Role of the receptor for the globular domain of C1q protein in the pathogenesis of hepatitis C virus-related cryoglobulin vascular damage

Abstract

Mixed cryoglobulinemia (MC) is a lymphoproliferative disorder observed in approximately 10 to 15% of hepatitis C virus (HCV)-infected patients. Circulating, nonenveloped HCV core protein, which has been detected in cryoprecipitable immune complexes, interacts with immunocytes through the receptor for the globular domain of C1q protein (gC1q-R). In this study, we have evaluated circulating gC1q-R levels in chronically HCV-infected patients, with and without MC. These levels were significantly higher in MC patients than in those without MC and in healthy controls and paralleled specific mRNA expression in PBL. Soluble gC1q-R circulates as a complexed form containing both C1q and HCV core proteins. Higher serum gC1q-R levels negatively correlated with circulating concentrations of the C4d fragment. The presence of sequestered C4d in the vascular bed of skin biopsies from MC patients was indicative of in situ complement activation. In vitro studies showed that release of soluble gC1q-R is regulated by HCV core-mediated inhibition of cell proliferation. Our results indicate that up-regulation of gC1q-R expression is a distinctive feature of MC, and that dysregulated shedding of C1q-R molecules contributes to vascular cryoglobulin-induced damage via the classic complement-mediated pathway.

Figures

FIGURE 1

Serum levels of soluble gC1q-R in sera of different categories of patients and in the healthy subjects.

FIGURE 2

Circulating levels of gC1q-R/HCV core complex in sera of chronically HCV-infected patients.

FIGURE 3

Localization of HCV core (A) and C4d (C) proteins in skin biopsies of HCV-positive MC patients. Reactivity of control sections (B and D) is shown for comparison. Core protein is mainly located within the vessel lumen, whereas C4d is expressed along the walls. Note complete negativity of control sections.

FIGURE 4

In vitro effect of HCV core protein on C4d production. Scalar concentrations of HCV core protein were applied in microwells and C4d generation was determined after incubation with HCV-positive serum samples (■). C1q-depleted human serum (□) obtained from Quidel (lot 904184) was also incubated and C4d generation was quantified. Serum samples from a healthy subject before (◇) and after (◆) gC1q-R protein enrichment (2 ng/μl) were also tested.

FIGURE 5

Inhibition of PBL proliferation by HCV core protein. Upper panel, Degree of inhibition of PHA-induced proliferation of PBL in different categories. Lower panel, Relative concentrations of gC1q-R in the PBL culture medium.

FIGURE 6

gC1q-R mRNA expression in PBL. A, Frequency of cell surface gC1q-R on PBL by FACS analysis. B, Quantitative real-time RT-PCR performed on nucleic acids extracted from PBL. Data are means ± SD for each group.