Skip to main content
SpringerLink
Log in
Book cover

Cytokine Storm Syndrome pp 253–276Cite as

Cytokine Storm Syndromes Associated with Epstein–Barr Virus

  • Chapter
  • First Online:

Abstract

Epstein–Barr Virus (EBV) is a ubiquitous and predominantly B cell tropic virus. EBV, one of the most common viruses to infect humans, is best known as the causative agent of infectious mononucleosis (IM). Although most people experience asymptomatic infection, EBV is a potent immune stimulus and as such it elicits robust proliferation and activation not only of the B-lymphocytes it infects, but also the immune cells that respond to infection. In certain individuals, such as those with inherited or acquired defects affecting the immune system, failure to properly control EBV leads to accumulation of EBV-infected B cells as well as reactive immune cells, which together contribute to the development of often life-threatening cytokine storm syndromes (CSS). Here, we review the normal immune response to EBV and discuss several CSS associated with EBV, such as chronic active EBV infection, hemophagocytic lymphohistiocytosis, and posttransplant lymphoproliferative disorder. Given the critical role for cytokines in driving inflammation and contributing to disease pathogenesis, we also discuss how targeting specific cytokines might provide a more effective and less toxic treatment for EBV-driven CSS.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Kutok, J. L., & Wang, F. (2006). Spectrum of Epstein-Barr virus-associated diseases. Annual Review of Pathology, 1, 375–404.

    Article  CAS  PubMed  Google Scholar 

  2. Nagington, J., & Gray, J. (1980). Cyclosporin a immunosuppression, Epstein-Barr antibody, and lymphoma. Lancet, 1, 536–537.

    Article  CAS  PubMed  Google Scholar 

  3. Weiss, L. M., Strickler, J. G., Warnke, R. A., Purtilo, D. T., & Sklar, J. (1987). Epstein-Barr viral DNA in tissues of Hodgkin's disease. The American Journal of Pathology, 129, 86–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Jones, J. F., Shurin, S., Abramowsky, C., Tubbs, R. R., Sciotto, C. G., Wahl, R., et al. (1988). T-cell lymphomas containing Epstein-Barr viral DNA in patients with chronic Epstein-Barr virus infections. The New England Journal of Medicine, 318, 733–741.

    Article  CAS  PubMed  Google Scholar 

  5. Greenspan, J. S., Greenspan, D., Lennette, E. T., Abrams, D. I., Conant, M. A., Petersen, V., et al. (1985). Replication of Epstein-Barr virus within the epithelial cells of oral "hairy" leukoplakia, an AIDS-associated lesion. The New England Journal of Medicine, 313, 1564–1571.

    Article  CAS  PubMed  Google Scholar 

  6. Neparidze, N., & Lacy, J. (2014). Malignancies associated with epstein-barr virus: Pathobiology, clinical features, and evolving treatments. Clinical Advances in Hematology & Oncology, 12, 358–371.

    Google Scholar 

  7. Epstein, M. A., & Achong, B. G. (1977). Pathogenesis of infectious mononucleosis. Lancet, 2, 1270–1273.

    Article  CAS  PubMed  Google Scholar 

  8. Kimura, H., Hoshino, Y., Kanegane, H., Tsuge, I., Okamura, T., Kawa, K., et al. (2001). Clinical and virologic characteristics of chronic active Epstein-Barr virus infection. Blood, 98, 280–286.

    Article  CAS  PubMed  Google Scholar 

  9. Sullivan, J. L., Woda, B. A., Herrod, H. G., Koh, G., Rivara, F. P., & Mulder, C. (1985). Epstein-Barr virus-associated hemophagocytic syndrome: Virological and immunopathological studies. Blood, 65, 1097–1104.

    Article  CAS  PubMed  Google Scholar 

  10. Imashuku, S. (2002). Clinical features and treatment strategies of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Critical Reviews in Oncology/Hematology, 44, 259–272.

    Article  PubMed  Google Scholar 

  11. Paya, C. V., Fung, J. J., Nalesnik, M. A., Kieff, E., Green, M., Gores, G., et al. (1999). Epstein-Barr virus-induced posttransplant lymphoproliferative disorders. ASTS/ASTP EBV-PTLD task force and the mayo clinic organized international consensus development meeting. Transplantation, 68, 1517–1525.

    Article  CAS  PubMed  Google Scholar 

  12. Palser, A. L., Grayson, N. E., White, R. E., Corton, C., Correia, S., Ba Abdullah, M. M., et al. (2015). Genome diversity of Epstein-Barr virus from multiple tumor types and normal infection. Journal of Virology, 89, 5222–5237.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Neves, M., Marinho-Dias, J., Ribeiro, J., & Sousa, H. (2017). Epstein-Barr virus strains and variations: Geographic or disease-specific variants? Journal of Medical Virology, 89, 373–387.

    Article  CAS  PubMed  Google Scholar 

  14. Farrell, P. J. (2015). Epstein-Barr virus strain variation. Current Topics in Microbiology and Immunology, 390, 45–69.

    CAS  PubMed  Google Scholar 

  15. Shannon-Lowe, C., & Rowe, M. (2011). Epstein-Barr virus infection of polarized epithelial cells via the basolateral surface by memory B cell-mediated transfer infection. PLoS Pathogens, 7, e1001338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hutt-Fletcher, L. M. (2007). Epstein-Barr virus entry. Journal of Virology, 81, 7825–7832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Johannsen, E., Luftig, M., Chase, M. R., Weicksel, S., Cahir-McFarland, E., Illanes, D., et al. (2004). Proteins of purified Epstein-Barr virus. Proceedings of the National Academy of Sciences of the United States of America, 101, 16286–16291.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Moore, M. D., DiScipio, R. G., Cooper, N. R., & Nemerow, G. R. (1989). Hydrodynamic, electron microscopic, and ligand-binding analysis of the Epstein-Barr virus/C3dg receptor (CR2). The Journal of Biological Chemistry, 264, 20576–20582.

    CAS  PubMed  Google Scholar 

  19. Fingeroth, J. D., Weis, J. J., Tedder, T. F., Strominger, J. L., Biro, P. A., & Fearon, D. T. (1984). Epstein-Barr virus receptor of human B lymphocytes is the C3d receptor CR2. Proceedings of the National Academy of Sciences of the United States of America, 81, 4510–4514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Janz, A., Oezel, M., Kurzeder, C., Mautner, J., Pich, D., Kost, M., et al. (2000). Infectious Epstein-Barr virus lacking major glycoprotein BLLF1 (gp350/220) demonstrates the existence of additional viral ligands. Journal of Virology, 74, 10142–10152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Haddad, R. S., & Hutt-Fletcher, L. M. (1989). Depletion of glycoprotein gp85 from virosomes made with Epstein-Barr virus proteins abolishes their ability to fuse with virus receptor-bearing cells. Journal of Virology, 63, 4998–5005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Haan, K. M., Lee, S. K., & Longnecker, R. (2001). Different functional domains in the cytoplasmic tail of glycoprotein B are involved in Epstein-Barr virus-induced membrane fusion. Virology, 290, 106–114.

    Article  CAS  PubMed  Google Scholar 

  23. Miller, N., & Hutt-Fletcher, L. M. (1988). A monoclonal antibody to glycoprotein gp85 inhibits fusion but not attachment of Epstein-Barr virus. Journal of Virology, 62, 2366–2372.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sugano, N., Chen, W., Roberts, M. L., & Cooper, N. R. (1997). Epstein-Barr virus binding to CD21 activates the initial viral promoter via NF-kappaB induction. The Journal of Experimental Medicine, 186, 731–737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tanner, J. E., Alfieri, C., Chatila, T. A., & Diaz-Mitoma, F. (1996). Induction of interleukin-6 after stimulation of human B-cell CD21 by Epstein-Barr virus glycoproteins gp350 and gp220. Journal of Virology, 70, 570–575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hunter, C. A., & Jones, S. A. (2015). IL-6 as a keystone cytokine in health and disease. Nature Immunology, 16, 448–457.

    Article  CAS  PubMed  Google Scholar 

  27. Leveille, C., Castaigne, J. G., Charron, D., & Al-Daccak, R. (2002). MHC class II isotype-specific signaling complex on human B cells. European Journal of Immunology, 32, 2282–2291.

    Article  CAS  PubMed  Google Scholar 

  28. Ressing, M. E., van Gent, M., Gram, A. M., Hooykaas, M. J., Piersma, S. J., & Wiertz, E. J. (2015). Immune evasion by Epstein-Barr virus. Current Topics in Microbiology and Immunology, 391, 355–381.

    CAS  PubMed  Google Scholar 

  29. van Gent, M., Braem, S. G., de Jong, A., Delagic, N., Peeters, J. G., Boer, I. G., et al. (2014). Epstein-Barr virus large tegument protein BPLF1 contributes to innate immune evasion through interference with toll-like receptor signaling. PLoS Pathogens, 10, e1003960.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Bentz, G. L., Liu, R., Hahn, A. M., Shackelford, J., & Pagano, J. S. (2010). Epstein-Barr virus BRLF1 inhibits transcription of IRF3 and IRF7 and suppresses induction of interferon-beta. Virology, 402, 121–128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Quinn, L. L., Zuo, J., Abbott, R. J., Shannon-Lowe, C., Tierney, R. J., Hislop, A. D., et al. (2014). Cooperation between Epstein-Barr virus immune evasion proteins spreads protection from CD8+ T cell recognition across all three phases of the lytic cycle. PLoS Pathogens, 10, e1004322.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Lanier, L. L. (2015). NKG2D receptor and its ligands in host defense. Cancer Immunology Research, 3, 575–582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Strowig, T., Brilot, F., Arrey, F., Bougras, G., Thomas, D., Muller, W. A., et al. (2008). Tonsilar NK cells restrict B cell transformation by the Epstein-Barr virus via IFN-gamma. PLoS Pathogens, 4, e27.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Azzi, T., Lunemann, A., Murer, A., Ueda, S., Beziat, V., Malmberg, K. J., et al. (2014). Role for early-differentiated natural killer cells in infectious mononucleosis. Blood, 124, 2533–2543.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chung, Y., Yamazaki, T., Kim, B. S., Zhang, Y., Reynolds, J. M., Martinez, G. J., et al. (2013). Epstein Barr virus-induced 3 (EBI3) together with IL-12 negatively regulates T helper 17-mediated immunity to Listeria monocytogenes infection. PLoS Pathogens, 9, e1003628.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chijioke, O., Azzi, T., Nadal, D., & Munz, C. (2013). Innate immune responses against Epstein Barr virus infection. Journal of Leukocyte Biology, 94, 1185–1190.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Chijioke, O., Landtwing, V., & Munz, C. (2016). NK cell influence on the outcome of primary Epstein-Barr virus infection. Frontiers in Immunology, 7, 323.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Kempkes, B., & Ling, P. D. (2015). EBNA2 and its coactivator EBNA-LP. Current Topics in Microbiology and Immunology, 391, 35–59.

    CAS  PubMed  Google Scholar 

  39. Kieser, A., & Sterz, K. R. (2015). The latent membrane protein 1 (LMP1). Current Topics in Microbiology and Immunology, 391, 119–149.

    CAS  PubMed  Google Scholar 

  40. Eliopoulos, A. G., Gallagher, N. J., Blake, S. M., Dawson, C. W., & Young, L. S. (1999). Activation of the p38 mitogen-activated protein kinase pathway by Epstein-Barr virus-encoded latent membrane protein 1 coregulates interleukin-6 and interleukin-8 production. The Journal of Biological Chemistry, 274, 16085–16096.

    Article  CAS  PubMed  Google Scholar 

  41. Allday, M. J., Bazot, Q., & White, R. E. (2015). The EBNA3 family: Two oncoproteins and a tumour suppressor that are central to the biology of EBV in B cells. Current Topics in Microbiology and Immunology, 391, 61–117.

    CAS  PubMed  Google Scholar 

  42. Taylor, G. S., Long, H. M., Brooks, J. M., Rickinson, A. B., & Hislop, A. D. (2015). The immunology of Epstein-Barr virus-induced disease. Annual Review of Immunology, 33, 787–821.

    Article  CAS  PubMed  Google Scholar 

  43. Palendira, U., & Rickinson, A. B. (2015). Primary immunodeficiencies and the control of Epstein-Barr virus infection. Annals of the New York Academy of Sciences, 1356, 22–44.

    Article  PubMed  Google Scholar 

  44. Callan, M. F., Fazou, C., Yang, H., Rostron, T., Poon, K., Hatton, C., et al. (2000). CD8(+) T-cell selection, function, and death in the primary immune response in vivo. The Journal of Clinical Investigation, 106, 1251–1261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Amyes, E., Hatton, C., Montamat-Sicotte, D., Gudgeon, N., Rickinson, A. B., McMichael, A. J., et al. (2003). Characterization of the CD4+ T cell response to Epstein-Barr virus during primary and persistent infection. The Journal of Experimental Medicine, 198, 903–911.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Long, H. M., Chagoury, O. L., Leese, A. M., Ryan, G. B., James, E., Morton, L. T., et al. (2013). MHC II tetramers visualize human CD4+ T cell responses to Epstein-Barr virus infection and demonstrate atypical kinetics of the nuclear antigen EBNA1 response. The Journal of Experimental Medicine, 210, 933–949.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Petrara, M. R., Freguja, R., Gianesin, K., Zanchetta, M., & De Rossi, A. (2013). Epstein-Barr virus-driven lymphomagenesis in the context of human immunodeficiency virus type 1 infection. Frontiers in Microbiology, 4, 311.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Rooney, C. M., Smith, C. A., Ng, C. Y., Loftin, S. K., Sixbey, J. W., Gan, Y., et al. (1998). Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients. Blood, 92, 1549–1555.

    Article  CAS  PubMed  Google Scholar 

  49. Haque, T., Wilkie, G. M., Jones, M. M., Higgins, C. D., Urquhart, G., Wingate, P., et al. (2007). Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: Results of a phase 2 multicenter clinical trial. Blood, 110, 1123–1131.

    Article  CAS  PubMed  Google Scholar 

  50. Hadinoto, V., Shapiro, M., Sun, C. C., & Thorley-Lawson, D. A. (2009). The dynamics of EBV shedding implicate a central role for epithelial cells in amplifying viral output. PLoS Pathogens, 5, e1000496.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Thorley-Lawson, D. A. (2015). EBV persistence–introducing the virus. Current Topics in Microbiology and Immunology, 390, 151–209.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Laichalk, L. L., Hochberg, D., Babcock, G. J., Freeman, R. B., & Thorley-Lawson, D. A. (2002). The dispersal of mucosal memory B cells: Evidence from persistent EBV infection. Immunity, 16, 745–754.

    Article  CAS  PubMed  Google Scholar 

  53. Callan, M. F., Tan, L., Annels, N., Ogg, G. S., Wilson, J. D., O'Callaghan, C. A., et al. (1998). Direct visualization of antigen-specific CD8+ T cells during the primary immune response to Epstein-Barr virus in vivo. The Journal of Experimental Medicine, 187, 1395–1402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Alfieri, C., Ghibu, F., & Joncas, J. H. (1984). Lytic, nontransforming Epstein-Barr virus (EBV) from a patient with chronic active EBV infection. Canadian Medical Association Journal, 131, 1249–1252.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Alfieri, C., & Joncas, J. H. (1987). Biomolecular analysis of a defective nontransforming Epstein-Barr virus (EBV) from a patient with chronic active EBV infection. Journal of Virology, 61, 3306–3309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Cohen, J. I. (2009). Optimal treatment for chronic active Epstein-Barr virus disease. Pediatric Transplantation, 13, 393–396.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Katano, H., Ali, M. A., Patera, A. C., Catalfamo, M., Jaffe, E. S., Kimura, H., et al. (2004). Chronic active Epstein-Barr virus infection associated with mutations in perforin that impair its maturation. Blood, 103, 1244–1252.

    Article  CAS  PubMed  Google Scholar 

  58. Kasahara, Y., Yachie, A., Takei, K., Kanegane, C., Okada, K., Ohta, K., et al. (2001). Differential cellular targets of Epstein-Barr virus (EBV) infection between acute EBV-associated hemophagocytic lymphohistiocytosis and chronic active EBV infection. Blood, 98, 1882–1888.

    Article  CAS  PubMed  Google Scholar 

  59. Scott, R. B. (1939). Leukopenic myelosis: (section of medicine). Proceedings of the Royal Society of Medicine, 32, 1429–1434.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Daum, G. S., Sullivan, J. L., Ansell, J., Mulder, C., & Woda, B. A. (1987). Virus-associated hemophagocytic syndrome: Identification of an immunoproliferative precursor lesion. Human Pathology, 18, 1071–1074.

    Article  CAS  PubMed  Google Scholar 

  61. Imashuku, S., Hlbi, S., & Todo, S. (1997). Hemophagocytic lymphohistiocytosis in infancy and childhood. The Journal of Pediatrics, 130, 352–357.

    Article  CAS  PubMed  Google Scholar 

  62. George, M. R. (2014). Hemophagocytic lymphohistiocytosis: Review of etiologies and management. Journal of Blood Medicine, 5, 69–86.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Takahashi, S., Oki, J., Miyamoto, A., Koyano, S., Ito, K., Azuma, H., et al. (1999). Encephalopathy associated with haemophagocytic lymphohistiocytosis following rotavirus infection. European Journal of Pediatrics, 158, 133–137.

    Article  CAS  PubMed  Google Scholar 

  64. Henter, J. I., Elinder, G., & Ost, A. (1991). Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL study Group of the Histiocyte Society. Seminars in Oncology, 18, 29–33.

    CAS  PubMed  Google Scholar 

  65. Gartner, B. C., Kortmann, K., Schafer, M., Mueller-Lantzsch, N., Sester, U., Kaul, H., et al. (2000). No correlation in Epstein-Barr virus reactivation between serological parameters and viral load. Journal of Clinical Microbiology, 38, 2458.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Greiner, T. C., and T. G. Gross. 2004. Atypical immune lymphoproliferations. In Hematology: Basic principles and practice, 3rd ed. R. Hoffman, B. Furie, E. J. Benz, Jr., , and P. McGlave, eds. Churchill Livingston, Philadelphia. 1449.

    Google Scholar 

  67. Harrington, D. S., Weisenburger, D. D., & Purtilo, D. T. (1988). Epstein-Barr virus–associated lymphoproliferative lesions. Clinics in Laboratory Medicine, 8, 97–118.

    Article  CAS  PubMed  Google Scholar 

  68. Mroczek, E. C., Weisenburger, D. D., Grierson, H. L., Markin, R., & Purtilo, D. T. (1987). Fatal infectious mononucleosis and virus-associated hemophagocytic syndrome. Archives of Pathology & Laboratory Medicine, 111, 530–535.

    CAS  Google Scholar 

  69. Chen, J. H., Fleming, M. D., Pinkus, G. S., Pinkus, J. L., Nichols, K. E., Mo, J. Q., et al. (2010). Pathology of the liver in familial hemophagocytic lymphohistiocytosis. The American Journal of Surgical Pathology, 34, 852–867.

    Article  PubMed  Google Scholar 

  70. Seemayer, T. A., Gross, T. G., Hinrichs, S. H., & Egeler, R. M. (1994). Massive diffuse histiocytic myocardial infiltration in Epstein-Barr virus-associated hemophagocytic syndrome and fulminant infectious mononucleosis. Cell Vision, 1, 260.

    Google Scholar 

  71. Purtilo, D. T., Cassel, C., & Yang, J. P. (1974). Letter: Fatal infectious mononucleosis in familial lymphohistiocytosis. The New England Journal of Medicine, 291, 736.

    CAS  PubMed  Google Scholar 

  72. Purtilo, D. T., Cassel, C. K., Yang, J. P., & Harper, R. (1975). X-linked recessive progressive combined variable immunodeficiency (Duncan's disease). Lancet, 1, 935–940.

    Article  CAS  PubMed  Google Scholar 

  73. Seemayer, T. A., Gross, T. G., Egeler, R. M., Pirruccello, S. J., Davis, J. R., Kelly, C. M., et al. (1995). X-linked lymphoproliferative disease: Twenty-five years after the discovery. Pediatric Research, 38, 471–478.

    Article  CAS  PubMed  Google Scholar 

  74. Talaat, K. R., Rothman, J. A., Cohen, J. I., Santi, M., Choi, J. K., Guzman, M., et al. (2009). Lymphocytic vasculitis involving the central nervous system occurs in patients with X-linked lymphoproliferative disease in the absence of Epstein-Barr virus infection. Pediatric Blood & Cancer, 53, 1120–1123.

    Article  Google Scholar 

  75. Booth, C., Gilmour, K. C., Veys, P., Gennery, A. R., Slatter, M. A., Chapel, H., et al. (2011). X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: A multicenter study on the manifestations, management and outcome of the disease. Blood, 117, 53–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Sumegi, J., Huang, D., Lanyi, A., Davis, J. D., Seemayer, T. A., Maeda, A., et al. (2000). Correlation of mutations of the SH2D1A gene and epstein-barr virus infection with clinical phenotype and outcome in X-linked lymphoproliferative disease. Blood, 96, 3118–3125.

    CAS  PubMed  Google Scholar 

  77. Nichols, K. E., Harkin, D. P., Levitz, S., Krainer, M., Kolquist, K. A., Genovese, C., et al. (1998). Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome. Proceedings of the National Academy of Sciences of the United States of America, 95, 13765–13770.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Nichols, K. E., Ma, C. S., Cannons, J. L., Schwartzberg, P. L., & Tangye, S. G. (2005). Molecular and cellular pathogenesis of X-linked lymphoproliferative disease. Immunological Reviews, 203, 180–199.

    Article  CAS  PubMed  Google Scholar 

  79. Coffey, A. J., Brooksbank, R. A., Brandau, O., Oohashi, T., Howell, G. R., Bye, J. M., et al. (1998). Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nature Genetics, 20, 129–135.

    Article  CAS  PubMed  Google Scholar 

  80. Gifford, C. E., Weingartner, E., Villanueva, J., Johnson, J., Zhang, K., Filipovich, A. H., et al. (2014). Clinical flow cytometric screening of SAP and XIAP expression accurately identifies patients with SH2D1A and XIAP/BIRC4 mutations. Cytometry. Part B, Clinical Cytometry, 86, 263–271.

    Article  PubMed  Google Scholar 

  81. Cohen, J. I. (2015). Primary immunodeficiencies associated with EBV disease. Current Topics in Microbiology and Immunology, 390, 241–265.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Tangye, S. G., Palendira, U., & Edwards, E. S. (2017). Human immunity against EBV-lessons from the clinic. The Journal of Experimental Medicine, 214, 269–283.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Ruffo, E., Malacarne, V., Larsen, S. E., Das, R., Patrussi, L., Wulfing, C., et al. (2016). Inhibition of diacylglycerol kinase alpha restores restimulation-induced cell death and reduces immunopathology in XLP-1. Science Translational Medicine, 8, 321ra327.

    Article  CAS  Google Scholar 

  84. Czar, M. J., Kersh, E. N., Mijares, L. A., Lanier, G., Lewis, J., Yap, G., et al. (2001). Altered lymphocyte responses and cytokine production in mice deficient in the X-linked lymphoproliferative disease gene SH2D1A/DSHP/SAP. Proceedings of the National Academy of Sciences of the United States of America, 98, 7449–7454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Coquet, J. M., Chakravarti, S., Kyparissoudis, K., McNab, F. W., Pitt, L. A., McKenzie, B. S., et al. (2008). Diverse cytokine production by NKT cell subsets and identification of an IL-17-producing CD4-NK1.1- NKT cell population. Proceedings of the National Academy of Sciences of the United States of America, 105, 11287–11292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Rigaud, S., Fondaneche, M. C., Lambert, N., Pasquier, B., Mateo, V., Soulas, P., et al. (2006). XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature, 444, 110–114.

    Article  CAS  PubMed  Google Scholar 

  87. Filipovich, A. H., Zhang, K., Snow, A. L., & Marsh, R. A. (2010). X-linked lymphoproliferative syndromes: Brothers or distant cousins? Blood, 116, 3398–3408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Marsh, R. A., Madden, L., Kitchen, B. J., Mody, R., McClimon, B., Jordan, M. B., et al. (2010). XIAP deficiency: A unique primary immunodeficiency best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked lymphoproliferative disease. Blood, 116, 1079–1082.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Pachlopnik Schmid, J., Canioni, D., Moshous, D., Touzot, F., Mahlaoui, N., Hauck, F., et al. (2011). Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood, 117, 1522–1529.

    Article  PubMed  CAS  Google Scholar 

  90. Wong, W. W., Vince, J. E., Lalaoui, N., Lawlor, K. E., Chau, D., Bankovacki, A., et al. (2014). cIAPs and XIAP regulate myelopoiesis through cytokine production in an RIPK1- and RIPK3-dependent manner. Blood, 123, 2562–2572.

    Article  CAS  PubMed  Google Scholar 

  91. Lawlor, K. E., Khan, N., Mildenhall, A., Gerlic, M., Croker, B. A., D'Cruz, A. A., et al. (2015). RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL. Nature Communications, 6, 6282.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Lawlor, K. E., Feltham, R., Yabal, M., Conos, S. A., Chen, K. W., Ziehe, S., et al. (2017). XIAP loss triggers RIPK3- and caspase-8-driven IL-1beta activation and cell death as a consequence of TLR-MyD88-induced cIAP1-TRAF2 degradation. Cell Reports, 20, 668–682.

    Article  CAS  PubMed  Google Scholar 

  93. Huck, K., Feyen, O., Niehues, T., Ruschendorf, F., Hubner, N., Laws, H. J., et al. (2009). Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation. The Journal of Clinical Investigation, 119, 1350–1358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Andreotti, A. H., Schwartzberg, P. L., Joseph, R. E., & Berg, L. J. (2010). T-cell signaling regulated by the Tec family kinase, Itk. Cold Spring Harbor Perspectives in Biology, 2, a002287.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Schaeffer, E. M., Debnath, J., Yap, G., McVicar, D., Liao, X. C., Littman, D. R., et al. (1999). Requirement for Tec kinases Rlk and Itk in T cell receptor signaling and immunity. Science, 284, 638–641.

    Article  CAS  PubMed  Google Scholar 

  96. Mueller, C., & August, A. (2003). Attenuation of immunological symptoms of allergic asthma in mice lacking the tyrosine kinase ITK. Journal of Immunology, 170, 5056–5063.

    Article  CAS  Google Scholar 

  97. Fowell, D. J., Shinkai, K., Liao, X. C., Beebe, A. M., Coffman, R. L., Littman, D. R., et al. (1999). Impaired NFATc translocation and failure of Th2 development in Itk-deficient CD4+ T cells. Immunity, 11, 399–409.

    Article  CAS  PubMed  Google Scholar 

  98. Korn, T., Bettelli, E., Oukka, M., & Kuchroo, V. K. (2009). IL-17 and Th17 cells. Annual Review of Immunology, 27, 485–517.

    Article  CAS  PubMed  Google Scholar 

  99. Li, F. Y., Chaigne-Delalande, B., Su, H., Uzel, G., Matthews, H., & Lenardo, M. J. (2014). XMEN disease: A new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus. Blood, 123, 2148–2152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Ravell, J., Chaigne-Delalande, B., & Lenardo, M. (2014). X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia disease: A combined immune deficiency with magnesium defect. Current Opinion in Pediatrics, 26, 713–719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Grubbs, R. D., & Maguire, M. E. (1987). Magnesium as a regulatory cation: Criteria and evaluation. Magnesium, 6, 113–127.

    CAS  PubMed  Google Scholar 

  102. Chaigne-Delalande, B., Li, F. Y., O'Connor, G. M., Lukacs, M. J., Jiang, P., Zheng, L., et al. (2013). Mg2+ regulates cytotoxic functions of NK and CD8 T cells in chronic EBV infection through NKG2D. Science, 341, 186–191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Cohen, J. I. (2000). Epstein-Barr virus infection. The New England Journal of Medicine, 343, 481–492.

    Article  CAS  PubMed  Google Scholar 

  104. McGowan Jr., J. E., Chesney, P. J., Crossley, K. B., & LaForce, F. M. (1992). Guidelines for the use of systemic glucocorticosteroids in the management of selected infections. Working group on steroid use, antimicrobial agents committee, infectious diseases society of America. The Journal of Infectious Diseases, 165, 1–13.

    Article  PubMed  Google Scholar 

  105. Pagano, J. S., Sixbey, J. W., & Lin, J. C. (1983). Acyclovir and Epstein-Barr virus infection. The Journal of Antimicrobial Chemotherapy, 12(Suppl B), 113–121.

    Article  PubMed  Google Scholar 

  106. Heslop, H. E. (2009). How I treat EBV lymphoproliferation. Blood, 114, 4002–4008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Heslop, H. E., Slobod, K. S., Pule, M. A., Hale, G. A., Rousseau, A., Smith, C. A., et al. (2010). Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood, 115, 925–935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Imashuku, S., Hibi, S., Fujiwara, F., Ikushima, S., & Todo, S. (1994). Haemophagocytic lymphohistiocytosis, interferon-gamma-naemia and Epstein-Barr virus involvement. British Journal of Haematology, 88, 656–658.

    Article  CAS  PubMed  Google Scholar 

  109. Jordan, M. B., Allen, C. E., Weitzman, S., Filipovich, A. H., & McClain, K. L. (2011). How I treat hemophagocytic lymphohistiocytosis. Blood, 118, 4041–4052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Imashuku, S., Hibi, S., Tabata, Y., Sako, M., Sekine, Y., Hirayama, K., et al. (1998). Biomarker and morphological characteristics of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis. Medical and Pediatric Oncology, 31, 131–137.

    Article  CAS  PubMed  Google Scholar 

  111. Han, X. C., Ye, Q., Zhang, W. Y., Tang, Y. M., Xu, X. J., & Zhang, T. (2017). Cytokine profiles as novel diagnostic markers of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in children. Journal of Critical Care, 39, 72–77.

    Article  CAS  PubMed  Google Scholar 

  112. Rood, J. E., Rao, S., Paessler, M., Kreiger, P. A., Chu, N., Stelekati, E., et al. (2016). ST2 contributes to T-cell hyperactivation and fatal hemophagocytic lymphohistiocytosis in mice. Blood, 127, 426–435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Lotz, M., Tsoukas, C. D., Fong, S., Dinarello, C. A., Carson, D. A., & Vaughan, J. H. (1986). Release of lymphokines after Epstein Barr virus infection in vitro. I. Sources of and kinetics of production of interferons and interleukins in normal humans. Journal of Immunology, 136, 3636–3642.

    CAS  Google Scholar 

  114. Gosselin, J., Flamand, L., D'Addario, M., Hiscott, J., & Menezes, J. (1992). Infection of peripheral blood mononuclear cells by herpes simplex and Epstein-Barr viruses. Differential induction of interleukin 6 and tumor necrosis factor-alpha. The Journal of Clinical Investigation, 89, 1849–1856.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Gosselin, J., Menezes, J., D'Addario, M., Hiscott, J., Flamand, L., Lamoureux, G., et al. (1991). Inhibition of tumor necrosis factor-alpha transcription by Epstein-Barr virus. European Journal of Immunology, 21, 203–208.

    Article  CAS  PubMed  Google Scholar 

  116. Roberge, C. J., McColl, S. R., Larochelle, B., & Gosselin, J. (1998). Granulocyte-macrophage colony-stimulating factor enhances EBV-induced synthesis of chemotactic factors in human neutrophils. Journal of Immunology, 160, 2442–2448.

    CAS  Google Scholar 

  117. Roberge, C. J., Poubelle, P. E., Beaulieu, A. D., Heitz, D., & Gosselin, J. (1996). The IL-1 and IL-1 receptor antagonist (IL-1Ra) response of human neutrophils to EBV stimulation. Preponderance of IL-Ra detection. Journal of Immunology, 156, 4884–4891.

    CAS  Google Scholar 

  118. Larochelle, B., Flamand, L., Gourde, P., Beauchamp, D., & Gosselin, J. (1998). Epstein-Barr virus infects and induces apoptosis in human neutrophils. Blood, 92, 291–299.

    Article  CAS  PubMed  Google Scholar 

  119. Linde, A., Andersson, B., Svenson, S. B., Ahrne, H., Carlsson, M., Forsberg, P., et al. (1992). Serum levels of lymphokines and soluble cellular receptors in primary Epstein-Barr virus infection and in patients with chronic fatigue syndrome. The Journal of Infectious Diseases, 165, 994–1000.

    Article  CAS  PubMed  Google Scholar 

  120. Hornef, M. W., Wagner, H. J., Kruse, A., & Kirchner, H. (1995). Cytokine production in a whole-blood assay after Epstein-Barr virus infection in vivo. Clinical and Diagnostic Laboratory Immunology, 2, 209–213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Setsuda, J., Teruya-Feldstein, J., Harris, N. L., Ferry, J. A., Sorbara, L., Gupta, G., et al. (1999). Interleukin-18, interferon-gamma, IP-10, and Mig expression in Epstein-Barr virus-induced infectious mononucleosis and posttransplant lymphoproliferative disease. The American Journal of Pathology, 155, 257–265.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Marshall, N. A., Culligan, D. J., Johnston, P. W., Millar, C., Barker, R. N., & Vickers, M. A. (2007). CD4(+) T-cell responses to Epstein-Barr virus (EBV) latent membrane protein 1 in infectious mononucleosis and EBV-associated non-Hodgkin lymphoma: Th1 in active disease but Tr1 in remission. British Journal of Haematology, 139, 81–89.

    Article  CAS  PubMed  Google Scholar 

  123. Steigerwald-Mullen, P., Kurilla, M. G., & Braciale, T. J. (2000). Type 2 cytokines predominate in the human CD4(+) T-lymphocyte response to Epstein-Barr virus nuclear antigen 1. Journal of Virology, 74, 6748–6759.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Imashuku, S., Kuriyama, K., Teramura, T., Ishii, E., Kinugawa, N., Kato, M., et al. (2001). Requirement for etoposide in the treatment of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Journal of Clinical Oncology, 19, 2665–2673.

    Article  CAS  PubMed  Google Scholar 

  125. Imashuku, S. (2011). Treatment of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis (EBV-HLH); update 2010. Journal of Pediatric Hematology/Oncology, 33, 35–39.

    Article  CAS  PubMed  Google Scholar 

  126. Abella, E. M., Artrip, J., Schultz, K., & Ravindranath, Y. (1997). Treatment of familial erythrophagocytic lymphohistiocytosis with cyclosporine a. The Journal of Pediatrics, 130, 467–470.

    Article  CAS  PubMed  Google Scholar 

  127. Perel, Y., Alos, N., Ansoborlo, S., Carrere, A., & Guillard, J. M. (1997). Dramatic efficacy of antithymocyte globulins in childhood EBV-associated haemophagocytic syndrome. Acta Paediatrica, 86, 911.

    Article  CAS  PubMed  Google Scholar 

  128. Marsh, R. A., Allen, C. E., McClain, K. L., Weinstein, J. L., Kanter, J., Skiles, J., et al. (2013). Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab. Pediatric Blood & Cancer, 60, 101–109.

    Article  CAS  Google Scholar 

  129. Keith, M. P., Pitchford, C., & Bernstein, W. B. (2012). Treatment of hemophagocytic lymphohistiocytosis with alemtuzumab in systemic lupus erythematosus. Journal of Clinical Rheumatology, 18, 134–137.

    Article  PubMed  Google Scholar 

  130. Patton, L. L., Ramirez-Amador, V., Anaya-Saavedra, G., Nittayananta, W., Carrozzo, M., & Ranganathan, K. (2013). Urban legends series: Oral manifestations of HIV infection. Oral Diseases, 19, 533–550.

    Article  CAS  PubMed  Google Scholar 

  131. Gianti, E., Messick, T. E., Lieberman, P. M., & Zauhar, R. J. (2016). Computational analysis of EBNA1 "druggability" suggests novel insights for Epstein-Barr virus inhibitor design. Journal of Computer-Aided Molecular Design, 30, 285–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Thompson, S., Messick, T., Schultz, D. C., Reichman, M., & Lieberman, P. M. (2010). Development of a high-throughput screen for inhibitors of Epstein-Barr virus EBNA1. Journal of Biomolecular Screening, 15, 1107–1115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Behrens, E. M., & Koretzky, G. A. (2017). Review: Cytokine storm syndrome: Looking toward the precision medicine era. Arthritis & Rhematology, 69, 1135–1143.

    Article  Google Scholar 

  134. Horne, A., Janka, G., Maarten Egeler, R., Gadner, H., Imashuku, S., Ladisch, S., et al. (2005). Haematopoietic stem cell transplantation in haemophagocytic lymphohistiocytosis. British Journal of Haematology, 129, 622–630.

    Article  PubMed  Google Scholar 

  135. Filipovich, A. H. (2005). Life-threatening hemophagocytic syndromes: Current outcomes with hematopoietic stem cell transplantation. Pediatric Transplantation, 9(Suppl 7), 87–91.

    Article  PubMed  Google Scholar 

  136. Miettunen, P. M., Narendran, A., Jayanthan, A., Behrens, E. M., & Cron, R. Q. (2011). Successful treatment of severe paediatric rheumatic disease-associated macrophage activation syndrome with interleukin-1 inhibition following conventional immunosuppressive therapy: Case series with 12 patients. Rheumatology (Oxford), 50, 417–419.

    Article  CAS  Google Scholar 

  137. Baker, K. F., & Isaacs, J. D. (2017). Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn's disease and ulcerative colitis? Annals of the Rheumatic Diseases, 77(2), 175–187.

    Article  PubMed  CAS  Google Scholar 

  138. Broglie, L., Pommert, L., Rao, S., Thakar, M., Phelan, R., Margolis, D., et al. (2017). Ruxolitinib for treatment of refractory hemophagocytic lymphohistiocytosis. Blood Advances, 1, 1533–1536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Brandon Stelter in the Biomedical Communications Department at St. Jude Children’s Research Hospital for assisting with the creation of Fig. 1.

Author information

Authors and Affiliations

  1. Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Katherine C. Verbist & Kim E. Nichols

Authors
  1. Katherine C. Verbist
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kim E. Nichols
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kim E. Nichols .

Editor information

Editors and Affiliations

  1. UAB School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    Randy Q. Cron

  2. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Edward M. Behrens

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Verbist, K.C., Nichols, K.E. (2019). Cytokine Storm Syndromes Associated with Epstein–Barr Virus. In: Cron, R., Behrens, E. (eds) Cytokine Storm Syndrome. Springer, Cham. https://doi.org/10.1007/978-3-030-22094-5_15

Download citation

Publish with us

Policies and ethics

Search

Navigation