Gastroenterology

Gastroenterology

Volume 137, Issue 4, October 2009, Pages 1289-1300
Gastroenterology

Clinical Advances in Liver, Pancreas, and Biliary Tract
Temporal Analysis of Early Immune Responses in Patients With Acute Hepatitis B Virus Infection

https://doi.org/10.1053/j.gastro.2009.06.054Get rights and content

Background & Aims

Hepatitis B virus (HBV) causes more than 1 million deaths annually from immune-mediated liver damage. The long incubation period has been difficult to study; by the time most patients present, massive viremia and the majority of viral clearance have already occurred. The aim of this study was to investigate the contribution of innate and adaptive immune mechanisms in early acute HBV through access to an unusual cohort of patients sampled in the preclinical phase and followed up to resolution of their infection.

Methods

Twenty-one patients with acute HBV were studied, 8 of them from before the peak of viremia. Circulating innate cytokines were quantitated by enzyme-linked immunosorbent assay and natural killer (NK) and T-cell effector function by flow cytometry. Results were correlated with temporal changes in viral load, serology, and liver inflammation and compared with healthy controls.

Results

Type I interferon (IFN) remained barely detectable throughout, with concentrations no higher than those found in healthy controls. Similarly, interleukin-15 and IFN-λ1 were not induced during peak viremia. NK cell activation and capacity for IFN-γ production were reduced at peak viremia. Early functional HBV-specific CD4 and CD8 T-cell responses were attenuated as viral load increased and recovered again as infection resolved. The transient inhibition of NK and T-cell responses coincided with a surge in the immunosuppressive cytokine interleukin-10 accompanying HBV viremia.

Conclusions

The early stages of acute HBV are characterized by induction of interleukin-10 rather than type I IFN, accompanied by a temporary attenuation of NK and T-cell responses.

Section snippets

Patients

Twenty-one patients with acute HBV were included in this study. Table 1 summarizes their clinical characteristics, laboratory parameters, and the number of available sera and peripheral blood mononuclear cells (PBMCs) for each patient. Infection was diagnosed on the basis of a positive HBV DNA test result by polymerase chain reaction and positive serum surface antigen (HBsAg), with the subsequent serologic, biochemical, and clinical evolution of acute HBV infection. HBsAg alone was detectable

The Production of Innate Cytokines Is Impaired in Early Acute HBV Infection

A cohort of patients was recruited in the preclinical phase of acute HBV infection and sampled longitudinally through the symptomatic phase to disease resolution (Table 1). Serum concentrations of IFN-α were initially measured using a high-sensitivity ELISA. IFN-α remained barely detectable in the circulation of these patients during the early incubation phase and throughout the peak of viral replication and subsequent reduction in viremia and onset of symptomatic liver inflammation (indicated

Discussion

The immune responses generated in the primary stages of a viral infection are believed to be critical determinants of subsequent disease outcome. Acute infection with HBV has a prolonged, clinically silent incubation phase; by the time of typical presentation with jaundice, the majority of viral clearance has already occurred. In this study, we took advantage of a cohort of patients who had been opportunistically sampled in the presymptomatic phase of initial viremia to examine the potential

Acknowledgments

The authors thank the staff and patients at the Mortimer Market Centre, Camden Primary Care NHS Trust, and the Royal Free Hospital Centre for Hepatology for clinical samples, as well as George Webster and Antonio Bertoletti for agreeing to use of their published T-cell data in Figure 4A.

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    To view this article's video abstract, go to theAGA's YouTube Channel.

    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by the Medical Research Council (New Investigator Award G0501132 to C.D. and Clinician Scientist Award G108515 to M.K.M.). D.P. was supported by fellowship E005 from the UCLH Clinical Research and Development Committee. P.K. was supported by the Wellcome Trust, the NIHR Biomedical Research Centre Programme, and the James Martin 21st Century School.

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