Role of the receptor for the globular domain of C1q protein in the pathogenesis of hepatitis C virus-related cryoglobulin vascular damage.
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.
Sansonno
Domenico
D
Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari Medical School, Policlinico, Piazza Giulio Cesare 11, 70124 Bari, Italy. d.sansonno@dimo.uniba.it
Tucci
Felicia Anna
FA
Ghebrehiwet
Berhane
B
Lauletta
Gianfranco
G
Peerschke
Ellinor I B
EI
Conteduca
Vincenza
V
Russi
Sabino
S
Gatti
Pietro
P
Sansonno
Loredana
L
Dammacco
Franco
F
D015922:Complement C1q / Q000378:metabolism*; D003171:Complement Pathway, Classical / Q000276:immunology; D003449:Cryoglobulinemia / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D003450:Cryoglobulins / Q000009:adverse effects*; D005260:Female; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D008875:Middle Aged; D017434:Protein Structure, Tertiary; D011951:Receptors, Complement / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D015854:Up-Regulation / Q000276:immunology; D014657:Vasculitis / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D014758:Viral Core Proteins / Q000276:immunology / Q000378:metabolism
D003450:Cryoglobulins; D008562:Membrane Glycoproteins; D011951:Receptors, Complement; D014758:Viral Core Proteins; C032402:complement 1q receptor; D015922:Complement C1q