Expansion of CD5 + B-cell overexpressing CD81 in HCV infection: towards better understanding the link between HCV infection, B-cell activation and lymphoproliferation

Abstract

Hepatitis C virus (HCV) infection is one of the major causes of chronic liver disease in the Western world affecting 1.8% of the American population and 170 million people worldwide [1]. Approximately 85% of HCVinfected individuals fail to clear the virus and develop chronic hepatitis with persistent viremia [2]. In addition to its being predominantly hepatotrophic, HCV is also a lymphotrophic virus [3]. This RNA virus is able to infect and replicate within peripheral mononuclear cells, while its genomic sequence may also be recovered from lymph nodes and lymphocytes infiltrating the liver [4–6]. This peculiar lymphotropism may be responsible, at least in part, for the multiple immune-mediated extra-hepatic manifestations of HCV infection, such as mixed cryoglobulinemia [7,8], Sjogren-like syndrome [9], presence of serum rheumatoid factor (RF), production of autoantibodies [10–12] and B-cell nonHodgkin lymphoma [13–15]. The pathogenetic link between HCV and immune system in inducing both autoimmunity and lymphproliferation is unclear. The persistence of HCV in peripheral blood mononuclear cells, preferentially in B-cells [16], results in chronic stimulation of B-cells leading to polyclonal and later to monoclonal proliferation of RF (IgMk)-producing cells, which eventually may result in malignant transformation and development of overt lymphoma [17,18]. The recent identification of CD81 protein as one of the HCV-receptor candidates on B-lymphocytes [19] provides a mechanism by which B-cells are infected with or activated by HCV and may raise a wide spectrum of interesting issues regarding the pathogenetic link between HCV infection, autoimmunity and lymphoproliferative disorders. CD81 is a promiscuous molecule participating in different molecular complexes on various cell types, a fact that may influence its capacity to deliver signals to target cells. On B-cells, CD81 is a member of a signaling complex that includes CD19 and CD21 [20], two molecules, which when appropriately engaged, lower the threshold for B-cell activation and proliferation. Similarly, binding of HCV particles to a CD81-containing complex might facilitate B-cell activation, possibly explaining, at least in part, the association between HCV, B-cell activation and lymphoproliferative diseases. Interestingly, analysis of mixed cryoglobulins from patients infected with HCV shows that hepatitis C virion is bound to monoclonal IgM bearing the WA cross-idiotype (XId) [8]. In addition, data on the molecular composition of WA monoclonal RF (mRF) and the characterization of monoclonal B-cells in the liver of patients with mixed cryoglobulinemia type II [21] suggest that a specific population of B-cells may be involved in the host response to HCV infection. These are B-cells that proliferate with little or no somatic mutations of the immunoglobulin genes, are self-replicating, are stimulated by self-antigens in a T cell independent manner and bear the CD5 marker [22]. CD5 B-cells are rare in adults, but they are the predominant Bcell population in the fetus, in which they appear to constitute a rather primitive but effective first line of defense against foreign antigens [23]. These cells are characterized by the production of low-affinity immunoglobulin M (IgM) with RF activity, arise early in ontogeny and are considered to represent the bridge linking the innate and acquired immune responses [23]. The expansion of CD5 B-cells in rheumatoid arthritis and Sjogren’s syndrome [24,25] coupled with their association with autoimmune manifestations in patients infected by HIV or Epstein–Barr virus [26,27] has implicated them in the development of autoimJournal of Hepatology 38 (2003) 674–676