Hepatitis C Virus (HCV) and Lymphomagenesis

Abstract

Hepatitis C virus (HCV) is the major cause for non-A, non-B hepatitis. Most HCV-infected individuals do not clear the virus resulting in a chronic infection that may potentially lead to liver cirrhosis and hepatocellular carcinoma. In addition to hepatic manifestations, HCV infection is associated with B cell lymphoproliferative disorders, including mixed cryoglobulinemia, usually a benign condition, and overt B cell lymphoma. A direct role of HCV infection in the genesis of these B cell lymphoproliferative disorders has been suggested initially by epidemiological studies and is supported by recent studies, which analyzed the monoclonal B cells that proliferate in these disorders. How HCV induces B cell lymphoproliferative disorders is still unclear, it is probably not due to direct change of phenotype in B cells after viral infection, but may be due to an HCV-antigen driven process. Support for this hypothesis comes from the analysis of monoclonal B cells found in these disorders, which use a restricted repertoire of immunoglobulin variable region genes that are similar to those used by B cells that secrete anti-HCV antibodies. The fact that monoclonal IgM is resolved in HCV-infected patients who responded to anti-viral treatment supports the linkage between antigen persistence and B cell proliferation. Finally, the linkage between benign B cell proliferation and overt lymphoma is supported by the identification of a pre-malignant B cell clone that subsequently converted to an overt B cell lymphoma. The molecular basis for viral induced B cell proliferation is still unknown. One possibility is that HCV stimulates the proliferation of monoclonal B cells via their HCV-specific B cell receptor (BCR) on the cell surface. Binding of the HCVenvelope proteins to a cellular ligand, CD81, may also enhance this antigen-driven process. A recent report on regression of splenic marginal zone lymphoma after anti-viral treatment with interferon and ribavirin has significantly strengthened the cause-effect relationship between HCV infection and lymphoma. Further studies should determine whether BCRs expressed on HCV-associated lymphomas, particularly those that regress in response to anti-viral therapy, bind HCV antigens that stimulate their proliferation.

Non-Hodgkin's lymphoma and other nonhepatic malignancies in Swedish patients with hepatitis C virus infection

“…It has been demonstrated that HCV-related lymphomas could be the result of HCV antigen stimulation of B cells. 18 Other indirect evidence for a possible role of HCV infection in the genesis of lymphoma is found in reports in which therapy against HCV is associated with regression of lymphoma. In one study of 9 patients with HCV infection and splenic marginal zone lymphoma, all 9 patients had a regression of the lymphoma as they cleared the virus when treated with interferon alfa with or without ribavirin.…”

“…[14][15][16] HCV has been suggested to be both hepatotropic and lymphotropic. 17,18 The incidence of malignant NHL has increased in many countries in recent years. 19 In Sweden the average annual increase between 1981 and 2000 was 1.2% for men and 1.5% for women.…”

Seroprevalence of HTLV I-II, HIV and HCV Antibodies in Lymphoma, Head and Neck Cancer Patients

“…23 HCV has been suggested to be both hepatotropic and nonhepatic in other words lymphotropic. 24,25 Furthermore, the HCV has nonhepatic oncogenic potential since chronic HCV confers an increased risk of NHL and other hematopoietic malignancies and thyroid cancer. A Swedish group studied the incidence of Chronic lymphocytic leukemia (CLL), Acute lymphocytic leukemia (ALL), NHL, HL, MM, and TC in the entire cohort of notified HCV patients in Sweden.…”

Hepatitis C virus and autoimmunity

“…The association between NHL and HCV infection has been examined in many retrospective case-control studies [7,65,66]. According to Monti et al [67] patients with MC have a 35 times higher risk of NHL than the general population.…”