Altered chemotactic response of myeloid and plasmacytoid dendritic cells from patients with chronic hepatitis C: role of alpha interferon

Abstract

Dendritic cell (DC) frequencies in the blood of patients with chronic hepatitis C virus (HCV) infection have been shown to be reduced significantly compared with those in healthy individuals. There is a further reduction of circulating myeloid DCs (MDCs) and plasmacytoid DCs (PDCs) in HCV patients receiving alpha interferon (IFN-a)-based antiviral therapy. Altered homing behaviour of DCs may be a possible mechanism for their 'loss' in peripheral blood in these clinical conditions. Systemic chemokine levels were measured by ELISA. Phenotypes and migratory properties of MDCs and PDCs from HCV patients were analysed by flow cytometry and chemotaxis assay. Compared with healthy controls, HCV patients had increased serum levels of inflammatory and constitutively expressed chemokines. Spontaneously generated MDCs from HCV patients were less mature, and both MDCs and PDCs showed intrinsic activation of receptors for inflammatory chemokines, thus suggesting an increased propensity to migrate towards inflammatory sites. IFN-a treatment in vitro induced MDC maturation and skewed the migratory response of both MDCs and PDCs towards chemokines expressed constitutively in secondary lymphoid organs. In conclusion, our results hint at altered homing behaviour of DCs during chronic HCV infection. IFN-a therapy may redirect DC migration from inflamed hepatic portal areas towards secondary lymphoid tissue.

Dynamics of regulatory T cells and plasmacytoid dendritic cells as immune markers for virological response in pegylated interferon-α and ribavirin therapy for chronic hepatitis C patients

“…Therefore, it is plausible that PDC may migrate from the liver to periphery/lymphoid tissue after being unleashed from chemokines in the liver. In support for this, it is reported that IFN-a alters the profiles of chemokine receptors on DC, resulting in changes of the DC migrating ability [34].…”

Trafficking properties of plasmacytoid dendritic cells in health and disease

“…31 No.7 are fully competent in inducing PDCs adhesion and migration when immobilized on heparan sulphates expressed by endothelial cells [33]. Two recent reports showed that PDCs purified from patients with chronic hepatitis C, or exposed in vitro to IFN-a, acquire the ability to respond to CCR2, CCR5 and CXCR3 ligands [44,45]. These results suggest that under appropriate stimulatory conditions, additional chemokine receptors may be involved in human PDCs recruitment.…”

Dendritic cell recruitment and activation in autoimmunity

“…However, when CXCR3 ligands were immobilized on heparan sulphates expressed by endothelial cells, they became totally competent to induce pDC migration [105]. In addition, pDCs purified from patients with chronic hepatitis C, or exposed in vitro to IFN-a, acquire the ability to respond to CCR2, CCR5 and CXCR3 ligands [106,107], suggesting that appropriate stimulatory conditions may increase the range of chemokines able to recruit pDCs to inflamed tissues. pDCs were also described to express functional receptors for adenosine [108], F2L [109] and for the complement anaphylatoxins C3a and C5a [110], and to migrate in response to IL-18 [111]; all these signals are released in inflamed tissues.…”