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Role of the Receptor for the Globular Domain of C1q Protein in the Pathogenesis of Hepatitis C Virus-Related Cryoglobulin Vascular Damage¹

Domenico Sansonno,^2* Felicia Anna Tucci,^* Berhane Ghebrehiwet, Gianfranco Lauletta,^* Ellinor I. B. Peerschke, Vincenza Conteduca,^* Sabino Russi,^* Pietro Gatti,^* Loredana Sansonno,^* and Franco Dammacco^*

^*Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy; Department of Medicine, Stony Brook University, Stony Brook, NY 11794; and Department of Pathology, Mt. Sinai School of Medicine, New York, NY 10029

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported in part by Italian Ministry of University and Scientific and Technologic Research, National Project "Chronic liver damage induced by hepatitis C virus" (to D.S.); Agenzia Italiana del Farmaco, funds for independent studies, 2007, contract no. FARM7SJX (to D.S.); National Institutes of Health, Grants AI 060866 (to B.G.) and HL67211 (to E.I.B.P.); and Associazione Italiana per la Ricerca sul Cancro, Milan, Italy (to F.D.).

² Address correspondence and reprint requests to Dr. Domenico Sansonno, 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. E-mail address: d.sansonno{at}dimo.uniba.it

³ Abbreviations used in this paper: MC, mixed cryoglobulinemia; CAH, chronic active hepatitis; gC1q-R, globular domain of C1q protein; HBsAg, hepatitis B surface Ag; HCV, hepatitis C virus; IC, immune complexes; moAb, monoclonal Ab; RBV, ribavirin; RF, rheumatoid factor.