Abstract
Type I Interferon (IFN) is one of the first lines of defense against viral infection. Plasmacytoid dendritic cells (pDCs) are professional IFN-α-producing cells that play an important role in the antiviral immune response. Previous studies have reported that IFN-α production is impaired in chronic hepatitis B (CHB) patients. However, the mechanisms underlying the impairment in IFN-α production are not fully understood. Here, we report that plasma-derived hepatitis B surface antigen (HBsAg) and HBsAg expressed in CHO cells can significantly inhibit toll like receptor (TLR) 9-mediated Interferon-α (IFN-α) production in peripheral blood mononuclear cells (PBMCs) from healthy donors. Further analysis indicated that monocytes participate in the inhibitory effect of HBsAg on pDCs through the secretion of TNF-α and IL-10. Furthermore, TLR9 expression on pDCs was down-regulated by TNF-α, IL-10 and HBsAg treatment. This down-regulation may partially explain the inhibition of IFN-α production in pDCs. In conclusion, we determined that HBsAg inhibited the production of IFN-α by pDCs through the induction of monocytes that secreted TNF-α and IL-10 and through the down-regulation of TLR9 expression on pDCs. These data may aid in the development of effective antiviral treatments and lead to the immune control of the viral infections.
Highlights
More than 350 million people worldwide are chronically infected with hepatitis B virus (HBV), and chronic infection with HBV causes significant morbidity and mortality [1,2]
IFN-a Production is Impaired in peripheral blood mononuclear cells (PBMCs) and Plasmacytoid dendritic cells (pDCs) from Treatment-naıve, Chronic Hepatitis B (CHB) Patients
IFN-a is critical for the innate immune control of HBV replication and for the activation of the adaptive immune response. pDCs account for most of the IFN-a production in PBMCs due to their high expression of TLR7, TLR9 and interferon regulatory factor 7 (IRF-7)
Summary
More than 350 million people worldwide are chronically infected with hepatitis B virus (HBV), and chronic infection with HBV causes significant morbidity and mortality [1,2]. A reduced HBV DNA level was observed to accompany an increased pDCs amounts This suggested that HBV is important in the observed deficiency in the function of pDCs [9,10]. It has been reported that HBV and the HBV surface antigen can enter dendritic cells, but the cells do not support viral replication [11] This suggests a possible role of the HBV surface antigen in the impairment of pDC function. Vincent, I.E et al have reported that HBV, but not HBsAg, can inhibit IFN-a production and TLR9 expression in pDCs [17]. HBsAg induced the secretion of TNF-a and IL-10 in monocytes, and these cytokines down-regulated the expression of TLR9 in pDCs to subsequently inhibit IFN-a production by pDCs
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