Persistent expression of the full genome of hepatitis C virus in B cells induces spontaneous development of B-cell lymphomas in vivo.
Extrahepatic manifestations of hepatitis C virus (HCV) infection occur in 40%-70% of HCV-infected patients. B-cell non-Hodgkin lymphoma is a typical extrahepatic manifestation frequently associated with HCV infection. The mechanism by which HCV infection of B cells leads to lymphoma remains unclear. Here we established HCV transgenic mice that express the full HCV genome in B cells (RzCD19Cre mice) and observed a 25.0% incidence of diffuse large B-cell non-Hodgkin lymphomas (22.2% in males and 29.6% in females) within 600 days after birth. Expression levels of aspartate aminotransferase and alanine aminotransferase, as well as 32 different cytokines, chemokines and growth factors, were examined. The incidence of B-cell lymphoma was significantly correlated with only the level of soluble interleukin-2 receptor α subunit (sIL-2Rα) in RzCD19Cre mouse serum. All RzCD19Cre mice with substantially elevated serum sIL-2Rα levels (> 1000 pg/mL) developed B-cell lymphomas. Moreover, compared with tissues from control animals, the B-cell lymphoma tissues of RzCD19Cre mice expressed significantly higher levels of IL-2Rα. We show that the expression of HCV in B cells promotes non-Hodgkin-type diffuse B-cell lymphoma, and therefore, the RzCD19Cre mouse is a powerful model to study the mechanisms related to the development of HCV-associated B-cell lymphoma.
Kasama
Yuri
Y
Department of Experimental Phylaxiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Sekiguchi
Satoshi
S
Saito
Makoto
M
Tanaka
Kousuke
K
Satoh
Masaaki
M
Kuwahara
Kazuhiko
K
Sakaguchi
Nobuo
N
Takeya
Motohiro
M
Hiasa
Yoichi
Y
Kohara
Michinori
M
Tsukiyama-Kohara
Kyoko
K
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002472:Cell Transformation, Viral / Q000235:genetics; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005814:Genes, Viral; D016174:Hepacivirus / Q000235:genetics*; D007150:Immunohistochemistry; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D016403:Lymphoma, Large B-Cell, Diffuse / Q000473:pathology / Q000821:virology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D053645:Interleukin-2 Receptor alpha Subunit; D012333:RNA, Messenger