The B-cell receptor of a hepatitis C virus (HCV)–associated non-Hodgkin lymphoma binds the viral E2 envelope protein, implicating HCV in lymphomagenesis

Abstract

Hepatitis C virus (HCV) infection is associated with extrahepatic B-cell lymphoproliferative disorders. To determine whether a viral antigen drives this B-cell expansion, the B-cell receptors were cloned from HCV-associated lymphomas and were expressed as soluble immunoglobulins. The rescued immunoglobulins were then tested for their ability to bind the HCV-E2 envelope glycoprotein, an antigen that was previously implicated in the pathogenesis of HCV-associated B-cell diseases. One of 2 lymphoma immunoglobulin test cases bound the E2 protein in a manner identical to a bona fide human anti-E2 antibody. Moreover, it bound E2 from multiple viral genotypes, suggesting reactivity with a conserved E2 epitope. IntroductionMore than 100 million people worldwide are infected by hepatitis C virus (HCV). 1 Infection causes prolonged and persistent disease in the majority of carriers, often leading to chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (reviewed in Houghton 2 and Liang et al 3 ). HCV is also the leading cause of mixed cryoglobulinemia (MC), a systemic immune complex-mediated disorder characterized by polyclonal or monoclonal B-cell proliferation. 4,5 MC can evolve into overt B-cell non-Hodgkin lymphoma (NHL), 6,7 although the incidence of malignant transformation appears to be restricted to certain areas of the world.In type II MC, immunoglobulin immune complexes contain both monoclonal immunoglobulin M (IgM) and polyclonal IgG. 8 The monoclonal IgM has rheumatoid factor (RF) activity and is encoded mostly by a restricted set of variable (V) region genes, specifically V H 1-69 (also known as 51p1) and V3-A27 (also known as v325). 9-12 The same set of V region genes is expressed by the majority of HCV-associated NHL, suggesting a malignant progression from type II MC. 13 Immunoglobulin V region genes expressed by these lymphomas exhibit an ongoing process of somatic mutations, indicative of antigen selection. 13 Moreover, the histologic presentation of many HCV-associated NHLs is typical of germinal center (GC) and post-GC B cells. 14 Therefore, it is likely that lymphomagenesis occurs when B cells proliferate in response to antigen. To date, the antigen driving these extrahepatic lymphoproliferative diseases is unknown.Nevertheless, immune responses occurring in HCV patients against one HCV antigen, the E2 envelope glycoprotein (E2), suggest that the restricted V gene usage seen in the lymphoproliferative disorders may be linked to this antigen. V region genes from human anti-E2 antibodies, derived from B cells of HCV-infected individuals, show similar V gene bias to that observed in HCV-associated MC and NHL. 15,16 These studies implicate the specific immune response to the E2 antigen in the pathogenesis of B-cell lymphoproliferative diseases and potentially in HCV-associated lymphomas.A possibility exists that cognate B cells, which bind E2 via their specific B-cell receptor (BCR) could engage 2 signaling complexes simultaneously-the BCR and the CD19/CD21/CD81 complex (CD81 is the putative E...

HCV-NS3 and IgG-Fc crossreactive IgM in patients with type II mixed cryoglobulinemia and B-cell clonal proliferations

“…12 Alternatively, the positive signals may be hidden by the high diversity of HCV sequences. 30,31 It is known that during HCV infection, NS3 can induce an important humoral and cellular immune response. [32][33][34][35][36][37] Nevertheless, the structural details about the antigen presenting cells and the B-cell epitope recognition in vivo are still unknown.…”

Effect of hepatitis C virus infection on the risk of non‐Hodgkin's lymphoma: A meta‐analysis of epidemiological studies

“…38) Envelope protein E2 is now considered as a candidate antigen based on several lines of evidence: anti-HCV E2 B-cell clones from an HCV-infected patient preferentially used V H 1-69 39) and B-cell receptor from one HCV-associated lymphoma patient bound to E2. 40) CD81 is a cellular ligand for E2 envelope on the surface of lymphocytes. 41) CD19/CD21/CD81 complex along with B-cell receptor stimulation is considered to activate proliferation of lymphocytes.…”

Response to antiviral treatment in hepatitis C virus-associated marginal zone lymphomas

“…Anti-HCV antibodies, the monoclonal compound of type II cryoglobulinemia and the lymphoma's immunoglobulins were found to be part of the same phenomenon, that is, the immunological response to HCV antigens. [21][22][23][24][25][26][27][28] Moreover, interaction between the virus and the cell surface activates STAT3 and leads to cellular transformation. 29 Finally, recent research showed that tumoral HCV-infected B cells have an increased rate of mutations of IgH, BCL-6, P53 and b-catenin.…”