Preserved T-Cell Function in Children and Young Adults With Immune-Tolerant Chronic Hepatitis B
ABSTRACT Chronic hepatitis B (CHB) infection acquired perinatally or in early childhood has been associated with a prolonged phase of immune tolerance from viral exposure into early adulthood. The immune-tolerant phase of the disease is characterized by high levels of hepatitis B virus (HBV) DNA and normal liver biochemistry, with minimal or no fibrosis. We investigated whether the age of patients with CHB affects their antiviral immunity and whether children and young adults have a veritable state of immunologic tolerance.
We isolated T cells from different age groups of patients with CHB and used flow cytometric methods to measure production of effector and inflammatory cytokines (interferon, tumor necrosis factor, interleukin [IL]-17A, IL-22, and IL-8), T-helper (Th)2 cytokines (IL-10, IL-4), Th1 cytokines (IL-2 and IL-21), and the CC chemokine CCL3 (MIP-1). We also measured markers of T-cell exhaustion or inhibition (PD-1, LAG-3, TIM3, LAIR-1, and CTLA-4) and HBV-specific T cells.
Young patients with CHB have a Th1-cell cytokine profile and a partial profile of T-cell exhaustion. Direct quantification of the HBV-specific T-cell response showed that young patients with CHB have more HBV-specific T cells with the ability to proliferate and produce cytokines than adult patients with CHB.
HBV infection in younger patients is not associated with an immune profile of T-cell tolerance. On the contrary, children and young adults with chronic HBV infection have an HBV-specific immune profile that is less compromised than that observed in older patients.
SourceAvailable from: Antonio Bertoletti[Show abstract] [Hide abstract]
ABSTRACT: Immune responses change during the life of an individual. While this concept has been well accepted for adaptive immunity, only recently it is becoming clear that the innate immune responses also acquire distinct features in different phases of life. We believe that this concept can offer a different interpretation of the pathological manifestations that can be observed in HBV-infected subjects during the patient's life. Here, we will review the age-related immunopathological features of HBV infection and discuss how the different virological and clinical manifestations might be linked to the developmental pathway of the immune system from newborns to adults. We will discuss how the age of patients can affect the degree of inflammatory responses, but not the levels of antiviral specific immunity. We then propose that the different clinical manifestations occurring during the natural history of HBV infection are related to the host ability to trigger an inflammatory immune response.Frontiers in Immunology 09/2014; 5:441. DOI:10.3389/fimmu.2014.00441
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ABSTRACT: Natural Killer (NK) cells exhibit dysregulated effector function in adult chronic HBV infection (CHB), which may contribute to virus persistence. The role of NK cells in children infected perinatally with HBV is less studied. Access to a unique cohort enabled the cross-sectional evaluation of NK cell frequency, phenotype and function in HBV-infected children relative to uninfected children. We observed a selective defect in NK cell IFN-γ production, with conserved cytolytic function, mirroring the functional dichotomy observed in adult infection. Reduced expression of NKp30 on NK cells suggests a role of impaired NK-Dendritic Cell (DC) cellular interactions as a potential mechanism leading to reduced IFN-γ production. The finding that NK cells are already defective in paediatric CHB, albeit less extensively than in adult CHB, has potential implications for the timing of antiviral therapy aiming to restore immune control.Clinical & Experimental Immunology 10/2014; 179(3). DOI:10.1111/cei.12470 · 3.28 Impact Factor
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ABSTRACT: Purpose of reviewHepatitis B virus (HBV) causes a large proportion of chronic liver disease worldwide. The limited efficiency of current treatments based on the use of nucleotide/nucleoside analogues or interferon-alpha requires the development of new therapeutic tools for the treatment of chronic HBV. We summarize the most recent therapeutic strategies designed to directly target HBV-infected hepatocytes or to restore antiviral immunity during chronic HBV infection.Recent findingsNovel therapies directly target HBV-infected hepatocytes by inducing covalently closed circular DNA degradation or by inhibiting HBV entry or the expression of viral proteins. In addition, immunotherapeutic approaches may boost HBV-specific T-cell responses or stimulate the intrahepatic innate response.SummaryThese new therapeutic approaches have mainly been tested in animal models. In humans, therapeutic strategies could be tailored to different chronic HBV patients in relation to their clinical and virological disease profile.Current Opinion in Infectious Diseases 10/2014; 27(6). DOI:10.1097/QCO.0000000000000110 · 5.03 Impact Factor