Science China Life Sciences

, Volume 55, Issue 8, pp 735–743 | Cite as

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

  • YeWei Zhang
  • HeWei Zhao
  • Xia He
  • SuWen Zheng
  • TaiHong Wang
  • DongLiang Yan
  • JingFeng Sun
  • Xiang Lu
  • JianFei Wen
  • Wan Yee Lau
Open Access
Research Paper


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.


liver transplantation CD40 CD40L multiple myeloma EBV 


  1. 1.
    Berenson J R, Vescio R A. HHV-8 is present in multiple myeloma patients. Blood, 1999, 93: 3157–3159PubMedGoogle Scholar
  2. 2.
    Bishop G A, Hostager B S. The CD40-CD154 interaction in B cell-T cell liaisons. Cytokine Growth Factor Rev, 2003, 14: 297–309PubMedCrossRefGoogle Scholar
  3. 3.
    Busch L K, Bishop G A. The EBV transforming protein, LMP1, mimics and cooperates with CD40 signaling in B lymphocyte. J Immunol, 1999, 162: 2555–2561PubMedGoogle Scholar
  4. 4.
    Cacciarelli T V, Green M, Jaffe R, et al. Management of posttransplant lymphoproliferative disease in pediatric liver transplant recipients receiving primary tacrolimus (FK506) therapy. Transplantation, 1998, 66: 1047–1052PubMedCrossRefGoogle Scholar
  5. 5.
    Challa A, Eulopulos A G, Holder M J, et al. Population depletion activates autonomous CD154-dependent survival in biopsy-like Burkitt’s lymphoma cells. Blood, 2002, 99: 3411–3418PubMedCrossRefGoogle Scholar
  6. 6.
    Clodi K, Asgary Z, Zhao S, et al. Coexpression of CD40 and CD40 ligand in B-cell lymphoma cells. Br J Haematol, 1998, 103: 270–275PubMedCrossRefGoogle Scholar
  7. 7.
    Fuleihan R, Ramesh N, Horner A, et al. Cyclosporin A inhibits CD40 ligand expression in T lymphocytes. J Clin Invest, 1994, 93: 1315–1320PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Hallek M, Bergsagel P L, Anderson K C. Multiple myeloma: increasing evidence for a multistep transformation process. Blood, 1998, 91: 3–21PubMedPubMedCentralGoogle Scholar
  9. 9.
    Hanissian S H, Geha R S. Jak3 is associated with CD40 and is critical for CD40 induction of gene expression in B cells. Immunity, 1997, 6: 379–387PubMedCrossRefGoogle Scholar
  10. 10.
    Imadome K, Shirakata M, Shimizu N, et al. CD40 ligand is a critical effector of Epstein-Barr virus in host cell survival and transformation. Proc Natl Acad Sci USA, 2003, 100: 7836–7840PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Kaykas A, Worringer K, Sugden B. CD40 and LMP-1 both signal from lipid rafts but LMP-1 assembles a distinct, more efficient signaling complex. EMBO J, 2001, 20: 2641–2654PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Oh H M, Oh J M, Choi S C, et al. An efficient method for the rapid establishment of Epstein-Barr virus immortalization of human B lymphocytes. Cell Prolif, 2003, 36: 191–197PubMedCrossRefGoogle Scholar
  13. 13.
    Larsen C P, Elwood E T, Alexander D Z, et al. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature, 1996, 381: 434–438PubMedCrossRefGoogle Scholar
  14. 14.
    Arcipowski K M, Stunz L L, Graham J P, et al. Molecular mechanisms of TNFR-associated factor 6 (TRAF6) utilization by the oncogenic viral mimic of CD40, latent membrane protein 1 (LMP1). J Biol Chem, 2011, 286: 9948–9955PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Wang Z, Yang S, Zhou L, et al. Specific cellular immune responses in mice immunized with DNA, adeno-associated virus and adenoviral vaccines of Epstein-Barr virus-LMP2 alone or in combination. Sci China Life Sci, 2011, 54: 263–266PubMedCrossRefGoogle Scholar
  16. 16.
    Mathur R K, Awasthi A, Wadhone P, et al. Reciprocal CD40 signals through p38MAPK and ERK-1/2 induce counteracting immune responses. Nat Med, 2004, 10: 540–544PubMedCrossRefGoogle Scholar
  17. 17.
    Mutimer D, Kaur N, Tang H, et al. Quantification of Epstein-Barr virus DNA in the blood after adult liver transplantation. Transplantation, 2000, 69: 954–959PubMedCrossRefGoogle Scholar
  18. 18.
    Nalesnik M A, Rao A S, Furukawa H, et al. Autologous lymphokine-activated killer cell therapy of Epstein-Barr virus-positive and -negative lymphoproliferative disorders arising in organ transplant recipients. Transplantation, 1997, 63: 1200–1205PubMedCrossRefGoogle Scholar
  19. 19.
    Xu H, Zhao G, Huang X, et al. CD40-expressing plasmid induces anti-CD40 antibody and enhances immune responses to DNA vaccination. J Gene Med, 2010, 12: 97–106PubMedCrossRefGoogle Scholar
  20. 20.
    Qi C J, Zheng L, Zhou X, et al. Cross-linking of CD40 using anti-CD40 antibody, 5C11, has different effects on XG2 multiple myeloma cells. Immunol Lett, 2004, 93: 151–158PubMedCrossRefGoogle Scholar
  21. 21.
    The International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Hematol, 2003, 121: 749–757CrossRefGoogle Scholar
  22. 22.
    Tong A W, Seamour B, Chen J, et al. CD40 ligand-induced apoptosis is Fas-independent in human multiple myeloma cells. Leuk Lymphoma, 2000, 36: 543–558PubMedCrossRefGoogle Scholar
  23. 23.
    Uchida J, Yasui T, Takaoka-Shichijo Y, et al. Mimicry of C40 signals by EBV LMP1 in B lymphocyte responses. Science, 1999, 286: 300–303PubMedCrossRefGoogle Scholar
  24. 24.
    Young L S, Rickinson A B. Epstein-Barr virus: 40 years on. Nat Rev Cancer, 2004, 4: 757–768PubMedCrossRefGoogle Scholar
  25. 25.
    Zimber-Strobl U, Kempkes B, Marschall G, et al. Epstein-Barr virus latent membrane protein (LMP1) is not sufficient to maintain proliferation of B cells but both it and activated CD40 can prolong their survival. EMBO J, 1996, 15: 7070–7078PubMedPubMedCentralGoogle Scholar
  26. 26.
    Cao J, Shen C, Zhang J, et al. Comparison of alternative extraction methods for secretome profiling in human hepatocellular carcinoma cells. Sci China Life Sci, 2011, 54: 34–38PubMedCrossRefGoogle Scholar

Copyright information

© The Author(s) 2012

Authors and Affiliations

  • YeWei Zhang
    • 1
  • HeWei Zhao
    • 1
  • Xia He
    • 2
  • SuWen Zheng
    • 1
  • TaiHong Wang
    • 1
  • DongLiang Yan
    • 3
  • JingFeng Sun
    • 1
  • Xiang Lu
    • 4
  • JianFei Wen
    • 1
  • Wan Yee Lau
    • 5
  1. 1.Department of Hepatobiliary and Pancreatic SurgeryAffiliated Jiangsu Cancer Hospital of Nanjing Medical UniversityNanjingChina
  2. 2.Department of RadiotherapyAffiliated Jiangsu Cancer Hospital of Nanjing Medical UniversityNanjingChina
  3. 3.Department of General surgeryThe Second Affiliated Hospital of Nantong UniversityNantongChina
  4. 4.Departimen of GeriatricsThe Second Affiliated Hospital of Nanjing Medical UniversityNanjingChina
  5. 5.Faculty of MedicineThe Chinese University of Hong Kong, Prince of Wales HospitalShatin, Hong KongChina

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