling pathway and progeny virus production were also inhibited. Conclusions: HBV core protein acidic amimo acids E77K, D78 were critical

for HBV core protein interplay and capsid formation. Changing the charge round the region disrupts core protein assembly and function. Our work provides a new angle and framework selleck screening library for further exploring the novel antiviral

strategy. Disclosures: Lai Wei – Advisory Committees or Review Panels: Gilead, AbbVie; Consulting: Gilead; Grant/Research Support: BMS, Roche, Novartis The following people have nothing to disclose: Kai Deng, Dong Jiang Background: Chronic hepatitis B virus (HBV) infection causes liver cirrhosis and hepatocellular carcinoma. Host autoimmune reactions against the virus and infected cells as well as direct cytotoxic effects of viral components contribute to liver injury. The accumulation of the large HBV surface protein (LHBs) in the endoplasmic reticulum (ER) of hepatocytes leads to ER stress. Severely affected cells finally undergo apoptosis or

transform into tumor cells. In this work we show that cytokeratins (CK) are responsible for the intracellular distribution of LHBs. Methods: DNA sequences of LHBs and the small surface protein of HBV (SHBs) were cloned separately into lentiviral vectors. The human hepatoma cell line Huh7 and the untransformed mouse fibroblast cell line NIH3T3 were stably transduced using these vectors. HBs expressing cells were treated with the phospha-tase inhibitor okadaic acid (Oka) and the microtubule (MT) and microfilament (MF) disrupting substances nocodazole and cytochalasin D, respectively. Furthermore immunofluorescence staining, confocal microscopy, proximity ligation assay (PLA) 上海皓元医药股份有限公司 and surface-plasmon resonance (SPR) were performed. We also analysed the effects of Oka on HBsAg secretion in a separate HBV infection and secretion experiment on primary hepatocytes from Tupaia belangeri (PTHs). Results: Whereas the accumulation of SHBs in both cell lines was finely distributed within the cells, the expression of LHBs in NIH3T3 led to formation of large intracellular aggregates of LHBs protein. In contrast, LHBs was finely distributed within Huh7. Treatment with Oka caused a breakdown of the LHBs together with the CK filament network followed by formation of perinuclear aggregates of CK8/18 together with LHBs.

6% [47/63] this website vs 75.0% [24/32]). Of the 65 patients who initially received 2250 mg/day TVR, 41 were IL28B TT, 21 were IL28B non-TT and three were

undetermined. RVR (83.3% [20/24] vs 80.0% [12/15], P > 0.999) and SVR12 (81.8% [18/22] vs 94.1% [16/16], P = 0.363) rates were similar in IL28B TT patients with low and high IP-10. In contrast, the RVR rate was significantly higher in IL28B non-TT patients with low than high IP-10 (88.9% [8/9] vs 33.3% [4/12], P = 0.024), whereas SVR12 rate in patients with IL28B non-TT and low IP-10 was not significantly higher than that in patients with IL28B non-TT and high IP-10 (66.7% [6/9] vs 33.3% [4/12], P = 0.198). Of the 32 patients who initially received 1500 mg/day TVR, 26 were IL28B TT and six were IL28B non-TT. In terms of RVR and SVR12 rates, the difference between patients with IL28B

TT and low IP-10 and those with IL28B TT and high IP-10 was not significant (RVR, 100% [11/11] vs 71.4% [10/14], P = 0.105; SVR12, 91.7% [11/12] vs 71.4% [10/14], P = 0.330). Because of the small sample size (n = 6), we did not perform subgroup analyses of patients with IL28B non-TT. To our knowledge, few studies have examined the effects of pretreatment serum IP-10 concentration on virological responses in genotype 1 CHC patients treated with TVR-based triple therapy.[27] Baseline IP-10 has been found predictive of treatment outcomes in HCV genotype 1-infected patients treated with PEG IFN and RBV.[17, 18, 25] IL28B SNP has also been associated with virological responses to antiviral treatment in HCV-infected patients.[12, 13] However, PD0325901 mw currently, data on combining these predictors in patients

with genotype 1 HCV infection treated with TVR-based triple therapy are limited; hence, the reason for the current study. Our multivariate analyses showed that pretreatment serum IP-10 concentration was a significant predictor of 上海皓元医药股份有限公司 RVR, but not of SVR12. In patients with the IL28B risk allele, the RVR rate was significantly higher in those with low than high IP-10 concentrations. The SVR12 rate also tended to be higher in the former subgroup, although the difference did not reach statistical significance, probably due to the small sample size. Similar results were observed in patients receiving initial TVR doses of 1500 and 2250 mg/day per protocol. These results suggest that, in patients with HCV genotype 1 treated with TVR-based triple therapy, baseline IP-10 level is useful for predicting virological response, especially in those with the IL28B risk allele who are considered difficult to treat. We found that pretreatment serum IP-10 differed significantly (P = 0.001) in patients who did and did not achieve RVR. Low systemic IP-10 was found to predict a favorable first-phase decline in HCV RNA and RVR during treatment with PEG IFN and RBV.

47, 48 What other aspects of autoantibody development are revealed in this study? The finding of crossreactivity being greater with IgM than IgG antibodies is consistent with the general properties of IgM that tend to be lower affinity.49 The likely scenario is that the xenobiotic-modified

self-protein (in this case SAc-conjugated proteins) induces IgM antibody production that is originally specific for xenobiotic-modified self-protein. Second, due to the www.selleckchem.com/products/Trichostatin-A.html close structural similarity between xenobiotic-modified self-protein and native self-protein, the immune system of genetically susceptible individuals starts to generate IgM antibodies that are crossreactive or specific to native self-protein (in this case PDC-E2) through affinity maturation and epitope spreading mechanisms. Third, at the same time with affinity maturation, isotype switching occurs and this process

generates IgG antibodies that are more specific to native self-protein (PDC-E2) than xenobiotic-modified self-protein (SAc-conjugated proteins), which may have by that time disappeared. Thus, IgG antibodies mainly show the reactivity against native self-protein and demonstrate very low reactivity against the xenobiotics. Fourth, the affinity maturation with repeated exposure of the native self-protein continues to increase the affinity of IgM and IgG antibodies against VX-809 in vitro the native self-protein. Eventually, some clones of these IgM and IgG antibodies become highly specific for only native self-protein with diminished reactivity against modified self-protein.

Due to the high affinity of these clones compared to the crossreactive clones, most rPDC-E2-purified antibodies obtained in our experiment could only bind to rPDC-E2, but not SAc-conjugated proteins. This phenomenon can also explain the results of our inhibition ELISA experiments and why the SAc-conjugated protein absorption could not inhibit MCE the serum reactivity to rPDC-E2 in both AMA populations. Patient AMAs may be categorized on the basis of two distinct profiles of crossreactivity such that PDC-E2 absorption either removes or leaves anti-SAc antibodies present in PBC sera. This may relate to the degree of polyclonality of the sera and perhaps to levels of IgM, which are known generally of lower specificity. Whether this reflects two mechanisms by which autoantibodies are induced or different subsequent histories is unknown. It should be noted that crossreactivity is being detected many years after the initiating event and the time at which tolerance is broken. Thus, it may be that the crossreactivity is more readily detected early in the course of disease and that it disappears later. It would be of interest to perform a correlative study in which patient parameters such as duration of disease, age of diagnosis, severity, IgM levels, and rate of progression are correlated with the type of crossreactivity pattern present in sera.

In our HCC cohort, BCL9 was located in the amplification peak at 1q21.1,

which is highly amplified in 8.7% of HCCs (Table 2 and Supporting Table 3). There was a significant correlation between its somatic copy number and gene expression in primary HCCs (Fig. 2A), and protein expression measured by immunohistochemical (IHC) staining (Supporting Materials; Supporting Fig. 5A) correlated well with mRNA expression (Fig. 2B; Supporting Table 7). Transient transfection of siRNA SMARTpool for BCL9 significantly RXDX-106 mw reduced gene expression of BCL9 in all four cell lines tested (Fig. 2C,D) and significantly decreased cell growth and survival in both proliferation assays (Fig. 2E) and colony formation assays (CFAs) (Fig. 2F) in MHCC97H and MHCC97L, the two

cell lines with BCL9 gene amplification (Supporting Fig. 6). By contrast, siRNA-mediated inhibition of BCL9 gene expression had minimal effect on the SK-HEP-1 cell line, which is copy number neutral for BCL9, although the other BCL9 copy-number–neutral cell line (HUH6) showed significant growth inhibition GS1101 upon BCL9 knockdown, suggesting that mechanisms other than BCL9 amplification may confer dependence on BCL9 expression. Our analysis also identified a peak at 8q22.1 containing a single gene (MTDH), which encodes metadherin. MTDH has been implicated as an oncogene in a number of cancer types, including HCC.[19] However, previous work in HCC has not yet established the dependency of MTDH-driven tumorigenesis on MTDH focal amplification, especially in relevant preclinical models that harbor the MTDH amplification. In our study, MTDH was highly amplified in 12.9% of HCCs (Table 2 and Supporting Table 3). There was a significant cis-correlation between somatic

copy number and mRNA expression of MTDH in primary HCCs (Fig. 3A), and protein expression by IHC (Supporting Fig. 5B) correlated well with mRNA expression (Fig. 3B; and Supporting Table 8). We further identified MCE two HCC models (MHCC97H and SNU-398) with amplification of the MTDH locus (Supporting Fig. 6). Transient transfection of siRNA SMARTpool for MTDH significantly reduced the gene expression levels of MTDH in all four cell lines tested (Fig. 3C,D). In the two MTDH amplified HCC models, siRNA-mediated inhibition of MTDH gene expression significantly decreased cell growth and survival in both proliferation assays (Fig. 3E) and CFAs (Fig. 3F), whereas knockdown had a less-prominent effect on the two MTDH copy-number–neutral lines (L-02 and SMMC-7721). Our study represents one of the most comprehensive characterizations of the genomic landscape in a large primary HCC cohort and models.

For the analysis, an inhibitor was defined as a current or history of an inhibitor ≥1 Bethesda unit (BU). The procedures followed were in accordance Belinostat with the ethical standards of the responsible committees on human experimentation for all three cohorts and with the Helsinki Declaration. The MIBS and HIGS

are registered at ClinicalTrials.gov. To determine factor VIII haplotypes, four non-synonymous SNPs on the F8 gene, G1679A, A2554G, C3951G and A6940G, were genotyped using the Assay-on-Demand from Applied Biosystems standard protocols (www.AppliedBiosystems.com). Haplotypes were constructed using the four markers that were genotyped. Because the population was almost exclusively male (99.9%), all but one individual was hemizygous, as all markers are located on the X chromosome. Typing was completed for all but 7.1% of the markers. An EM algorithm [11, 12] was used to infer haplotypes for individuals with missing information. Individuals with missing Dinaciclib cost genotypes were assigned the haplotype that demonstrated the highest posterior probability. One of the 833 study participants was not haplotyped, reducing the analysis sample to 832. Approximately 96% of the participants in the HIGS Combined Cohort were F8 mutation typed. The remaining 4% of subjects were not typed for either technical reasons or lack of sufficient DNA. For HIGS and MIBS, if the F8 gene mutation was

not already documented at enrolment, a blood sample was sent for determination to the Institute of Experimental Haematology and Transfusion Medicine, Bonn, Germany. Standard methods for the analyses of the F8 gene were used [13]. In HGDS, the presence or absence of an inversion mutation in the F8 gene was determined for 58% of the HGDS cohort [14]. The remaining HGDS samples were mutation typed at the

Institute of Experimental Haematology and Transfusion Medicine, Bonn, Germany by the methods outlined above. Class II HLA genotyping was performed using high-resolution (4-digit) sequence based typing (SBT) protocols recommended by the 13th International Histocompatibility Workshop [15]. Typing was completed for 99.9% of the Combined Cohort. The recombinant FVIII replacement products included MCE公司 in the current analysis were as follow: Recombinate, antihaemophilic factor concentrate manufactured by Baxter Healthcare Corporation (Westlake Village, CA, USA) [16, 17], derived from H2 proteins; Advate, antihaemophilic factor produced by a plasma- and albumin-free method, manufactured by Baxter Healthcare Corporation [18], also derived from H2 proteins; and Kogenate, antihaemophilic factor manufactured by Bayer HealthCare Pharmaceuticals (Berkeley, CA, USA) [19], derived from H1 proteins. Association tests, including Fisher’s exact test, were carried out using two by two tables to evaluate the probability of inhibitor occurrence. Generalized estimating equations (GEE) models were used to account for the relatedness of participants.

[3H]acetate labeling showed fatty acids are synthesized in the cytosol, with little incorporation in chloroplasts, consistent with a Type I FAS system. However, although 29 sequences

in a K. brevis expressed sequence tag database have similarity (BLASTx e-value <10−10) to PKSs, no transcripts for either Type I (cytosolic) or Type II (chloroplast) FAS are present. Further characterization of the FAS complexes may help to elucidate the functions of the Selleck Enzalutamide PKS enzymes identified in dinoflagellates. “
“Prymnesium parvum blooms have become more frequent in the south-central United States, leading to significant ecological and economic impacts. Allelopathic effects from cyanobacteria were suggested as a mechanism that might limit the development of P. parvum blooms. This research focused on the effects of cultured cyanobacteria, Anabaena sp., on P. parvum. Over a 6-d period, daily additions of filtrate from the senescent Anabaena culture were made to P. parvum cultures growing in log phase. All treatments, including several types of controls, showed reductions in P. parvum biomass over the course of the experiment, but the treatments receiving Anabaena filtrate were reduced to a lesser degree, suggesting

that filtrate from the senescent cyanobacteria culture was beneficial to P. parvum in some way. This unexpected outcome may have resulted from stimulation of heterotrophic bacteria by the addition of Anabaena filtrate, which likely contained exudates rich in dissolved organic carbon compounds. P. parvum click here was then able to supplement its nutritional requirements for growth by feeding on the elevated bacteria population. These findings coupled MCE公司 to previous observations suggest that interactions between cyanobacteria and P. parvum in natural environments are complex, where both allelopathic and growth-stimulating interactions are possible. “
“The red seaweed Gracilariopsis is an important

crop extensively cultivated in China for high-quality raw agar. In the cultivation site at Nanao Island, Shantou, China, G. lemaneiformis experiences high variability in environmental conditions like seawater temperature. In this study, G. lemaneiformis was cultured at 12, 19, or 26°C for 3 weeks, to examine its photosynthetic acclimation to changing temperature. Growth rates were highest in G. lemaneiformis thalli grown at 19°C, and were reduced with either decreased or increased temperature. The irradiance-saturated rate of photosynthesis (Pmax) decreased with decreasing temperature, but increased significantly with prolonged cultivation at lower temperatures, indicating the potential for photosynthesis acclimation to lower temperature. Moreover, Pmax increased with increasing temperature (~30 μmol O2 · g−1FW · h−1 at 12°C to 70 μmol O2 · g−1FW · h−1 at 26°C).

, Santa Monica, CA). An ELISPOT response was considered positive if the number of spots in the HBV antigen-stimulated cultures exceeded that of the HCV antigen control by 5. This cut-off value was set as the mean plus 2 standard deviations of the number of spots in cultures without antigen stimulation.[17] To test the role of IL-21 in Ab production, rIL-21R-Fc (10 μg/mL) or rIL-21 (50 ng/mL) was included in the culture in some cases as described. The concentration of IL-21 was quantitated in duplicate wells using a commercial human

IL-21 ELISA kit (Bender MedSystems GmbH, Vienna, Austria) in accord with the manufacturer’s instructions. Fresh PBMCs (1 × 106 cells/mL) were labeled with carboxyfluorescein succinimidyl ester SCH727965 price (CFSE; 1.5 µM; Molecular Probes, Eugene, OR) and resuspended at 106 cells/mL in the RAD001 medium; labeled cells were cultured with rHBeAg, rHBcAg, or rHCV (5 μg/mL) for 7 days or with medium only as a negative control. At the end of culture, cells were harvested and stained with α-CD4/allophycocyanin and α-CXCR5/PerCP-Cy5.5. The proliferation rate of CXCR5+CD4+ T cells was expressed

as the percentage of cells that diluted CFSE intensity at least once at time of harvest.[18, 19] Data are expressed as median (range). Mann-Whitney’s U test, Wilcoxcon’s signed-rank test, and the chi-square test were used when two groups were compared. Kruskal-Wallis’s H test was used when more than two groups were compared. A receiver MCE operating characteristic (ROC) curve was constructed to identify the optimal cut-off value for predicting

HBeAg seroconversion to treatment. Correlations between variables were assessed with Spearman’s rank-order correlation coefficient. All statistical analyses were based on a two-tailed hypothesis test with a significance level of P < 0.05. To find out whether chronic HBV infection could drive CXCR5+CD4+ T-cell differentiation, frequencies of circulating CXCR5+CD4+ T cells in CD4+ T cells were measured in patients with chronic HBV infection and HCs (Fig. 1A; Supporting Table 1). A significantly higher frequency of CXCR5+CD4+ T cells was observed in patients with chronic HBV infection, relative to the HC group (15.58 [6.61-28.87] versus 11.97 [7.63-16.62]%; P < 0.001; Fig. 1B). To illustrate the presence of HBV-specific cells in the overall increased CXCR5+CD4+ T-cell population in chronic HBV infection, we examined IL-21 production by these cells in response to HBV peptide stimulation. Although only a small fraction of CXCR5+CD4+ T cells could secrete IL-21, their representation was significantly higher in the chronic HBV infection group than that in the HC group (0.79 [0.00-3.42] versus 0.00 [0.00-0.38]%; P < 0.001; Fig. 1C). Likewise, a small, but definite, fraction of CXCR5+CD4+ T cells from chronic HBV infection patients proliferated in the presence of either rHBeAg or rHBcAg, relative to negative controls (P < 0.001; Fig. 1D).