Int J Mol Med. 2015 Dec;36(6):1464-78. doi: 10.3892/ijmm.2015.2372. Epub 2015 Oct 13.
Pre-stimulation of CD81 expression by resting B cells increases proliferation following EBV infection, but the overexpression of CD81 induces the apoptosis of EBV-transformed B cells.
Park GB1, Kim D1, Park SJ2, Lee HK2, Kim JH2, Kim YS1, Park SG3, Choi IH3, Yoon SH4, Lee YJ2, Paeng S5, Hur DY1.
1Department of Anatomy and Research Center for Tumor Immunology, Inje University College of Medicine, Busan 614-735, Republic of Korea.
2Department of Internal Medicine, Inje University Busan Paik Hospital, Busan 614-735, Republic of Korea.
3Department of Microbiology, Inje University College of Medicine, Busan 614-735, Republic of Korea.
4Department of Plastic Surgery, Inje University Haeundae Paik Hospital, Busan 614-735, Republic of Korea.
5Department of Neurosurgery, Inje University Busan Paik Hospital, Busan 614-735, Republic of Korea.
Hepatitis C virus (HCV) E2 protein binds to CD81, which is a component of the B cell co-stimulatory complex. The E2-CD81 interaction leads to B cell proliferation, protein tyrosine phosphorylation and to the hypermutation of immunoglobulin genes. Epidemiological studies have reported a high prevalence of B cell non-Hodgkin lymphoma (NHL) in HCV-positive patients, suggesting a potential association between HCV and Epstein-Barr virus (EBV) in the genesis of B lymphocyte proliferative disorders. In the present study, in order to investigate the association between EBV and HCV in B cells, we created an in vitro EBV-induced B cell transformation model. CD81 was gradually overexpressed during transformation by EBV. B cells isolated from HCV-positive patients grew more rapidly and clumped together earlier than B cells isolated from healthy donors following EBV infection. Pre-stimulation of CD81 expressed by resting B cells with anti-CD81 monoclonal antibody (mAb) or HCV E2 accelerated the generation of lymphoblastoid cell lines (LCLs) by EBV infection. These cells proliferated prominently through the early expression of interleukin-10 and intracellular latent membrane protein (LMP)-l. By contrast, the overexpression of CD81 on EBV-transformed B cells by anti-CD81 mAb or HCV E2 protein induced apoptosis through reactive oxygen species (ROS)-mediated mitochondrial dysfunction. These results suggest that the engagement of CD81 expressed by B cells has differential effects on B cell fate (proliferation or apoptosis) according to EBV infection and the expression level of CD81.