Hepatitis C virus infection, cryoglobulinaemia, and beyond

Rheumatology 2007;46:572–578 Advance Access publication 22 February 2007 doi:10.1093/rheumatology/kel425 Review Hepatitis C virus infection, cryoglobulinaemia, and beyond D. Sansonno, A. Carbone1, V. De Re2 and F. Dammacco Hepatitis C virus (HCV) infection is the major cause of mixed cryoglobulinaemia (MC), an immune complex (IC)-mediated systemic vasculitis mainly involving the small blood vessels. The precise mechanism of cryoprotein production is currently unknown. HCV virions and non-enveloped core protein participate in the formation of cold-insoluble ICs. Cryoglobulinaemic patients represent a distinct HCV-infected population, in that significant HCV enrichment of lymphoid cells is accompanied by evidence of productive virus infection and increased frequency of B cells. Liver, the major target organ of HCV, is the site of accumulation of inflammatory infiltrates that shares many architectural features with lymphoid tissue and reflects a distorted homeostatic balance between factors that enhance cellular recruitment, proliferation and retention, and those that decrease cellularity (cell death and emigration). There is now overwhelming evidence of a direct contribution to B-cell growth and survival through production of a variety of cytokines and chemokines. Liver tissue over-expression and abnormal circulating levels of B-cell activating factor belonging to the TNF family can provide effective costimulatory mechanisms to sustain the B-cell clonal expansion, which constitutes molecular stigmata of MC. Indolent lymphoproliferation might act as the starting point of chronic, multistage lymphomagenesis. An innovative therapeutic strategy is directed to ‘eradication of the virus’ and deletion of B-cell clonalities. conserved untranslated region (UTR) [10]. The 50 UTR harbours an internal ribosome entry site that directs a cap-independent translation of the viral gene and synthesis of the viral polyprotein, which is cleaved into structural (C, E1, E2 and p7) and non-structural (NS2, NS3, NS4A, NS4B, NS5A and NS5B) proteins. RNA replication takes place in distinct cytoplasmic compartments and requires both viral (NS3 to NS5) and host proteins. During replication, HCV genomic RNA is transcribed into a complementary RNA strand, which subsequently constitutes a template for synthesis of a new genome [10]. The complementary RNA stretch at the 30 end of the replicative strand contains the initiation site for replication by viral RNA-dependent RNA polymerase [11]. Helicase activity of NS3 specifically recognizes the 30 ends of both the minus and the plus virus strands [12]. It has been speculated that the NS3/NS4A complex may associate with NS5B, which subsequently recognizes the 30 UTR of the plus strand, where initiation of minus strand synthesis occurs. HCV forms a membrane-associated replication complex composed of viral proteins, replicating RNA, and altered cellular membranes [13]. Viral proteins are generated by co- and post-translational cleavage of the precursor polyprotein, while host peptidases located in the endoplasmic reticulum catalyse the cleavage of structural proteins. After genome amplification and protein expression, progeny virions are assembled and released, probably through a constitutive pathway [14]. Introduction Hepatitis C virus (HCV) is a member of the genus Hepacivirus in the Flaviviridae family [1]. It is an enveloped RNA virus that causes chronic infection in
200 million people worldwide [2]. Almost 80% of the infected patients develop chronic hepatitis, followed by cirrhosis in 10–20% and hepatocellular carcinoma in 1–5% [3]. Its complete replication in cell culture has recently been achieved [4]. Even so, its characterization and that of its life cycle are still difficult questions. A surprising feature of HCV is that its association with some B-cell-related disorders is becoming increasingly evident. It is a major causal factor of mixed cryoglobulinaemia (MC), a chronic immune complex (IC)-mediated systemic vasculitis with underlying B-cell proliferation [5, 6], and contributes to the development of monoclonal gammopathy of undetermined significance (MGUS) [7] and post-transplant proliferative disorders [8]. B-cell malignant conversion may be the consequence of additional genetic accidents in the latently infected cells, or abnormal conditions resulting from modifications of host cell genes involved in the control of oncogenes and oncoproteins. In this review we will discuss the mechanisms underlying the production of cryoglobulins in chronically infected MC patients; how signalling from B-cell receptor (BCR) and cytokines contributes to sustain B-cell clonal expansions; the role of ICs in the production of tissue damage and the therapeutical prospects offered by combining selective B-cell depletion with antiviral treatment. Little will be said about the clinical picture since this has been the subject of a recent comprehensive review [9]. Cryoglobulins and related clinical features Cryoglobulins are immunoglobulins (Igs) that become insoluble below 378C and give rise to high-molecular-weight aggregates [15]. They are found in small quantities in normal serum [16], but in variable concentrations in many pathological conditions, including tumours of the lymphoid system, autoimmune disorders and several infectious diseases. Conventionally, cryoglobulins are classified on the basis of their Ig composition as type I, consisting of a monoclonal Ig alone, type II as a mixture of monoclonal and polyclonal Igs and type III consisting of polyclonal Igs. In MC, which comprises types II and III, IgM typically has rheumatoid factor (RF) activity [17]. Type I cryoglobulinaemia accounts for 10–15% of people with cryoprecipitates. IgM cryoglobulins (the most common type I variety) occur in almost 6% of malignant IgM paraproteinaemia. IgG (usually IgG2 or IgG3) cryoglobulins usually occur in almost Hepatitis C virus The HCV genome carries a single positive-strand RNA containing a single open reading frame encoding for a long polyprotein of 3010–3040 amino acids, flanked at either end by a highly Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, 1Department of Pathology, Istituto Nazionale Tumori, Milano and 2 Division of Experimental Oncology I, Centro di Riferimento Oncologico, Aviano (PN), Italy. Submitted 4 November 2006; revised version accepted 28 November 2006. Correspondence to: D. Sansonno, MD, Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Policlinico, Piazza Giulio Cesare 11, 70124 Bari, Italy. E-mail: 572 ß The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: HCV and cryoglobulinaemia 2% of all myelomas. IgA cryoglobulins are rare and cryo-Bence Jones proteins have been occasionally described [18]. MC contains Ig/anti-Ig complexes and frequentl (...truncated)