HCV and Lymphoproliferation

Hindawi Publishing Corporation Clinical and Developmental Immunology Volume 2012, Article ID 980942, 8 pages doi:10.1155/2012/980942 Review Article HCV and Lymphoproliferation Anna Linda Zignego,1, 2 Carlo Giannini,1, 2 and Laura Gragnani1, 2 1 Center for Systemic Manifestations of Hepatitis Viruses (MASVE), Department of Internal Medicine, University of Florence, 50134 Florence, Italy 2 Istituto Toscano Tumori (ITT), 50139 Firenze, Italy Correspondence should be addressed to Anna Linda Zignego, Received 27 April 2012; Accepted 20 June 2012 Academic Editor: Domenico Sansonno Copyright © 2012 Anna Linda Zignego et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Hepatitis C virus (HCV) infection is a serious public health problem because of its worldwide diffusion and sequelae. It is not only a hepatotropic but also a lymphotropic agent and is responsible not only for liver injury—potentially evolving to cirrhosis and hepatocellular carcinoma—but also for a series of sometimes severely disabling extrahepatic diseases and, in particular, B-cell lymphoproliferative disorders. These latter range from benign, but prelymphomatous conditions, like mixed cryoglobulinemia, to frank lymphomas. Analogously with Helicobacter pylori related lymphomagenesis, the study of the effects of viral eradication confirmed the etiopathogenetic role of HCV and showed it is an ideal model for better understanding of the molecular mechanisms involved. Concerning these latter, several hypotheses have been proposed over the past two decades which are not mutually exclusive. These hypotheses have variously emphasized the important role played by sustained stimulation of the immune system by HCV, infection of the lymphatic cells, viral proteins, chromosomal aberrations, cytokines, or microRNA molecules. In this paper we describe the main hypotheses that have been proposed with the corresponding principal supporting data. 1. Introduction Hepatitis C virus (HCV) infection is a major public health problem with an estimated 3-4 million people infected each year worldwide and about 170–200 million carriers. These latter are at risk of developing liver cirrhosis and/or liver cancer. More than 350,000 people die from HCV-related liver diseases each year. Moreover, these estimates do not take into account the extrahepatic aspects of HCV infection. Early after its discovery, it was shown that HCV is also a lymphotropic virus [1]. As a consequence of the lymphatic infection, several lymphoproliferative disorders (LPDs) have been associated with this virus [2], including mixed cryoglobulinemia (MC), B-cell non-Hodgkin’s lymphoma (NHL) [3–10] and monoclonal gammopathies [11–13]. Mixed cryoglobulinemia is the most frequent and well known LPD developing during HCV infection. Although clinically benign, MC is a prelymphomatous disorder leading to NHL in about 5–10% of cases. This makes MC a valuable model for study of pathogenetic mechanisms of HCV-related LPDs [2–14]. MC was previously interpreted as a lymphoma in situ, being characterized by bone marrow and/or liver infiltrates closely resembling NHL [15]. Therefore, it was hypothesized that HCV may be involved in the pathogenesis of NHL as well [1, 4]. This hypothesis was substantiated by several observations, including the significantly high prevalence of HCV infection in NHL patients in several studies [6, 7, 10, 12, 16–18]. A lot of data are presently available showing, in most cases, a significant association with B-cell NHL, even with a clear south-north gradient and involving different histopathological types of lymphoma, the most strictly associated being the lymphoplasmacytic, marginal zone and diffuse large B-cell lymphoma [19]. A case-control study has shown that HCV infection increases the risk for NHL involving the liver and major salivary glands by about 50-fold (i.e., a risk higher than that for hepatocellular carcinoma) and the risk for NHLs at other sites by about 4-fold [20]. The observation of the effect of viral eradication using antiviral agents strongly supports the etiopathogenetic link between HCV infection and lymphomagenesis. Analogously with what has been reported for MC, in the case of low 2 Clinical and Developmental Immunology Sustained antigenic stimulation Lymphotropism Host genetic predisposition HCV proteins HCV-related LPDs Inhibition of apoptosis Chromosomal aberrations CD81-E2 interaction Cytokines Figure 1: Pathogenesis of HCV-related lymphoproliferative disorders (LPDs). Main working hypotheses and their principal interconnections. grade B-cell lymphoma—and especially in cases of splenic lymphoma—clinical remission following effective antiviral therapy in HCV-associated cases has been observed [21– 23]. Interestingly, in a recent Japanese study involving about 3,000 HCV-infected patients observed during a long-term follow-up, it was shown that the annual incidence of lymphoma was 0.23% and the cumulative rate of lymphoma development after 15 years was 2.6% in both the untreated and non-responder patients with persisting infection versus 0% in treated patients achieving viral eradication, strongly suggesting that antiviral therapy protects against the development of lymphoma [24]. 2. Mechanisms of HCV-Related Lymphomagenesis Several hypotheses, frequently interconnected with each other, have been proposed in regard to the possible mechanisms of HCV-related lymphomagenesis (Figure 1). These include a key role played by the sustained antigenic stimulation of the B-cell compartment, the role of viral lymphotropism and viral proteins, chromosomal aberrations, cytokines, and microRNAs. 2.1. The Role of Sustained Antigenic Stimulation. Sustained HCV-driven antigenic stimulation has been suggested to play a key role in inducing B-cell clonal expansion characterizing these disorders (Figure 2). The presence in the liver of lymphatic structures resembling lymphatic follicles is characteristic of HCV infection. It has been suggested that they represent an important site of B-cell clonal expansion, especially in patients with MC, where they have been found in almost all cases [25]. Furthermore, B lymphocytes isolated from hepatic follicles produced rheumatoid factor (RF) that most frequently display the WA cross-reactive idiotype, considered to be characteristic of MC [25]. In particular, it was observed that intrahepatic B-cell clonalities were invariably associated with extrahepatic manifestations of HCV infection, including high serum levels of RF activity, cryoglobulins, monoclonal gammopathy of undetermined significance (MGUS), and frank B-cell NHL [26]. The key role of antigen-driven stimulation in HCV-related lymphoproliferation was also supported by a study investigating mutations in the V(H) and V(K) genes of the B-cell clone inducing a frank NH (...truncated)