Pathogenetic Mechanisms of T Cell Dysfunction in Chronic HBV Infection and Related Therapeutic Approaches

Fisicaro, Paola; Barili, Valeria; Rossi, Marzia; Montali, Ilaria; Vecchi, Andrea; Acerbi, Greta; Laccabue, Diletta; Zecca, Alessandra; Penna, Amalia; Missale, Gabriele; Ferrari, Carlo; Boni, Carolina

doi:10.3389/fimmu.2020.00849

Cited by 97 publications

(96 citation statements)

References 192 publications

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“…Because CHB patients are typically characterized by the dysfunction and exhaustion of HBV-specific CD4+ and CD8+ T cells (6,7), specific T cellmediated immune responses have become the focus of attention in HBV infection and clearance. At present, there are a substantial number of studies that have described T cell defects during a persistent HBV infection, which are mainly characterized by the sustained expression of multiple inhibitory receptors, poor effector cytotoxic activity, and impaired cytokine production (7)(8)(9). However, the role of B cells in HBV infection is often overlooked.…”

Section: Introductionmentioning

confidence: 99%

The Multiple Functions of B Cells in Chronic HBV Infection

Cai

Yin

2020

Front. Immunol.

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Chronic hepatitis B virus (HBV) infection is one of the main causes of liver diseases, of which the natural history and clinical outcomes are associated with the role of B cells. As humoral immune cells, B cells play a critical role in the process of anti-HBV antibody production. In addition, some studies have also characterized other B cell subsets involved in antigen presentation and regulating the immune response beyond antibody secretion. However, not all B cell subsets play a positive role in the immune response to chronic HBV infection, and various B cell subsets jointly mediate persistent HBV infection, tolerance, and liver damage. Thus, we further sought to elucidate the multiple functions of B cells to gain novel insight into the understanding of chronic hepatitis B (CHB) pathogenesis. We also reviewed the current immunotherapies targeting B cells to explore novel therapeutic interventions for the treatment of chronic HBV infection.

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Section: Introductionmentioning

confidence: 99%

The Multiple Functions of B Cells in Chronic HBV Infection

Cai

Yin

2020

Front. Immunol.

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“…High HBV DNA load, high HBeAg and HBsAg levels in patients with immune tolerance may also be related to the lack of immune response, [16] that is, there is a speci c T cell response to HBV, but not enough to achieve viral clearance. [17] In HBeAg-positive CHB patients, HBsAg and HBeAg can inhibit the secretion of surface functional molecules and cytokines in a variety of immune cells, which plays a role in inducing immune tolerance to HBV infection. [18] In this study, although the levels of Flt3-L, IFN-γ and IL-17A in patients with chronic hepatitis B were signi cantly lower than those in patients with immune tolerance, the levels of IFN-a and IL-10 in patients with chronic hepatitis B were signi cantly higher than those in patients with immune tolerance.…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor -β Level Might Be An Independent Factor Related to Occurrence of Chronic Hepatitis B

Yao

Sun

et al. 2021

Preprint

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To investigate association between immune cell-related cytokines and development of chronic hepatitis B (CHB). Patients with chronic hepatitis B virus (HBV) infection in immune tolerance (IT, n=30) and hepatitis B envelope antigen (HBeAg) positive CHB (n=250) were enrolled in the study. HBV virus, serological indicators, and plasma cytokine levels were detected at the time of enrollment. The results showed that there were significant differences in median age of patients (27 vs. 31y), alanine aminotransferase level (ALT, 29.85 vs 234.70 U/L), alanine aminotransferase level (AST, 23.40 vs. 114.90 U/L), HBsAg level (4.79 vs. 3.88 log10 IU/ml), HBeAg (1606.36 vs. 862.47 S/CO) and HBV DNA load (8.17 vs 6.71 log10 IU/ml) between IT and CHB groups (all P<0.01). The median values of Fms-like tyrosine kinase 3 ligand (FLT3-L), interferon-γ (IFN-γ), interleukin- 17A (IL-17A) and transforming growth factor- beta (TGF-β1) in IT group were significantly higher than those in CHB group (FLT3-L: 41.62 vs. 27.47 pg/ml; IFN-γ: 42.48 vs. 33.18 pg/ml; IL-17A: 15.66 vs. 8.90 pg/ml; TGF-β1: 4921.50 vs. 2234 pg/ml. All P<0.01). The median values of IFN-a2, TGF-β3 and IL-10 levels in IT group were significantly lower than those in CHB group (IFN-α2: 15.24 vs. 35.78 pg/ml, P=0.000; TGF-β3: 131.69 vs. 162.61 pg/ml, P=0.025; IL-10: 5.02 vs. 7.9 pg/ml, P=0.012). The multivariate logistic regression analysis indicated that TGF-β 1 (OR=0.999, 95% CI 0.999-1.000, P<0.001) and TGF-β2 levels (OR=1.008, 95%CI 1.004-1.012, P <0.001) were significantly associated with the incidence of CHB. The results suggest that TGF-β level might be an independent factor related to the occurrence of CHB.

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“…Wesentliche Faktoren dabei sind die Freisetzung von Arginase und IDO aus den zerstörten Hepatozyten, die eine Depletion einzelner Aminosäuren bedingen, die essenziell für den Erhalt der T-Zellfunktionalität sind. So bedingt eine Verminderung des Argininspiegels eine geringere CD3zeta-Menge in T-Zellen, was letztlich zu einer gestörten Funktion TCR-abhängiger Signalwege führt [16].…”

Section: Chronische Hbv-infektionunclassified

Immuntherapien zur Behandlung der chronischen Hepatitis-B-Virusinfektion – eine Übersicht unter besonderer Berücksichtigung von CAR-T-Zellen

Ivics

Amberger

Zahn

et al. 2020

Bundesgesundheitsbl

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Zusammenfassung Derzeit leiden weltweit mehr als 250 Mio. Menschen an einer chronischen Infektion mit Hepatitis-B-Virus (CHB). Eine chronische Infektion geht mit einem erhöhten Risiko der Entwicklung einer Leberfibrose/-zirrhose und der Entwicklung eines hepatozellulären Karzinoms einher. Derzeit versterben jährlich ca. 0,8–1 Mio. Menschen an den Folgen einer chronischen Infektion. Eine Schwierigkeit bei der Therapie der CHB besteht darin, dass das virale Genom in Form eines Minichroms sehr lange Zeit persistieren kann bzw. dass virale Sequenzen in das Wirtsgenom inserieren können. Chronische Infektionen sind häufig durch funktionale Defekte der zellulären Immunantwort, insbesondere der T‑Zell-Antwort charakterisiert, was einer Eliminierung HBV-infizierter Zellen entgegensteht. Immuntherapien zur Heilung der CHB zielen daher darauf ab, die antivirale Funktion der zellulären Immunantwort wiederherzustellen. Im Rahmen dieser Übersicht sollen verschiedene aktuelle Ansätze zur Immuntherapie der CHB beschrieben werden, insbesondere gentechnisch veränderte autologe T‑Zellen als mögliches Werkzeug zur Therapie der CHB. Weiterhin werden die Modulation von Checkpointinhibitoren der Immunantwort, metabolische T‑Zelltherapien und die therapeutische Impfung zur Stimulation der T‑Zellantwort als immuntherapeutische Strategien zur Therapie der chronischen HBV-Infektion zusammenfassend dargestellt.

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Pathogenetic Mechanisms of T Cell Dysfunction in Chronic HBV Infection and Related Therapeutic Approaches

Cited by 97 publications

References 192 publications

The Multiple Functions of B Cells in Chronic HBV Infection

The Multiple Functions of B Cells in Chronic HBV Infection

Transforming Growth Factor -β Level Might Be An Independent Factor Related to Occurrence of Chronic Hepatitis B

Immuntherapien zur Behandlung der chronischen Hepatitis-B-Virusinfektion – eine Übersicht unter besonderer Berücksichtigung von CAR-T-Zellen

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Pathogenetic Mechanisms of T Cell Dysfunction in Chronic HBV Infection and Related Therapeutic Approaches

Cited by 97 publications

References 192 publications

The Multiple Functions of B Cells in Chronic HBV Infection

The Multiple Functions of B Cells in Chronic HBV Infection

Transforming Growth Factor -β Level&nbsp;Might&nbsp;Be An Independent Factor Related to Occurrence of Chronic Hepatitis B

Immuntherapien zur Behandlung der chronischen Hepatitis-B-Virusinfektion – eine Übersicht unter besonderer Berücksichtigung von CAR-T-Zellen

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Transforming Growth Factor -β Level Might Be An Independent Factor Related to Occurrence of Chronic Hepatitis B