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 ∼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.

Basic and Translational Concepts of Immune-Mediated Glomerular Diseases

“…[196][197][198][199]208 These soluble, but cryoprecipitable, aggregates of IgG, IgM, viral proteins/nucleic acids, and C1q constitute the mesangial and subendothelial immune deposits found in glomeruli and cause local inflammation through direct interaction with TLRs 3, 7, and 9 on both infiltrating inflammatory cells and/or resident glomerular cells as well as by inducing more classic pathway C activation. [196][197][198][209][210][211][212][213] As in lupus, the subepithelial deposits often seen in MPGN I (and sometimes referred to as type III MPGN) may represent subendothelial deposits that dissociate and reform in situ or autoantibodies to as yet unidentified podocyte antigens. 45,46 As in lupus, complement likely plays both nephritogenic and protective roles in MPGN I. C1q seems to be important in mediating the initial interaction between IgM, IgG, HCV complexes, B cells, and TLRs, 196,197,212 and complement activation by immune deposits through the classic pathway likely aggravates tissue injury, 7,10 although overexpression of a complement regulatory protein, Crry, in a well studied murine model did not significantly ameliorate the disease.…”

Antibodies reactive to cleaved sites in complement proteins enable highly specific measurement of soluble markers of complement activation

“…The most widely used assay for assessment of soluble C4d is manufactured by Quidel and has been used in a number of clinical studies regarding vasculitis (Gou et al, 2013), cardiac arrest (Bisschops et al, 2012) (Jenei et al, 2014), graft rejection (Flechner et al, 2010), mixed cryoglobulinemia (Sansonno et al, 2009), Sjögren's syndrome (Sudzius et al, 2014), lupus (Manzi et al, 1996) and lung cancer (Ajona et al, 2013). According to the manufacturer, this ELISA is based on a neoepitope C4d catching antibody and detection is completed by goat polyclonal anti-C4d.…”

Hepatitis C Virus Cryoglobulinemia and Non-Hodgkin Lymphoma

“…Moreover, the importance of the complement system must not be forgotten, because complement components that may be generated in the course of an infection are involved in the immune complex-mediated reactions. This system is highly activated in cryoglobulinemic patients (31), and efficient engagement of C1q protein by cryoglobulins may be the chief pathogenetic mechanism involved in the cryoglobulin-related pathway (32). There is no doubt that dysregulation of helper T cells and their cytokines aids in the production of autoantibodies, such as cryoglobulins.…”