Functional impairment of myeloid and plasmacytoid dendritic cells of patients with chronic hepatitis B

Abstract

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.)

A six‐color flow cytometric assay for the analysis of peripheral blood dendritic cells

“…The lower constitutive expression of the costimulatory molecules CD80, CD86, and CD40 on pDCs than mDCs clearly documented with our assay is in accordance with the tolerogenic function ascribed to pDCs (16). A few observations of lower expression of these markers on pDCs have been previously reported, but with methods that used isolated or cultured PBDCs, or compared data obtained from different tubes (17)(18)(19)(20). In this respect, the direct comparison between DC subsets made possible by our 6-color assay may be more reliable.…”

Dendritic cells take up viral antigens but do not support the early steps of hepatitis B virus infection

“…So far, no correlation was observed between the amount of HBV-DNA present in mDC or pDC, 10 or the presence of viral antigens in moDC and the allostimulatory capacity of DC. 12 Thus, to which extent and how the function of DC is altered during HBV infection remains unclear.…”

“…In previous studies, possible HBV infection of DC was mostly studied by PCR methods detecting HBV rcDNA genomes 9,10,12 or by PCR in situ hybridization. 31 These methods, however, hardly distinguish input viruses from newly synthesized particles.…”

“…[6][7][8] The role of DC during HBV infection was intensively studied during the last years, but whether total numbers of DC are reduced during chronic infection is discussed controversary. [9][10][11] In some studies, functional deficits of these cells were reported on contact of moDC with HBV, 14 whereas they remained minor in others. 12 Whether the weak or absent T-cell response described in chronic hepatitis B patients results from a defect in the DC compartment, which is caused by the virus itself, is unclear.…”

“…15 Detection of HBV-DNA in DC lysates by polymerase chain reaction (PCR) has been proposed to indicate HBV infection of DC. 9,10,12,13 However, this conclusion can be questioned, because the detection of HBV-DNA and even HBV-RNA in peripheral blood mononuclear cells (PBMC) can be explained by adsorbed virus and does not necessarily correlate with detection of cccDNA and thus with infection. 16 Therefore, whether HBV can infect DC, induce expression of viral antigens, and initiate replication of the viral genome remains unknown.…”