Abstract
B cell non-Hodgkin lymphoma is a typical extrahepatic manifestation frequently associated with hepatitis C virus (HCV) infection. The mechanism by which HCV infection leads to lymphoproliferative disorder remains unclear. Our group established HCV transgenic mice that expressed the full HCV genome in B cells (RzCD19Cre mice). We observed a 25.0% incidence of diffuse large B cell non-Hodgkin lymphomas (22.2% in male and 29.6% in female mice) within 600 days of birth. Interestingly, RzCD19Cre mice with substantially elevated serum-soluble interleukin-2 receptor α-subunit (sIL-2Rα) levels (>1000 pg/mL) developed B cell lymphomas. Another mouse model of lymphoproliferative disorder was established by persistent expression of HCV structural proteins through disruption of interferon regulatory factor-1 (irf-1_/_/CN2 mice). Irf-1_/_/CN2 mice showed extremely high incidences of lymphomas and lymphoproliferative disorders. Moreover, these mice showed increased levels of interleukin (IL)-2, IL-10, and Bcl-2 as well as increased Bcl-2 expression, which promoted oncogenic transformation of lymphocytes.
Highlights
The incidence of non-Hodgkin lymphoma (NHL) is rising worldwide and is higher in developed countries than in Africa and Asia [1]
B cell non-Hodgkin lymphoma is a typical extrahepatic manifestation frequently associated with hepatitis C virus (HCV) infection
Our results show that the conditional expression of HCV proteins induces inflammation and lymphoproliferative disorders
Summary
The incidence of non-Hodgkin lymphoma (NHL) is rising worldwide and is higher in developed countries than in Africa and Asia [1]. To investigate the mechanism of development of lymphoproliferation or B cell non-Hodgkin lymphoma in HCV patients, we developed a transgenic mouse model that conditionally expressed HCV cDNA (nucleotides 294–3435), including the viral genes that encode the core, E1, E2, and NS2 proteins, by using the Cre/loxP system (in core-NS2 [CN2] mice) [10, 11]. Transgenic mice that expressed the HCV core protein were established using a promoter derived from hepatitis B virus [13], whereas mice that expressed structural or complete viral proteins were established using promoters derived from the albumin gene [14] These mice were immunotolerant to the transgene and did not develop hepatic inflammation. We established an irf-1−/− CN2 mouse model of persistent HCV expression, which allowed us to investigate the effects of HCV on lymphatic tissue tumor development
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