Effects of Epstein-Barr virus infection on the development of multiple myeloma after liver transplantation

Science China Life Sciences, Aug 2012

Reduced cellular immune function in patients after liver transplantation easily results in many types of viral infections, such as Epstein-Barr virus. Epstein-Barr virus is a Γ-herpesvirus and is related to many malignant diseases, especially epithelial and lymph tumors. The abnormal interaction of cluster of differentiation 40 with cluster of differentiation 40 ligand and expression of cluster of differentiation 40 ligand are considered closely related to the development of myeloma cells. This study explored the influence and mechanism of Epstein-Barr virus infection on the phenotype and biological behavior of myeloma cells after liver transplantation. Flow cytometry was used to detect coexpression of cluster of differentiation 40 and cluster of differentiation 40 ligand in 10 samples of freshly isolated multiple myeloma cells. Cluster of differentiation 40 and cluster of differentiation 40 ligand were coexpressed in sample Nos. 5, 8, 9, and 10, particularly in sample No. 5. Western blot analysis was used to detect the expression of the Epstein-Barr virus antigens latent membrane protein 1 and Epstein-Barr virus nuclear antigen 2 in the multiple myeloma cell line RPMI 8226 infected with Epstein-Barr virus. The antigen expression indicated that Epstein-Barr virus can infect multiple myeloma virus cells in vitro. Reverse transcription-polymerase chain reaction revealed upregulated expression of cluster of differentiation 40 ligand on the infected RPMI 8226 cells, which may be involved in the anti-apoptosis activity of the infected cells. Confocal microscopy showed that pairs of molecules of cluster of differentiation 40, cluster of differentiation 40 ligand, and latent membrane protein 1 were colocalized on the surface of the infected cells. CXC chemokine receptor 4 was upregulated on the RPMI 8226 cells after Epstein-Barr virus infection. The migratory ability of the infected cells improved in the presence of the chemokine stromal cell-derived factor-1α. Anti-apoptosis and migration are known important biological characteristics of malignant cells. Our results indicate the involvement of Epstein-Barr virus in the origin and development of multiple myeloma. The risk of multiple myeloma increases when Epstein-Barr virus infects B cells in the germinal center, which may result in an anti-apoptosis effect of B cells and an improved ability to migrate from the germinal center to peripheral blood.

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Effects of Epstein-Barr virus infection on the development of multiple myeloma after liver transplantation

ZHANG YeWei ) 2 3 ZHAO HeWei 2 3 HE Xia 1 2 ZHENG SuWen 2 3 WANG TaiHong 2 3 YAN DongLiang 0 2 SUN JingFeng 2 3 LU Xiang 2 5 WEN JianFei 2 3 LAU Wan Yee 2 4 0 Department of General surgery, The Second Affiliated Hospital of Nantong University , Nantong 226001, China 1 Department of Radiotherapy, Affiliated Jiangsu Cancer Hospital of Nanjing Medical University , Nanjing 210009, China 2 liver transplantation, CD40, CD40L, multiple myeloma, EBV 3 Department of Hepatobiliary and Pancreatic Surgery, Affiliated Jiangsu Cancer Hospital of Nanjing Medical University , Nanjing 210009, China 4 Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital , Shatin, Hong Kong, China 5 Departimen of Geriatrics, The Second Affiliated Hospital of Nanjing Medical University , Nanjing 210011, China Reduced cellular immune function in patients after liver transplantation easily results in many types of viral infections, such as Epstein-Barr virus. Epstein-Barr virus is a -herpesvirus and is related to many malignant diseases, especially epithelial and lymph tumors. The abnormal interaction of cluster of differentiation 40 with cluster of differentiation 40 ligand and expression of cluster of differentiation 40 ligand are considered closely related to the development of myeloma cells. This study explored the influence and mechanism of Epstein-Barr virus infection on the phenotype and biological behavior of myeloma cells after liver transplantation. Flow cytometry was used to detect coexpression of cluster of differentiation 40 and cluster of differentiation 40 ligand in 10 samples of freshly isolated multiple myeloma cells. Cluster of differentiation 40 and cluster of differentiation 40 ligand were coexpressed in sample Nos. 5, 8, 9, and 10, particularly in sample No. 5. Western blot analysis was used to detect the expression of the Epstein-Barr virus antigens latent membrane protein 1 and Epstein-Barr virus nuclear antigen 2 in the multiple myeloma cell line RPMI 8226 infected with Epstein-Barr virus. The antigen expression indicated that Epstein-Barr virus can infect multiple myeloma virus cells in vitro. Reverse transcription-polymerase chain reaction revealed upregulated expression of cluster of differentiation 40 ligand on the infected RPMI 8226 cells, which may be involved in the anti-apoptosis activity of the infected cells. Confocal microscopy showed that pairs of molecules of cluster of differentiation 40, cluster of differentiation 40 ligand, and latent membrane protein 1 were colocalized on the surface of the infected cells. CXC chemokine receptor 4 was upregulated on the RPMI 8226 cells after Epstein-Barr virus infection. The migratory ability of the infected cells improved in the presence of the chemokine stromal cell-derived factor-1. Anti-apoptosis and migration are known important biological characteristics of malignant cells. Our results indicate the involvement of Epstein-Barr virus in the origin and development of multiple myeloma. The risk of multiple myeloma increases when Epstein-Barr virus infects B cells in the germinal center, which may result in an anti-apoptosis effect of B cells and an improved ability to migrate from the germinal center to peripheral blood. - After liver transplantation, patients are immunosuppressed [1] and become susceptible to all types of infection. A common viral infection is caused by Epstein-Barr virus (EBV). The clinical presentation of this infection can vary from no symptoms to serious fulminant infection [2]. Patients usually recover spontaneously from the infection, but complications such as hepatitis, infectious mononucleosis, and post-transplant lymphoproliferative disorder can develop. Under immunosuppression after liver transplantation, T-cell function is suppressed, allowing monoclonicity hyperplasia of B cells and tumors to occur [2,3]. EBV is a -herpesvirus that is related to many malignant diseases, particularly to tumors that are epithelial and lymphatic in origin. EBV can infect B cells in vitro and transform them into immortalized lymphoblastoid cell lines. The viral antigens expressed by lymphoblastoid cell lines include the EBV-determined nuclear antigens (EBNA-1 to -6), EBV-encoded latent membrane proteins (LMP1 and LMP2), and EBV-encoded RNAs [4]. LMP1 plays an important role in B-cell transformation. However, B-cell multiplication in vitro cannot be maintained by the expression of LMP1 alone, and a second signal is required [5]. Cluster of differentiation 40 (CD40) is the main accessory of LMP1 signal transduction. CD40 is a type-I transmembrane glycoprotein that belongs to the tumor necrosis factor (TNF) receptor (TNFR) superfamily. CD40 is expressed in the different stages of B-cell differentiation [6] and in malignant tumor induction by B cells, such as in multiple myeloma (MM). CD40 ligand (CD40L) is mainly expressed in active CD4+ T cells, but was recently also found to be expressed in normal or tumor B cells [7,8]. The in (...truncated)


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YeWei Zhang, HeWei Zhao, Xia He, SuWen Zheng, TaiHong Wang, DongLiang Yan, JingFeng Sun, Xiang Lu, JianFei Wen, Wan Yee Lau. Effects of Epstein-Barr virus infection on the development of multiple myeloma after liver transplantation, Science China Life Sciences, 2012, pp. 735-743, Volume 55, Issue 8, DOI: 10.1007/s11427-012-4362-3