Chronic hepatitis B virus (HBV) infection is H epatitis B virus (HBV) is a common noncyto-pathic DNA virus. Infection with HBV in adults results frequently in a self-limiting, acute hepatitis, which confers protective immunity and causes no further disease. In 10% of infected adults, HBV leads to a chronic infection. Chronic HBV infection is an important risk factor for the development of cirrhosis and hepatocellular carcinoma. Worldwide, 350 million people suffer from chronic HBV infection, and approximately 1 million people die annually from HBV-related liver disease. 1,2 T helper 1 type cytokines such as interferon ␥ (IFN-␥) and interleukin 2 are involved in cell-mediated immunity and play a crucial role in the protection against intracellular pathogens, including HBV. 3 In patients with an acute self-limiting HBV infection, a multispecific CD4 ϩ and CD8 ϩ T-cell response with a type 1 cytokine profile is important for control of the infection. 4 These multispecific T-cell responses are maintained for decades after clinical recovery. 5 In contrast, patients with a chronic HBV infection lack such a vigorous multispecific response. These patients have a weak or undetectable virus-specific T-cell response. 4 The precise mechanism responsible for this T-cell hyporesponsiveness or tolerance is still unknown. One scenario that has not been explored in relation to chronic HBV infection is the potential role of host-mediated immunosuppressive mechanisms that might be activated in the face of persistent antigenic exposure.

Summary Differences in susceptibility to immune-mediated diseases are determined by variability in immune responses. In three studies within the Human Functional Genomics Project we assessed the effect of environmental and non-genetic host factors, of the genetic make-up of the host, and of the intestinal microbiome, on the cytokine responses in humans. We analyzed the association of these factors with circulating mediators and with six cytokines after stimulation with 19 bacterial, fungal, viral and non-microbial metabolic stimuli in 534 healthy subjects. In this first study we show a strong impact of non-genetic host factors (e.g. age and gender) on cytokine production and circulating mediators. Additionally, annual seasonality is found to be an important environmental factor influencing cytokine production. Alpha-1-antitrypsin concentrations partially mediate the seasonality of cytokine responses, whereas the effect of vitamin D levels is limited. The complete dataset has been made publicly available as a comprehensive resource for future studies.

Dendritic cells (DC) play an important role in the induction of T-cell responses. We hypothesize that the hampered antiviral T-cell response in chronic hepatitis B patients is a result of impaired dendritic cell function. In this study, we compared the number, phenotype and functionality of two important blood precursor DC, myeloid DC (mDC) and plasmacytoid DC (pDC), of chronic hepatitis B patients with healthy volunteers. No differences in percentages of mDC and pDC in peripheral blood mononuclear cells were observed between chronic hepatitis B patients and healthy controls. The allostimulatory capacity of isolated and in vitro matured mDC, but not of pDC, was significantly decreased in patients compared to controls. Accordingly, a decreased percentage of mDC expressing CD80 and CD86 was observed after maturation, compared to controls. In addition, mDC of patients showed a reduced capacity to produce tumor necrosis factor ␣ after a stimulus with synthetic double-stranded RNA and interferon ␥. Purified pDC from patients produced less interferon ␣, an important antiviral cytokine, in response to stimulation with Staphylococcus aureus Cowan strain I than pDC isolated from controls. In conclusion, mDC and pDC are functionally impaired in patients with chronic hepatitis B. This might be an important way by which hepatitis B virus evades an adequate immune response, leading to viral persistence and disease chronicity. (HEPATOLOGY 2004;40:738 -746.)