BTLA contributes to acute-on-chronic liver failure infection and mortality through CD4+ T-cell exhaustion.

B- and T-lymphocyte attenuator (BTLA) levels are increased in patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). This condition is characterized by susceptibility to infection and T-cell immune exhaustion. However, whether BTLA can induce T-cell immune exhaustion and increase the risk of infection remains unclear. Here, we report that BTLA levels are significantly increased in the circulating and intrahepatic CD4+ T cells from patients with HBV-ACLF, and are positively correlated with disease severity, prognosis, and infection complications. BTLA levels were upregulated by the IL-6 and TNF signaling pathways. Antibody crosslinking of BTLA activated the PI3K-Akt pathway to inhibit the activation, proliferation, and cytokine production of CD4+ T cells while promoting their apoptosis. In contrast, BTLA knockdown promoted their activation and proliferation. BTLA-/- ACLF mice exhibited increased cytokine secretion, and reduced mortality and bacterial burden. The administration of a neutralizing anti-BTLA antibody reduced Klebsiella pneumoniae load and mortality in mice with ACLF. These data may help elucidate HBV-ACLF pathogenesis and aid in identifying novel drug targets.

Decreased frequency of a novel T-lymphocyte subset, CD3+ CD4- CD7+ CD57- T cells, in hepatitis B virus-related end-stage liver disease might contribute to disease progression.

CD7 and CD57 are related to the differentiation and functional stages of CD8+ T cells. However, the role of their combined presence in CD8+ T cells in patients with chronic hepatitis B virus (HBV) infection, especially those with end-stage liver disease, remains unclear. Blood samples from healthy volunteers and patients with chronic hepatitis B were analyzed via Luminex assay and ELISA to measure plasma cytokine levels. Further, recombinant IL-22 was used to stimulate peripheral blood mononuclear cells from healthy volunteers, and the frequency of CD3+ CD4- CD7+ CD57- T cells and apoptosis rates were investigated via flow cytometry. Patients with end-stage liver disease, particularly those with acute to chronic liver failure, showed decreased CD3+ CD4- CD7+ CD57- T cell frequency. Furthermore, the prevalence of CD3+ CD4- CD7+ CD57- T cells was negatively correlated with disease severity, prognosis, and complications (ascites). We also observed that IL-22 promoted apoptosis and brought about a decrease in the number of CD3+ CD4- CD7+ CD57- T cells in a dose-dependent manner. CD3+ CD4- CD7+ CD57- T cells displayed a B and T lymphocyte attenuator (BTLA)high CD25high CD127high immunosuppressive phenotype and showed low interferon-γ, tumor necrosis factor-α, granzyme A, and perforin expression levels. The present findings will elucidate the pathogenesis of HBV-related end-stage liver disease and aid the identification of novel drug targets.

The Association of Human Leukocyte Antigen and COVID-19 in Southern China.

Human leukocyte antigen (HLA) polymorphism is hypothesized to be associated with diverse immune responses toward infectious diseases. Herein, by comparing against multiple subpopulation groups as control, we confirmed that HLA-B*15:27 and HLA-DRB1*04:06 were associated with coronavirus disease 2019 susceptibility in China. Both alleles were predicted to have weak binding affinities toward viral proteins.

A Retrospective Study of the Epidemiologic and Clinical Characteristics of COVID-19 Among Hospitalized Patients in Quanzhou, China.

Coronavirus disease 2019 (COVID-19) has spread throughout China. However, information about COVID-19 in cities and regions outside Wuhan is limited and the indicators that predict the length of hospital stay for patients with COVID-19 are unclear. Therefore, we collected clinical data from 47 patients with COVID-19 in Quanzhou City. The median age was 38 years [interquartile range (IQR): 31-50 years], and 24 (51%) were male. There were 8 mild, 36 moderate, and 3 severe/critical cases. The median interval from exposure to disease onset was 13 days (IQR: 8-18 days). The incidence of severe/critical cases was 33% (3/10) in patients with hypertension. Common symptoms included fever (83%), cough (77%), fatigue (40%), a sore, dry throat (28%), and diarrhea (21%). One patient (2%) developed respiratory distress syndrome on day 13 of inpatient treatment. Six patients had leukopenia, 17 had elevated C-reactive protein (CRP), and 8 had lymphocytopenia and elevated lactate dehydrogenase (LDH). The median length of hospitalization was 22 days (IQR: 16-30 days). Dynamic monitoring of LDH, CRP, and neutrophil-lymphocyte ratio predicted whether length of hospitalization would exceed 21 days. Most patients presented with mild and moderate disease. Patients with hypertension were more likely to become severe or critical. Dynamic monitoring of LDH, CRP, and neutrophil-lymphocyte ratio levels can help predict delayed discharge from the hospital.

Serum Interleukin (IL)-9 and IL-10, but not T-Helper 9 (Th9) Cells, are Associated With Survival of Patients With Acute-on-Chronic Hepatitis B Liver Failure.

CD4 T helper (Th) cells are reported to be essential for initiating and maintaining an effective immune response to hepatitis B virus (HBV) infection. Th9 cells are a new subset of CD4 Th cells that produce interleukin (IL)-9 and IL-10. The present study aimed to investigate the percentage of Th9 cells relative to the number of CD4 cells in peripheral blood. We also measured serum IL-9 and IL-10 levels in different stages of HBV infection and their relationship with progress and prognosis of liver disease. Whole blood samples from 111 patients with HBV infection, including 39 chronic hepatitis B (CHB), 25 HBV-liver cirrhosis (HBV-LC), 21 acute-on-chronic liver failure (ACLF) patients, and 26 healthy controls were collected. The percentage of Th9 cells and serum IL-9 and IL-10 levels were determined. There was no significant difference in the percentage of Th9 cells and serum IL-9 and IL-10 levels among different groups, nor were these related to hepatitis B e antigen status, complications of cirrhosis, inflammation index, or prognosis indexes. There was no change in the percentage of Th9 cells before and after antiviral treatment in CHB patients. There was no correlation of Th9 cells with survival of ACLF patients. However, IL-9 and IL-10 levels were significantly higher in the nonsurvived ACLF patients compared to survived ACLF patients. Furthermore, baseline IL-9 level predicted the prognosis of ACLF patients with 87.5% sensitivity and 61.5% specificity.Thus, our data indicate that Th9 cells were unlikely involved in the pathogenesis of HBV infection, but elevation in IL-9 and IL-10 may signal poor prognosis for ACLF.

The Transforming Growth Factor ß1/Interleukin-31 Pathway Is Upregulated in Patients with Hepatitis B Virus-Related Acute-on-Chronic Liver Failure and Is Associated with Disease Severity and Survival.

The transforming growth factor ß1/interleukin-31 (TGF-ß1/IL-31) pathway plays an important role in the process of cell injury and inflammation. The purpose of this work was to explore the role of the TGF-ß1/IL-31 pathway in the cytopathic process of hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). The quantitative serum levels of TGF-ß1, IL-9, IL-10, IL-17, IL-22, IL-23, IL-31, IL-33, and IL-35 were analyzed among chronic hepatitis B (CHB) patients (n = 17), ACLF patients (n = 18), and normal control (NC) subjects (n = 18). Disease severity in patients with ACLF was assessed using the model for end-stage liver disease (MELD) and Child-Pugh scores. Serum TGF-ß1 levels were strongly positively correlated with IL-31 in all subjects, and both of them were positively correlated with IL-17, IL-22, and IL-33. In CHB and ACLF patients, serum levels of TGF-ß1 and IL-31 were both increased significantly compared with those in NC subjects and positively correlated with total bilirubin (TBil) and alpha-fetoprotein (AFP) levels. ACLF patients showed the highest levels of TGF-ß1 and IL-31, which were positively correlated with Child-Pugh scores. Furthermore, the recovery from the liver injury in CHB was accompanied by decreased TGF-ß1 and IL-31 levels. More importantly, serum levels of TGF-ß1 and IL-31 were markedly upregulated in ACLF nonsurvivors, and IL-31 displayed the highest sensitivity and specificity (85.7% and 100.0%, respectively) in predicting nonsurvival of ACLF patients. Increasing activity of the TGF-ß1/IL-31 pathway is well correlated with the extent of liver injury, disease severity, and nonsurvival of ACLF patients, while reducing activity is detected along the recovery from liver injury in CHB, suggesting its potential role in the pathogenesis of liver injury during chronic HBV infection.

Elevated TGF-ß1/IL-31 Pathway Is Associated with the Disease Severity of Hepatitis B Virus-Related Liver Cirrhosis.

The proinflammatory cytokines transforming growth factor beta 1 (TGF-ß1) and interleukin (IL)-31 have been implicated in tissue injury. However, whether TGF-ß1/IL-31 are stimulated and elevated in response to liver injury that leads to fibrogenesis in hepatitis B virus-related liver cirrhosis (HBV-LC) remains unclear. To investigate the association between TGF-ß1/IL-31 and stages of chronic HBV infection, serum TGF-ß1, IL-9, IL-10,IL-17, IL-22, IL-23, IL-31, IL-33, and IL-35 were determined among patients with chronic hepatitis B (CHB; n=19), HBV-LC (n=20), and a normal control population (NC; n=18). Disease severity in patients with HBV-LC was assessed using model for end-stage liver disease (MELD) scores. Serum TGF-ß1 and IL-31 levels were strongly positively linked in all subjects, and both correlated positively with IL-22, IL-33, and IL-17. TGF-ß1 and IL-31 levels in the blood were both significantly higher in CHB and HBV-LC patients than in NC subjects. Elevated serum TGF-ß1 and IL-31 levels were positively associated with albumin, alpha-fetoprotein, creatinine, white blood cell count, and platelet levels. Serum TGF-ß1 and IL-31 were markedly higher in HBV-LC patients who did not have esophageal varices, and IL-31 had the highest sensitivity and specificity (90.9% and 66.7%, respectively) for indicating the absence of this complication. In summary, TGF-ß1 and IL-31 were linked to progression from CHB to LC, and correlated well with the severity of HBV-LC. These findings suggest possible roles of the TGF-ß1/IL-31 pathway in the pathogenesis of liver fibrosis during chronic HBV infection.

Ratios of regulatory T cells/T-helper 17 cells and transforming growth factor-ß1/interleukin-17 to be associated with the development of hepatitis B virus-associated liver cirrhosis.

BACKGROUND AND AIM: The aim of this study is to evaluate the association of the regulatory T cells (Treg)/T-helper (Th) 17 cells and transforming growth factor-ß1 (TGF-ß1)/interleukin-17 (IL-17) ratios with the survival and disease progression in patients with hepatitis B virus (HBV)-associated liver cirrhosis (LC). METHODS: The frequencies of Treg and Th17 cells were analyzed in 28 patients with HBV-LC, 70 patients with chronic hepatitis B (CHB) and 20 normal controls (NC) by flow cytometry. The levels of cytokines related to Treg/Th17 differentiation, including IL-10, TGF-ß1, IL-17, and IL-23, were measured by ELISA. RESULTS: Compared with NC, Treg cells were significantly increased in CHB patients and slightly increased in HBV-LC patients, whereas Th17 cells were markedly increased both in patients with CHB and HBV-LC. HBV-LC patients, especially the nonsurvival ones, manifested a profound decrease in the Treg/Th17 ratio, which was negatively correlated with Child-Pugh and model of end-stage liver disease scores. Serum IL-10, TGF-ß1, IL-17, and IL-23 levels were all significantly higher in HBV-LC patients than in NC. In addition, the TGF-ß1/IL-17 ratio was also markedly increased in patients with HBV-LC, especially in nonsurvival and decompensated liver cirrhosis patients, and positively correlated with total bilirubin, Child-Pugh, and model of end-stage liver disease scores. CONCLUSIONS: The decreased Treg/Th17 ratio and increased TGF-ß1/IL-17 ratio may be associated with the survival and disease progression in HBV-LC patients, and both of the two ratios can be used independently to predict the prognosis and disease progression of HBV-LC patients.

Changes in the balance between Treg and Th17 cells in patients with chronic hepatitis B.

The purpose of this study was to explore the role of Treg cells, Th17 cells and cytokines associated with Treg/Th17 differentiation in the occurrence, development and outcome of chronic hepatitis B (CHB). To do so, we detected populations of Treg and Th17 cells and their associated cytokines in the peripheral blood of CHB patients. The populations of Treg cells (CD4(+)CD25(high)CD127(low) T cells) and Th17 cells (CD3(+)CD8(-)IL-17(+) T cells) were analyzed in 46 patients with low to moderate chronic hepatitis B (CHB-LM), 24 patients with severe chronic hepatitis B (CHB-S) and 20 healthy controls (HC) using flow cytometry. The levels of cytokines associated with Treg/Th17 differentiation, including IL-10, TGF-ß1, IL-17 and IL-23, were measured by enzyme-linked immunosorbent assay (ELISA). Our study showed that the imbalance of Treg and Th17 cells might play an important role in the occurrence, development and outcome of CHB.

Dynamic Changes of Treg and Th17 Cells and Related Cytokines Closely Correlate With the Virological and Biochemical Response in Chronic Hepatitis B Patients Undergoing Nucleos(t)ide Analogues Treatment.

BACKGROUND: The restoration of HBV-specific T-cell response during antiviral therapy is associated with CD4+T-cell activity. Treg cells and Th17 cells are subtypes of CD4+T cell. However, it has remained unknown how the Treg and Th17 cells and their associated cytokines affect nucleos(t)ide analogues (NA) antiviral efficacy. OBJECTIVES: The aim of the present study was to provide a new insight to evaluate the NA antiviral therapy for patients with chronic hepatitis B (CHB). PATIENTS AND METHODS: Forty-four CHB patients hospitalized between July 2010 and August 2011 were enrolled in this study. They were received NA (entecavir, lamivudine and adefovir) treatment for 14.42 ± 13.08 weeks, and the peripheral blood was collected. The frequencies of Treg and Th17 cells were detected by flow cytometric analysis, and the levels of IL-10, TGF-ß1, IL-17 and IL-23 were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: In complete and partial-responders, Treg cells frequencies and IL-10, TGF-ß1, IL-23 levels were all decreased significantly after NA therapy, while Th17 cells and the IL-17 levels were increased slightly. Treg/Th17 ratio was only dramatically declined in complete-responders. But there was no significant difference in non-responders. Either HBV DNA decreased by at least 2 log copies /mL or ALT turned to normal level, Treg cells frequencies and IL-10, TGF-ß1, IL-23 levels were significantly reduced. Meanwhile, Treg cells were positively correlated with HBV DNA and ALT. CONCLUSIONS: The changes of Treg and Th17 cells and their associated cytokines were related to virological and biochemical responses.