Abstract Background Complete clearance of intracellular viruses depends on effector cells of innate and adaptive immune system. This study aimed to identify the relationship between antiviral cytokines produced by natural killer (NK) and T cells and clinical-virological characteristics in untreated chronic hepatitis B (CHB) patients. Methods We measured antiviral cytokines interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-2 (IL-2) produced by T, NK and natural killer T (NKT) cells in a cohort of chronic hepatitis B virus (HBV) infection (CHB). We also correlated these cytokines with clinical-virological characteristics using a linear regression model. Results IFN-γ+ and TNF-α+ by CD4+ and CD8+ T cells were significantly higher in immune active (IA) than other phases. Immune tolerant (IT) patients showed the least expression of IFN-γ+ by NK and NKT cells, and TNF-α+ by NK cells. IFN-γ+, TNF-α+ and IL-2+ by CD4+ and CD8+ T cells were comparable between IA and gray zones (GZ) phases. Principal component analysis based on cytokines confirmed that most IT patients significantly differ from inactive carriers (IC) and IA patients, while GZ patients were widely scattered. Multivariate analysis showed both T and NK cells producing IFN-γ+ and TNF-α+, but not IL-2+, had significant association with serum alanine aminotransferase (ALT). Moreover, IFN-γ+ by NKT cells was associated with HBV DNA, while IFN-γ+ by CD4+ and CD8+ T cells had correlation with age. Conclusion HBV clinical phases are characterized by distinct cytokines signatures, which showed little relationship to viral features at a single time point in these untreated CHB patients.
Background. Anillin (ANLN), a ubiquitously expressed actin-binding protein, plays a critical tumor-promoting role in cell growth, migration, and cytokinesis. Numerous studies have suggested that ANLN is upregulated in many cancer types, as well as significantly associated with patient prognosis and malignant cancer characteristics. Herein, we performed an integrated pan-cancer analysis of ANLN and highlighted its underlying mechanism, which may benefit further exploration of the potential therapeutic options for cancer. Methods. ANLN expression data were extracted from online databases, including TCGA, GTEx, and CCLE databases. The TIMER database was used to study the association between ANLN expression with immune checkpoint genes and immunocyte infiltration. The ScanNeo pipeline was adopted for neoantigen discovery. KEGG analysis and the STRING tool were used to elucidate the potential mechanism of ANLN in cancer development. Results. ANLN is abnormally overexpressed in almost all cancer tissues compared with normal tissues. The high-ANLN expression level was positively associated with various malignant characteristics, suggesting its potential role in the immune microenvironment and poor prognosis. In addition, ANLN expression was correlated with the number of neoantigens and different phosphorylation pattern in various cancer types, revealing a functional role of genetic mutation accumulation and high phosphorylation in ANLN-mediated oncogenesis. Moreover, we found that ANLN was an important regulatory factor participating in many signaling events, especially the cell cycle and nucleocytoplasmic transport pathways. Conclusions. ANLN expression is generally overexpressed in various types of cancers, and it may have an important influence on tumor progression and development. ANLN expression is significantly associated with the immune checkpoint biomarkers and tumor immunity. Together, these findings suggest that ANLN may be a predictive marker for patient prognosis across cancers.
We generated an Immuno-Clinic score (ICS) model to evaluate T cell immunity based on the clustering of antiviral cytokines and inhibitory molecules in 229 naïve chronic hepatitis B (CHB) patients. 126 patients receiving antiviral therapy were used to validate the model for predicting antiviral therapy effectiveness. Through receiver-operator characteristic curve analysis, the area under the curve, sensitivity, and specificity of the ICS model were 0.801 (95%CI 0.703-0.900), 0.727, and 0.722, respectively. The cut-off value was 0.442. Re-evaluation of T cell immunity in different phases of CHB showed that patients in the immune tolerant phase had the lowest percentage of ICS-high (15%), while patients in the inactive carrier phase had the highest percentage of ICS-high (92%). Patients in the immune active and gray zone phases had 17% and 56% ICS-high, respectively. Elevation of ICS as early as four weeks after treatment could predict the effectiveness of hepatitis B virus (HBV) DNA loss and normalization of alanine aminotransferase, while eight weeks after treatment could predict HBV surface antigen decline. Thus, this ICS model helps clinicians choose an optimal time for initiating antiviral therapy and predicting its efficacy.
Abstract Background Complete clearance of intracellular viruses depends on effector cells of innate and adaptive immune system. This study aimed to identify the relationship between antiviral cytokines produced by natural killer (NK) and T cells and clinical-virological characteristics in untreated chronic hepatitis B (CHB) patients. Methods We measured antiviral cytokines interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-2 (IL-2) produced by T, NK and natural killer T (NKT) cells in a cohort of chronic hepatitis B virus (HBV) infection (CHB). We also correlated these cytokines with clinical-virological characteristics using a linear regression model. Results IFN-γ+ and TNF-α+ by CD4+ and CD8+ T cells were significantly higher in immune active (IA) than other phases. Immune tolerant (IT) patients showed the least expression of IFN-γ+ by NK and NKT cells, and TNF-α+ by NK cells. IFN-γ+, TNF-α+ and IL-2+ by CD4+ and CD8+ T cells were comparable between IA and gray zones (GZ) phases. Principal component analysis based on cytokines confirmed that most IT patients significantly differ from inactive carriers (IC) and IA patients, while GZ patients were widely scattered. Multivariate analysis showed both T and NK cells producing IFN-γ+ and TNF-α+, but not IL-2+, had significant association with serum alanine aminotransferase (ALT). Moreover, IFN-γ+ by NKT cells was associated with HBV DNA, while IFN-γ+ by CD4+ and CD8+ T cells had correlation with age. Conclusion HBV clinical phases are characterized by distinct cytokines signatures, which showed little relationship to viral features at a single time point in these untreated CHB patients.
Abstract Background and Aim Hepatitis B virus (HBV) load and antigens are related to the innate and adaptive immunity of chronic hepatitis B (CHB) patients. As a new HBV biomarker, the role of pregenomic RNA (pgRNA) in host immunity is not known. This study aimed to identify the relationship between serum HBV pgRNA and host immunity in CHB patients. Methods Two hundred twenty‐five treatment‐naïve CHB patients were enrolled. Serum cytokines were measured by cytokine antibody array (Luminex multiplex platform). Th1 (T‐helper cell, Th) and Th2 cells were tested by flow cytometry. Serum HBV pgRNA was detected by a reverse transcription‐polymerase chain reaction. Results Serum HBV pgRNA was significantly different among patients in different disease phases and significantly associated with both HBV antigens and antibodies. Serum HBV pgRNA was positively correlated with the HBsAg level ( P < .001) and the presence of HBeAg ( P < .001). Patients with higher HBcAb levels showed lower serum HBV pgRNA levels ( P = .003). Notably, HBsAb positivity was associated with higher levels of serum HBV pgRNA in HBeAg(−) patients ( P = .049). Serum HBV pgRNA was positively associated with ALT level, Th2 cell frequency, and related cytokine sCD30 ( P < .001, P < .001, and P = .003, respectively), but negatively associated with Th1‐related cytokine interleukin (IL)‐12P70 and cytotoxic lymphocytes (CTLs) ( P = .017 and P < .001, respectively). Conclusion Our study confirmed the relationship between serum HBV pgRNA and host immunity. The results demonstrated that serum HBV pgRNA is positively correlated with Th2 immunity but negatively correlated with Th1 immunity, indicating that it might have a relationship with HBV antigen conversion and CTL immunodeficiency in CHB patients.
Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is an inhibitory receptor that is expressed on the surface of multiple immune cells and plays key roles in immune modulation. In patients with chronic hepatitis B (CHB), T cell number and functions are abnormal and the expression of inhibitory receptors is elevated. However, the expression of LAIR-1 on T cells in patients with CHB is still undetermined.We recruited 320 patients with CHB in different disease phases and 17 healthy donors. Serum biochemical and virological examinations were performed for each participant, and their demographic and clinical data were collected. According to the latest American Association for the Study of Liver Disease guidelines, we categorized the patients into 4 groups: immune active, immune tolerant, inactive CHB, and gray zone. Additionally, we tested the expression of LAIR-1 on T cells and T cell subsets using flow cytometry.We observed a significant decrease in LAIR-1 expression on CD3+ T cells and its two subsets (CD4+ and CD8+ T cells) in patients with CHB. LAIR-1 expression on T cells was the lowest in the immune active group. LAIR-1 expression levels on CD4+ and CD8+ T cells showed a significant negative association with hepatitis B virus (HBV) DNA load and were lower in hepatitis B e antigen (HBeAg)-positive patients than in HBeAg-negative patients (P < .05). In addition, LAIR-1 expression levels on CD3+, CD4+, and CD8+ T cells were all negatively associated with liver inflammation and fibrosis parameters, such as alanine aminotransferase and aspartate aminotransferase levels, FibroScan value, and aspartate aminotransferase-to-platelet ratio index score.LAIR-1 expression levels on T cells were associated with HBV DNA load and liver inflammation and fibrosis parameters, indicating that LAIR-1 may play an important regulatory role in HBV-induced T cell immune pathogenesis and may be a therapeutic target for CHB.
Dendritic cells are the most potent antigen-presenting cells in immune therapeutic approaches for chronic hepatitis B (CHB) infection. Here, we developed a clinical trial to evaluate the efficacy and safety of autologous HBV vaccine-pulsed DCs and their induced T cells (HPDCT) in CHB patients. This was a randomised, prospective, open-label, multicentre, superiority study and 309 treatment-naive CHB patients were divided into HPDCT plus nucleos(t)ide analogues (NAs) group (n = 84), NAs mono-therapy group (n = 82), HPDCT plus Peg-interferon (Peg-IFN) group (n = 69), Peg-IFN mono-therapy group (n = 74). Twelve times of HPDCT vaccinations were given intravenously, and all the patients were followed up for 72 weeks. In total, 1836 HPDCT infusions were administered with no obvious toxicity and side effect although few patients had self-limited low fever. More patients got HBsAg loss in those receiving HPDCT therapy. Patients of HPDCT plus Peg-IFN group with HBV DNA < 1 × 107 IU/mL at baseline exhibited earlier, stronger and longer lasting of viral response, especially HBV DNA < 20 IU/mL, than those patients of Peg-IFN mono-therapy group, from week 24 till week 72 (p < 0.05). Comparable efficacy was observed between the patients of HPDCT plus NAs group and NAs mono-therapy groups. In addition, CD25 on CD8+ T cells and HBV-specific CD8+ T cell increased significantly in patients of HPDCT combined antiviral drugs therapy. HPDCT combined with antiviral drugs was safe and able to enhance T cell immunity. Furthermore, HPDCT combined with Peg-IFN could provide an incremental benefit to patients with baseline levels of lower HBV DNA. Trial Registration: ClinicalTrials.gov identifier: NCT01935635.
Background: Immune response mediated by T cells plays an important role in chronic hepatitis B (CHB). As an immunoregulatory molecule, little is known about the characteristics of T cell immunoglobulin and mucin-domain-containing molecule-3 (Tim-3) on T cells. In this study, the association of Tim-3 on T and its subset cells with clinical-virological features in treatment-naïve CHB patients were identified. Methods: From July 2015 to January 2017, we carried-out a cross-sectional study which 320 CHB patients in different phases (immune active-IA, immune tolerant phase-IT, inactive CHB-IC, and grey zone-GZ) and 17 healthy donors were enrolled. Demographic and clinical data were collected. Tim-3 expression on T cells and its subsets were tested by flowcytometry. Results: The Tim-3 MFI on Total T cells and T cells subsets were significantly higher in CHB patients than healthy controls (HC). Tim-3 expression levels were varied in CHB patients in different stages (P<0.05). The expression levels of Tim-3 (MFI or frequency) on total T cells and T cells subsets were positively correlated with liver inflammation (ALT and AST), TBIL, HBV-DNA, fibrosis (APRI-score). Moreover, significant higher Tim-3 expression levels on T cells and its subsets were observed on higher HBsAg groups compared to lower HBsAg groups. Besides, higher Tim-3 MFI on CD4+ T cells was observed on higher HBcAb group. Conclusions: In summary, we found that Tim-3 expression on T cells in CHB patients was associated with virology, liver inflammation and liver fibrosis, suggesting that Tim-3 may play an important role in the disease process and outcome in patients with CHB and would be a point for treatment.
Abstract Background: Complete clearance of intracellular viruses depends on effector cells of innate and adaptive immune systems. This study aimed to identify the relationships among antiviral cytokines produced by natural killer (NK) and T cells and clinical-virological characteristics in untreated chronic hepatitis B (CHB) patients. Methods: We measured antiviral cytokines interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-2 (IL-2) produced by T, NK and natural killer T (NKT) cells, respectively, in a cohort with chronic hepatitis B virus (HBV) infection (CHB). We also correlated these cytokines with clinical-virological characteristics using a linear regression model. Results: levels of IFN-γ + and TNF-α + CD4 + and CD8 + T cells were significantly higher in immune active (IA) phase than in other phases. Immune tolerant (IT) patients showed the lowest expression of IFN-γ by NK and NKT cells, and TNF-α by NK cells. IFN-γ + , TNF-α + and IL-2 + CD4 + and CD8 + T cells frequencies were similar between IA and gray zone (GZ) phases. Principal component analysis based on cytokines confirmed that most IT patients significantly differed from inactive carriers (IC) and IA patients, while GZ patients were widely scattered. Multivariate analysis showed both T and NK cells producing IFN-γ and TNF-α, but not IL-2, had significant association with serum alanine aminotransferase (ALT). Moreover, IFN-γ + NKT cells were associated with HBV DNA, while IFN-γ + CD4 + and CD8 + T cells were correlated with age. Conclusion : HBV clinical phases are characterized by distinct cytokine signatures, which showed relationship to viral features in these untreated CHB patients.
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)