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.)

SummaryEffective immunity requires a complex network of cellular and humoral components that interact with each other and are influenced by different environmental and host factors. We used a systems biology approach to comprehensively assess the impact of environmental and genetic factors on immune cell populations in peripheral blood, including associations with immunoglobulin concentrations, from ∼500 healthy volunteers from the Human Functional Genomics Project. Genetic heritability estimation showed that variations in T cell numbers are more strongly driven by genetic factors, while B cell counts are more environmentally influenced. Quantitative trait loci (QTL) mapping identified eight independent genomic loci associated with leukocyte count variation, including four associations with T and B cell subtypes. The QTLs identified were enriched among genome-wide association study (GWAS) SNPs reported to increase susceptibility to immune-mediated diseases. Our systems approach provides insights into cellular and humoral immune trait variability in humans.

The complex interplay of processes and cells involved in healthy pregnancy is still poorly understood. The correct receptive endometrial state, including the local immune environment, is crucial not only for fertility but also placenta formation since initiation of placentation highly depends on interaction with immune cells. Implantation failure, recurrent pregnancy loss, and other pathologies of endometrium and placenta, such as pre-eclampsia, represent an increasing societal burden. More robust studies are needed to investigate uterine colonization. Based on current data, future research needs to include the uterine microbiome as a relevant factor in order to understand the players needed for healthy pregnancy.

Summary Chronic hepatitis B virus (HBV) infection is the result of an inadequate immune response towards the virus. Myeloid dendritic cells (mDC) of patients with chronic HBV are impaired in their maturation and function, resulting in more tolerogenic rather than immunogenic responses, which may contribute to viral persistence. The mechanism responsible for altered mDC function remains unclear. The HBV‐infected patients display large amounts of HBV particles and viral proteins in their circulation, especially the surface antigen HBsAg, which allows multiple interactions between the virus, its viral proteins and DC. To assess whether HBV directly influences mDC function, the effects of HBV and HBsAg on human mDC maturation and function were investigated in vitro. As already described for internalization of HBV by DC, the present study shows that peripheral blood‐derived mDC of healthy controls also actively take up HBsAg in a time‐dependent manner. Cytokine‐induced maturation in the presence of HBV or HBsAg resulted in a significantly more tolerogenic mDC phenotype as demonstrated by a diminished up‐regulation of costimulatory molecules and a decreased T‐cell stimulatory capacity, as assessed by T‐cell proliferation and interferon‐γ production. In addition, the presence of HBV significantly reduced interleukin‐12 production by mDC. These results show that both HBV particles and purified HBsAg have an immune modulatory capacity and may directly contribute to the dysfunction of mDC in patients with chronic HBV. The direct immune regulatory effect of HBV and circulating HBsAg particles on the function of DC can be considered as part of the mechanism by which HBV escapes immunity.

Regulatory T cells (Treg) play a key role in the impaired immune response that is typical for a chronic Hepatitis B virus (HBV) infection. To gain more insight in the mechanism that is responsible for this impaired immune response, the effect of viral load reduction resulting from treatment with the nucleotide analogue adefovir dipivoxil on the percentages of Treg and HBV-specific T-cell responses was analyzed. Peripheral blood mononuclear cells (PBMC) of 12 patients were collected at baseline and during treatment. In parallel to the decline in viral load, we found a decline in circulating Treg, combined with an increase in HBV core antigen-specific IFN-gamma production and proliferation. The production of IL10 did not decrease during therapy. In conclusion, adefovir induced viral load reduction results in a decline of circulating Treg together with a partial recovery of the immune response.

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