Epstein–Barr virus and multiple sclerosis: potential opportunities for immunotherapy

Clinical and Translational Immunology

Volumn 3, Issue 10, 2014, Pages

  Pender, Michael P ^a,b,c   Burrows, Scott R ^a,c  

^a UNIVERSITY OF QUEENSLAND   (Australia)

^b ROYAL BRISBANE AND WOMEN'S HOSPITAL   (Australia)

^c QIMR BERGHOFER MEDICAL RESEARCH INSTITUTE   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 84929076265     PISSN: None     EISSN: 20500068     Source Type: Journal    
DOI: 10.1038/cti.2014.25     Document Type: Review

References (159)

1. Pender MP. Neurology 4: multiple sclerosis. Med J Aust 2000; 172: 556–562.
2. Compston A, Coles A. Multiple sclerosis. Lancet 2008; 372: 1502–1517.
3. Sospedra M, Martin R. Immunology of multiple sclerosis. Annu Rev Immunol 2005; 23: 683–747.
4. Pender MP, Greer JM. Immunology of multiple sclerosis. Curr Allergy Asthma Rep 2007; 7: 285–292.
5. Ascherio A, Munger KL. Epstein–Barr virus infection and multiple sclerosis: a review. J Neuroimmune Pharmacol 2010; 5: 271–277.
6. Pender MP. The essential role of Epstein-Barr virus in the pathogenesis of multiple sclerosis. Neuroscientist 2011; 17: 351–367.
7. Nemerow GR, Mold C, Schwend VK, Tollefson V, Cooper NR. Identification of gp350 as the viral glycoprotein mediating attachment of Epstein-Barr virus (EBV) to the EBV/C3d receptor of B cells: sequence homology of gp350 and C3 complement fragment C3d. J Virol 1987; 61: 1416–1420.
8. Altmann M, Hammerschmidt W. Epstein-Barr virus provides a new paradigm: a requirement for the immediate inhibition of apoptosis. PLoS Biol 2005; 3: e404.
9. Thorley-Lawson DA, Gross A. Persistence of the Epstein-Barr virus and the origins of associated lymphomas. New Engl J Med 2004; 350: 1328–1337.
10. Laichalk LL, Thorley-Lawson DA. Terminal differentiation into plasma cells initiates the replicative cycle of Epstein-Barr virus in vivo. J Virol 2005; 79: 1296–1307.
11. Hadinoto V, Shapiro M, Sun CC, Thorley-Lawson DA. The dynamics of EBV shedding implicate a central role for epithelial cells in amplifying viral output. PLoS Pathog 2009; 5: e1000496.
12. Souza TA, Stollar BD, Sullivan JL, Luzuriaga K, Thorley-Lawson DA. Peripheral B cells latently infected with Epstein-Barr virus display molecular hallmarks of classical antigen-selected memory B cells. Proc Natl Acad Sci USA 2005; 102: 18093–18098.
13. Mancao C, Hammerschmidt W. Epstein-Barr virus latent membrane protein 2A is a B-cell receptor mimic and essential for B-cell survival. Blood 2007; 110: 3715–3721.
14. Rastelli J, Hömig-Hölzel C, Seagal J, Müller W, Hermann AC, Rajewsky K et alLMP1 signaling can replace CD40 signaling in B cells in vivo and has unique features of inducing class-switch recombination to IgG1. Blood 2008; 111: 1448–1455.
15. Roughan JE, Thorley-Lawson DA. The intersection of Epstein-Barr virus with the germinal center. J Virol 2009; 83: 3968–3976.
16. Roughan JE, Torgbor C, Thorley-Lawson DA. Germinal center B cells latently infected with Epstein-Barr virus proliferate extensively but do not increase in number. J Virol 2010; 84: 1158–1168.
17. + T cell immunity via concerted actions of multiple gene products. Semin Cancer Biol 2008; 18: 397–408.
18. Khanna R, Burrows SR. Role of cytotoxic T lymphocytes in Epstein-Barr virus-associated diseases. Annu Rev Microbiol 2000; 54: 19–48.
19. Hislop AD, Taylor GS, Sauce D, Rickinson AB. Cellular responses to viral infection in humans: lessons from Epstein-Barr virus. Annu Rev Immunol 2007; 25: 587–617.
20. Chijioke O, Müller A, Feederle R, Barros MHM, Krieg C, Emmel V et alHuman natural killer cells prevent infectious mononucleosis features by targeting lytic Epstein-Barr virus infection. Cell Rep 2013; 5: 1489–1498.
21. Rickinson AB, Kieff E. Epstein-Barr virus. In: Knipe DM, Howley PM (ed). Epstein-Barr virus. Lippincott Williams & Wilkins:Philadelphia. 2001, pp 2575–2627.
22. Vetsika EK, Callan M. Infectious mononucleosis and Epstein–Barr virus. Expert Rev Mol Med 2004; 6(23): 1–16.
23. Macsween KF, Higgins CD, McAulay KA, Williams H, Harrison N, Swerdlow AJ et alInfectious mononucleosis in university students in the United Kingdom: evaluation of the clinical features and consequences of the disease. Clin Infect Dis 2010; 50: 699–706.
24. Hochberg D, Souza T, Catalina M, Sullivan JL, Luzuriaga K, Thorley-Lawson DA. Acute infection with Epstein-Barr virus targets and overwhelms the peripheral memory B-cell compartment with resting, latently infected cells. J Virol 2004; 78: 5194–5204.
25. + -activated T cells in primary EBV infection. J Immunol 1999; 163: 5735–5740.
26. Hadinoto V, Shapiro M, Greenough TC, Sullivan JL, Luzuriaga K, Thorley-Lawson DA. On the dynamics of acute EBV infection and the pathogenesis of infectious mononucleosis. Blood 2008; 111: 1420–1427.
27. Rickinson AB, Long HM, Palendira U, Münz C, Hislop AD. Cellular immune controls over Epstein–Barr virus infection: new lessons from the clinic and the laboratory. Trends Immunol 2014; 35: 159–169.
28. Comans-Bitter WM, de Groot R, van den Beemd R, Neijens HJ, Hop WCJ, Groeneveld K et alImmunophenotyping of blood lymphocytes in childhood. Reference values for lymphocyte subpopulations. J Pediatr 1997; 130: 388–393.
29. Smets F, Latinne D, Bazin H, Reding R, Otte JB, Buts JP et alRatio between Epstein-Barr viral load and anti-Epstein-Barr virus specific T-cell response as a predictive marker of posttransplant lymphoproliferative disease. Transplantation 2002; 73: 1603–1610.
30. Fraser KB, Millar JHD, Haire M, McCrea S. Increased tendency to spontaneous in-vitro lymphocyte transformation in clinically active multiple sclerosis. Lancet 1979; 314: 715–717.
31. Sumaya CV, Myers LW, Ellison GW. Epstein-Barr virus antibodies in multiple sclerosis. Arch Neurol 1980; 37: 94–96.
32. Bray PF, Bloomer LC, Salmon VC, Bagley MH, Larsen PD. Epstein-Barr virus infection and antibody synthesis in patients with multiple sclerosis. Arch Neurol 1983; 40: 406–408.
33. Wandinger K-P, Jabs W, Siekhaus A, Bubel S, Trillenberg P, Wagner H-J et alAssociation between clinical disease activity and Epstein-Barr virus reactivation in MS. Neurology 2000; 55: 178–184.
34. Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part I: The role of infection. Ann Neurol 2007; 61: 288–299.
35. Levin LI, Munger KL, O'Reilly EJ, Falk KI, Ascherio A. Primary infection with the Epstein-Barr virus and risk of multiple sclerosis. Ann Neurol 2010; 67: 824–830.
36. Pakpoor J, Disanto G, Gerber JE, Dobson R, Meier UC, Giovannoni G et alThe risk of developing multiple sclerosis in individuals seronegative for Epstein-Barr virus: a meta-analysis. Mult Scler 2013; 19: 162–166.
37. Thacker EL, Mirzaei F, Ascherio A. Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis. Ann Neurol 2006; 59: 499–503.
38. Krupp LB, Serafin DJ, Christodoulou C. Multiple sclerosis-associated fatigue. Expert Rev Neurother 2010; 10: 1437–1447.
39. Berger JR, Pocoski J, Preblick R, Boklage S. Fatigue heralding multiple sclerosis. Mult Scler 2013; 19: 1526–1532.
40. Warner HB, Carp RI. Multiple sclerosis and Epstein-Barr virus. Lancet 1981; 318: 1290.
41. Haahr S, Höllsberg P. Multiple sclerosis is linked to Epstein-Barr virus infection. Rev Med Virol 2006; 16: 297–310.
42. Larsen PD, Bloomer LC, Bray PF. Epstein-Barr nuclear antigen and viral capsid antigen antibody titers in multiple sclerosis. Neurology 1985; 35: 435–438.
43. Sumaya CV, Myers LW, Ellison GW, Ench Y. Increased prevalence and titer of Epstein-Barr virus antibodies in patients with multiple sclerosis. Ann Neurol 1985; 17: 371–377.
44. Ascherio A, Munger KL, Lennette ET, Spiegelman D, Hernán MA, Olek MJ et alEpstein-Barr virus antibodies and risk of multiple sclerosis: a prospective study. JAMA 2001; 286: 3083–3088.
45. Cepok S, Zhou D, Srivastava R, Nessler S, Stei S, Büssow K et alIdentification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis. J Clin Invest 2005; 115: 1352–1360.
46. Sundström P, Nyström M, Ruuth K, Lundgren E. Antibodies to specific EBNA-1 domains and HLA DRB1∗1501 interact as risk factors for multiple sclerosis. J Neuroimmunol 2009; 215: 102–107.
47. Jafari N, van Nierop GP, Verjans GMGM, Osterhaus ADME, Middeldorp JM, Hintzen RQ. No evidence for intrathecal IgG synthesis to Epstein Barr virus nuclear antigen-1 in multiple sclerosis. J Clin Virol 2010; 49: 26–31.
48. Lindsey JW, Hatfield LM, Vu T. Epstein–Barr virus neutralizing and early antigen antibodies in multiple sclerosis. Eur J Neurol 2010; 17: 1263–1269.
49. Lünemann JD, Tintoré M, Messmer B, Strowig T, Rovira A, Perkal H et alElevated Epstein–Barr virus-encoded nuclear antigen-1 immune responses predict conversion to multiple sclerosis. Ann Neurol 2010; 67: 159–169.
50. Ruprecht K, Wunderlich B, Gieß R, Meyer P, Loebel M, Lenz K et alMultiple sclerosis: The elevated antibody response to Epstein–Barr virus primarily targets, but is not confined to, the glycine–alanine repeat of Epstein–Barr nuclear antigen-1. J Neuroimmunol 2014; 272: 56–61.
51. Buljevac D, van Doornum GJJ, Flach HZ, Groen J, Osterhaus ADME, Hop W et alEpstein-Barr virus and disease activity in multiple sclerosis. J Neurol Neurosurg Psychiatry 2005; 76: 1377–1381.
52. Lindsey JW, Khan U, Ansari W, Powell T, Wang YH, Guirguis MS. The antibody response to Epstein-Barr virions is altered in multiple sclerosis. J Neuroimmunol 2013; 254: 146–153.
53. Sundström P, Juto P, Wadell G, Hallmans G, Svenningsson A, Nyström L et alAn altered immune response to Epstein-Barr virus in multiple sclerosis: a prospective study. Neurology 2004; 62: 2277–2282.
54. Levin LI, Munger KL, Rubertone MV, Peck CA, Lennette ET, Spiegelman D et alTemporal relationship between elevation of Epstein-Barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis. JAMA 2005; 293: 2496–2500.
55. Farrell RA, Antony D, Wall GR, Clark DA, Fisniku L, Swanton J et alHumoral immune response to EBV in multiple sclerosis is associated with disease activity on MRI. Neurology 2009; 73: 32–38.
56. Kvistad S, Myhr KM, Holm⊘y T, Bakke S, Beiske AG, Bjerve KS et alAntibodies to Epstein-Barr virus and MRI disease activity in multiple sclerosis. Mult Scler 2014; doi:10.1177/1352458514533843.
57. Hochberg D, Middeldorp JM, Catalina M, Sullivan JL, Luzuriaga K, Thorley-Lawson DA. Demonstration of the Burkitt's lymphoma Epstein–Barr virus phenotype in dividing latently infected memory cells in vivo. Proc Natl Acad Sci USA 2004; 101: 239–244.
58. Rand KH, Houck H, Denslow ND, Heilman KM. Epstein-Barr virus nuclear antigen-1 (EBNA-1) associated oligoclonal bands in patients with multiple sclerosis. J Neurol Sci 2000; 173: 32–39.
59. Jaquiéry E, Jilek S, Schluep M, Meylan P, Lysandropoulos A, Pantaleo G et alIntrathecal immune responses to EBV in early MS. Eur J Immunol 2010; 40: 878–887.
60. Reiber H, Lange P. Quantification of virus-specific antibodies in cerebrospinal fluid and serum: sensitive and specific detection of antibody synthesis in brain. Clin Chem 1991; 37: 1153–1160.
61. Castellazzi M, Tamborino C, Cani A, Negri E, Baldi E, Seraceni S et alEpstein–Barr virus-specific antibody response in cerebrospinal fluid and serum of patients with multiple sclerosis. Mult Scler 2010; 16: 883–887.
62. Pohl D, Rostasy K, Jacobi C, Lange P, Nau R, Krone B et alIntrathecal antibody production against Epstein-Barr and other neurotropic viruses in pediatric and adult onset multiple sclerosis. J Neurol 2010; 257: 212–216.
63. Otto C, Oltmann A, Stein A, Frenzel K, Schroeter J, Habbel P et alIntrathecal EBV antibodies are part of the polyspecific immune response in multiple sclerosis. Neurology 2011; 76: 1316–1321.
64. Reiber H, Ungefehr S, Jacobi C. The intrathecal, polyspecific and oligoclonal immune response in multiple sclerosis. Mult Scler 1998; 4: 111–117.
65. Otto C, Hofmann J, Finke C, Zimmermann M, Ruprecht K. The fraction of varicella zoster virus-specific antibodies among all intrathecally-produced antibodies discriminates between patients with varicella zoster virus reactivation and multiple sclerosis. Fluids Barriers CNS 2014; 11: 3.
66. Jacobi C, Lange P, Reiber H. Quantitation of intrathecal antibodies in cerebrospinal fluid of subacute sclerosing panencephalitis, herpes simplex encephalitis and multiple sclerosis: discrimination between microorganism-driven and polyspecific immune response. J Neuroimmunol 2007; 187: 139–146.
67. Pender MP. Infection of autoreactive B lymphocytes with EBV, causing chronic autoimmune diseases. Trends Immunol 2003; 24: 584–588.
68. Croia C, Serafini B, Bombardieri M, Kelly S, Humby F, Severa M et alEpstein–Barr virus persistence and infection of autoreactive plasma cells in synovial lymphoid structures in rheumatoid arthritis. Ann Rheum Dis 2013; 72: 1559–1568.
69. Croia C, Astorri E, Murray-Brown W, Willis A, Brokstad KA, Sutcliffe N et alImplication of Epstein-Barr virus infection in disease-specific autoreactive B cell activation in ectopic lymphoid structures of Sjögren's syndrome. Arthritis Rheumatol 2014; 66: 2545–2557.
70. Bonnan M. Does disease-irrelevant intrathecal synthesis in multiple sclerosis make sense in the light of tertiary lymphoid organs? Front Neurol 2014; 5: 27.
71. Craig JC, Haire M, Millar JHD, Fraser KB, Merrett JD. Immunological control of Epstein–Barr virus-transformed lymphocytes in multiple sclerosis. Clin Immunol Immunopathol 1983; 29: 86–93.
72. Craig JC, Hawkins SA, Swallow MW, Lyttle JA, Patterson VH, Merrett JD et alSubsets of T lymphocytes in relation to T lymphocyte function in multiple sclerosis. Clin Exp Immunol 1985; 61: 548–555.
73. Lünemann JD, Jelčić I, Roberts S, Lutterotti A, Tackenberg B, Martin R et alEBNA1-specific T cells from patients with multiple sclerosis cross react with myelin antigens and co-produce IFN-γ and IL-2. J Exp Med 2008; 205: 1763–1773.
74. Craig JC, Haire M, Merrett JD. T-cell-mediated suppression of Epstein-Barr virus-induced B lymphocyte activation in multiple sclerosis. Clin Immunol Immunopathol 1988; 48: 253–260.
75. Pender MP, Csurhes PA, Lenarczyk A, Pfluger CMM, Burrows SR. Decreased T cell reactivity to Epstein-Barr virus infected lymphoblastoid cell lines in multiple sclerosis. J Neurol Neurosurg Psychiatry 2009; 80: 498–505.
76. Lindsey JW, Hatfield LM. Epstein-Barr virus and multiple sclerosis: Cellular immune response and cross-reactivity. J Neuroimmunol 2010; 229: 238–242.
77. Pender MP, Csurhes PA, Pfluger CMM, Burrows SR. Decreased CD8+ T cell response to Epstein-Barr virus infected B cells in multiple sclerosis is not due to decreased HLA class I expression on B cells or monocytes. BMC Neurology 2011; 11: 95.
78. + effector memory T cells is an early and persistent feature of multiple sclerosis. Mult Scler 2014; doi:10.1177/1352458514536252.
79. Pender MP, Csurhes PA, Pfluger CMM, Burrows SR. CD8 T cell deficiency impairs control of Epstein–Barr virus and worsens with age in multiple sclerosis. J Neurol Neurosurg Psychiatry 2012; 83: 353–354.
80. Gronen F, Ruprecht K, Weissbrich B, Klinker E, Kroner A, Hofstetter HH et alFrequency analysis of HLA-B7-restricted Epstein-Barr virus-specific cytotoxic T lymphocytes in patients with multiple sclerosis and healthy controls. J Neuroimmunol 2006; 180: 185–192.
81. Höllsberg P, Hansen HJ, Haahr S. Altered CD8+ T cell responses to selected Epstein-Barr virus immunodominant epitopes in patients with multiple sclerosis. Clin Exp Immunol 2003; 132: 137–143.
82. Jilek S, Schluep M, Meylan P, Vingerhoets F, Guignard L, Monney A et alStrong EBV-specific CD8+ T-cell response in patients with early multiple sclerosis. Brain 2008; 131: 1712–1721.
83. Angelini DF, Serafini B, Piras E, Severa M, Coccia EM, Rosicarelli B et alIncreased CD8+ T cell response to Epstein-Barr virus lytic antigens in the active phase of multiple sclerosis. PLoS Pathog 2013; 9: e1003220.
84. Jilek S, Schluep M, Harari A, Canales M, Lysandropoulos A, Zekeridou A et alHLA-B7-restricted EBV-specific CD8+ T cells are dysregulated in multiple sclerosis. J Immunol 2012; 188: 4671–4680.
85. + immunodominance among Epstein-Barr virus lytic cycle antigens directly reflects the efficiency of antigen presentation in lytically infected cells. J Exp Med 2005; 201: 349–360.
86. Tynan FE, Elhassen D, Purcell AW, Burrows JM, Borg NA, Miles JJ et alThe immunogenicity of a viral cytotoxic T cell epitope is controlled by its MHC-bound conformation. J Exp Med 2005; 202: 1249–1260.
87. Shi Y, Smith KD, Kurilla MG, Lutz CT. Cytotoxic CD8+ T cells recognize EBV antigen but poorly kill autologous EBV-infected B lymphoblasts. Immunodominance is elicited by a peptide epitope that is presented at low levels in vitro. J Immunol 1997; 159: 1844–1852.
88. + T cells during viral persistence in the central nervous system. J Immunol 1999; 163: 3379–3387.
89. + T lymphocytes during neuroinflammation is dependent on α4 integrin. Brain 2011; 134: 3560–3577.
90. Galea I, Bernardes-Silva M, Forse PA, van Rooijen N, Liblau RS, Perry VH. An antigen-specific pathway for CD8 T cells across the blood-brain barrier. J Exp Med 2007; 204: 2023–2030.
91. Holm⊘y T, Vartdal F. Cerebrospinal fluid T cells from multiple sclerosis patients recognize autologous Epstein-Barr virus-transformed B cells. J Neurovirol 2004; 10: 52–56.
92. Lünemann JD, Edwards N, Muraro PA, Hayashi S, Cohen JI, Münz C et alIncreased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis. Brain 2006; 129: 1493–1506.
93. Wucherpfennig KW, Strominger JL. Molecular mimicry in T cell-mediated autoimmunity: Viral peptides activate human T cell clones specific for myelin basic protein. Cell 1995; 80: 695–705.
94. Lang HLE, Jacobsen H, Ikemizu S, Andersson C, Harlos K, Madsen L et alA functional and structural basis for TCR cross-reactivity in multiple sclerosis. Nat Immunol 2002; 3: 940–943.
95. Álvarez-Lafuente R, De Las Heras V, Bartolomé M, García-Montojo M, Arroyo R. Human herpesvirus 6 and multiple sclerosis: a one-year follow-up study. Brain Pathol 2006; 16: 20–27.
96. Sotelo J, Ordoñez G, Pineda B. Varicella-zoster virus at relapses of multiple sclerosis. J Neurol 2007; 254: 493–500.
97. Lindsey JW, Hatfield LM, Crawford MP, Patel S. Quantitative PCR for Epstein–Barr virus DNA and RNA in multiple sclerosis. Mult Scler 2009; 15: 153–158.
98. Lucas RM, Ponsonby A-L, Dear K, Valery P, Pender MP, Burrows JM et alCurrent and past Epstein-Barr virus infection in risk of initial CNS demyelination. Neurology 2011; 77: 371–379.
99. Cocuzza CE, Piazza F, Musumeci R, Oggioni D, Andreoni S, Gardinetti M et alQuantitative detection of Epstein-Barr virus DNA in cerebrospinal fluid and blood samples of patients with relapsing-remitting multiple sclerosis. PLoS ONE 2014; 9: e94497.
100. Sotelo J, Ordoñez G, Pineda B, Flores J. The participation of varicella zoster virus in relapses of multiple sclerosis. Clin Neurol Neurosurg 2014; 119: 44–48.
101. Ben Fredj N, Rotola A, Nefzi F, Chebel S, Rizzo R, Caselli E et alIdentification of human herpesviruses 1 to 8 in Tunisian multiple sclerosis patients and healthy blood donors. J Neurovirol 2012; 18: 12–19.
102. Martin C, Enbom M, Söderström M, Fredrikson S, Dahl H, Lycke J et alAbsence of seven human herpesviruses, including HHV-6, by polymerase chain reaction in CSF and blood from patients with multiple sclerosis and optic neuritis. Acta Neurol Scand 1997; 95: 280–283.
103. Villoslada P, Juste C, Tintore M, Llorenç V, Codina G, Pozo-Rosich P et alThe immune response against herpesvirus is more prominent in the early stages of MS. Neurology 2003; 60: 1944–1948.
104. Franciotta D, Bestetti A, Sala S, Perucca P, Jarius S, Price RW et alBroad screening for human herpesviridae DNA in multiple sclerosis cerebrospinal fluid and serum. Acta Neurol Belg 2009; 109: 277–282.
105. Ferrante P, Omodeo-Zorini E, Zuffolato MR, Mancuso R, Caldarelli-Stefano R, Puricelli S et alHuman T-cell lymphotropic virus tax and Epstein-Barr virus DNA in peripheral blood of multiple sclerosis patients during acute attack. Acta Neurol Scand Suppl 1997; 169: 79–85.
106. Höllsberg P, Kusk M, Bech E, Hansen HJ, Jakobsen J, Haahr S. Presence of Epstein–Barr virus and human herpesvirus 6B DNA in multiple sclerosis patients: associations with disease activity. Acta Neurol Scand 2005; 112: 395–402.
107. Babcock GJ, Decker LL, Freeman RB, Thorley-Lawson DA. Epstein-Barr virus-infected resting memory B cells, not proliferating lymphoblasts, accumulate in the peripheral blood of immunosuppressed patients. J Exp Med 1999; 190: 567–576.
108. Gross AJ, Hochberg D, Rand WM, Thorley-Lawson DA. EBV and systemic lupus erythematosus: a new perspective. J Immunol 2005; 174: 6599–6607.
109. Tosato G, Steinberg AD, Yarchoan R, Heilman CA, Pike SE, De Seau V et alAbnormally elevated frequency of Epstein-Barr virus-infected B cells in the blood of patients with rheumatoid arthritis. J Clin Invest 1984; 73: 1789–1795.
110. Kimura H, Miyake K, Yamauchi Y, Nishiyama K, Iwata S, Iwatsuki K et alIdentification of Epstein-Barr virus (EBV)-infected lymphocyte subtypes by flow cytometric in situ hybridization in EBV-associated lymphoproliferative diseases. J Infect Dis 2009; 200: 1078–1087.
111. Maurer M, Kuhle J, Fischer K, Kappos L, Hartung H-P, Goebels N. Increased frequency of Epstein-Barr virus infected B cells in cerebrospinal fluid and peripheral blood of patients with multiple sclerosis. Mult Scler 2013; 19 ((11 Suppl)): 394–395.
112. Munch M, M⊘ller-Larsen A, Christensen T, Morling N, Hansen HJ, Haahr S. B-lymphoblastoid cell lines from multiple sclerosis patients and a healthy control producing a putative new human retrovirus and Epstein–Barr virus. Mult Scler 1995; 1: 78–81.
113. T⊘rring C, Andreasen C, Gehr N, Bjerg L, Petersen T, Höllsberg P. Higher incidence of Epstein–Barr virus-induced lymphocyte transformation in multiple sclerosis. Acta Neurol Scand 2014; 130: 90–96.
114. Yea C, Tellier R, Chong P, Westmacott G, Marrie RA, Bar-Or A et alEpstein-Barr virus in oral shedding of children with multiple sclerosis. Neurology 2013; 81: 1392–1399.
115. Serafini B, Rosicarelli B, Franciotta D, Magliozzi R, Reynolds R, Cinque P et alDysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J Exp Med 2007; 204: 2899–2912.
116. Sargsyan SA, Shearer AJ, Ritchie AM, Burgoon MP, Anderson S, Hemmer B et alAbsence of Epstein-Barr virus in the brain and CSF of patients with multiple sclerosis. Neurology 2010; 74: 1127–1135.
117. Gulley ML, Tang W. Laboratory assays for Epstein-Barr virus-related disease. J Mol Diagn 2008; 10: 279–292.
118. Willis SN, Stadelmann C, Rodig SJ, Caron T, Gattenloehner S, Mallozzi SS et alEpstein–Barr virus infection is not a characteristic feature of multiple sclerosis brain. Brain 2009; 132: 3318–3328.
119. Peferoen LAN, Lamers F, Lodder LNR, Gerritsen WH, Huitinga I, Melief J et alEpstein Barr virus is not a characteristic feature in the central nervous system in established multiple sclerosis. Brain 2010; 133: e137.
120. Torkildsen Ø, Stansberg C, Angelskår SM, Kooi E-J, Geurts JJG, van der Valk P et alUpregulation of immunoglobulin-related genes in cortical sections from multiple sclerosis patients. Brain Pathol 2010; 20: 720–729.
121. Lassmann H, Niedobitek G, Aloisi F, Middeldorp JM NeuroproMiSe EBV Working Group. Epstein-Barr virus in the multiple sclerosis brain: a controversial issue—report on a focused workshop held in the Centre for Brain Research of the Medical University of Vienna, Austria. Brain 2011; 134: 2772–2786.
122. Tzartos JS, Khan G, Vossenkamper A, Cruz-Sadaba M, Lonardi S, Sefia E et alAssociation of innate immune activation with latent Epstein-Barr virus in active MS lesions. Neurology 2012; 78: 15–23.
123. Serafini B, Muzio L, Rosicarelli B, Aloisi F. Radioactive in situ hybridization for Epstein-Barr virus-encoded small RNA supports presence of Epstein-Barr virus in the multiple sclerosis brain. Brain 2013; 136: e233.
124. Mǎrgǎritescu O, Mogoantǎ L, Pirici I, Pirici D, Cernea D, Mǎrgǎritescu C. Histopathological changes in acute ischemic stroke. Rom J Morphol Embryol 2009; 50: 327–339.
125. Wang J. Preclinical and clinical research on inflammation after intracerebral hemorrhage. Prog Neurobiol 2010; 92: 463–477.
126. Serafini B, Rosicarelli B, Aloisi F, Stigliano E. Epstein-Barr virus in the central nervous system and cervical lymph node of a patient with primary progressive multiple sclerosis. J Neuropathol Exp Neurol 2014; 73: 729–731.
127. Serafini B, Severa M, Columba-Cabezas S, Rosicarelli B, Veroni C, Chiappetta G et alEpstein-Barr virus latent infection and BAFF expression in B cells in the multiple sclerosis brain: implications for viral persistence and intrathecal B-cell activation. J Neuropathol Exp Neurol 2010; 69: 677–693.
128. Brennan RM, Burrows JM, Bell MJ, Bromham L, Csurhes PA, Lenarczyk A et alStrains of Epstein–Barr virus infecting multiple sclerosis patients. Mult Scler 2010; 16: 643–651.
129. Simon KC, Yang X, Munger KL, Ascherio A. EBNA1 and LMP1 variants in multiple sclerosis cases and controls. Acta Neurol Scand 2011; 124: 53–58.
130. Lindsey JW, Patel S, Zou J. Epstein–Barr virus genotypes in multiple sclerosis. Acta Neurol Scand 2008; 117: 141–144.
131. Lay M-L, Lucas RM, Toi C, Ratnamohan M, Ponsonby A-L, Dwyer DE et alEpstein-Barr virus genotypes and strains in central nervous system demyelinating disease and Epstein-Barr virus-related illnesses in Australia. Intervirology 2012; 55: 372–379.
132. + encephalitogenic T cells. Eur J Immunol 1994; 24: 2609–2617.
133. White CA, McCombe PA, Pender MP. The roles of Fas, Fas ligand and Bcl-2 in T cell apoptosis in the central nervous system in experimental autoimmune encephalomyelitis. J Neuroimmunol 1998; 82: 47–55.
134. Pender MP. Genetically determined failure of activation-induced apoptosis of autoreactive T cells as a cause of multiple sclerosis. Lancet 1998; 351: 978–981.
135. Pender MP, Csurhes PA, Greer JM, Mowat PD, Henderson RD, Cameron KD et alSurges of increased T cell reactivity to an encephalitogenic region of myelin proteolipid protein occur more often in patients with multiple sclerosis than in healthy subjects. J Immunol 2000; 165: 5322–5331.
136. Greer JM, Csurhes PA, Muller DM, Pender MP. Correlation of blood T cell and antibody reactivity to myelin proteins with HLA type and lesion localization in multiple sclerosis. J Immunol 2008; 180: 6402–6410.
137. Van Noort JM, Bajramovic JJ, Plomp AC, van Stipdonk MJB. Mistaken self, a novel model that links microbial infections with myelin-directed autoimmunity in multiple sclerosis. J Neuroimmunol 2000; 105: 46–57.
138. Van Sechel AC, Bajramovic JJ, van Stipdonk MJB, Persoon-Deen C, Geutskens SB, van Noort JM. EBV-induced expression and HLA-DR-restricted presentation by human B cells of αB-crystallin, a candidate autoantigen in multiple sclerosis. J Immunol 1999; 162: 129–135.
139. Wardemann H, Yurasov S, Schaefer A, Young JW, Meffre E, Nussenzweig MC. Predominant autoantibody production by early human B cell precursors. Science 2003; 301: 1374–1377.
140. Tracy SI, Kakalacheva K, Lünemann JD, Luzuriaga K, Middeldorp J, Thorley-Lawson DA. Persistence of Epstein-Barr virus in self-reactive memory B cells. J Virol 2012; 86: 12330–12340.
141. Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ et alB-cell depletion with rituximab in relapsing-remitting multiple sclerosis. New Engl J Med 2008; 358: 676–688.
142. Pender MP, Csurhes PA, Smith C, Beagley L, Hooper KD, Raj M et al. Epstein–Barr virus-specific adoptive immunotherapy for progressive multiple sclerosis. Mult Scler 2014; 20: 1541–1544.
143. Tourtellotte WW, Potvin AR, Baumhefner RW, Potvin JH, Ma BI, Syndulko K et alMultiple sclerosis de novo CNS IgG synthesis. Effect of CNS irradiation. Arch Neurol 1980; 37: 620–624.
144. Kelly GL, Long HM, Stylianou J, Thomas WA, Leese A, Bell AI et alAn Epstein-Barr virus anti-apoptotic protein constitutively expressed in transformed cells and implicated in Burkitt lymphomagenesis: the Wp/BHRF1 link. PLoS Pathog 2009; 5: e1000341.
145. McCarthy NJ, Hazlewood SA, Huen DS, Rickinson AB, Williams GT. The Epstein–Barr virus gene BHRF1, a homologue of the cellular oncogene Bcl-2, inhibits apoptosis induced by gamma radiation and chemotherapeutic drugs. Adv Exp Med Biol 1996; 406: 83–97.
146. Pender MP. Does Epstein–Barr virus infection in the brain drive the development of multiple sclerosis? Brain 2009; 132: 3196–3198.
147. Pender MP, Khanna R. Epstein–Barr virus-specific adoptive immunotherapy: a new horizon for multiple sclerosis treatment? Immunotherapy 2014; 6: 659–661.
148. Pender MP. Preventing and curing multiple sclerosis by controlling Epstein–Barr virus infection. Autoimmun Rev 2009; 8: 563–568.
149. Pender MP. CD8+ T-cell deficiency, Epstein-Barr virus infection, vitamin D deficiency and steps to autoimmunity: a unifying hypothesis. Autoimmune Dis 2012; 2012: 189096.
150. Sokal EM, Hoppenbrouwers K, Vandermeulen C, Moutschen M, Léonard P, Moreels A et alRecombinant gp350 vaccine for infectious mononucleosis: a phase 2, randomized, double-blind, placebo-controlled trial to evaluate the safety, immunogenicity, and efficacy of an Epstein-Barr virus vaccine in healthy young adults. J Infect Dis 2007; 196: 1749–1753.
151. Haque T, Johannessen I, Dombagoda D, Sengupta C, Burns DM, Bird P et alA mouse monoclonal antibody against Epstein-Barr virus envelope glycoprotein 350 prevents infection both in vitro and in vivo. J Infect Dis 2006; 194: 584–587.
152. Sashihara J, Hoshino Y, Bowman JJ, Krogmann T, Burbelo PD, Coffield VM et alSoluble rhesus lymphocryptovirus gp350 protects against infection and reduces viral loads in animals that become infected with virus after challenge. PLoS Pathog 2011; 7: e1002308.
153. Lycke J, Svennerholm B, Hjelmquist E, Frisen L, Badr G, Andersson M et alAcyclovir treatment of relapsing-remitting multiple sclerosis. A randomized, placebo-controlled, double-blind study. J Neurol 1996; 243: 214–224.
154. Bech E, Lycke J, Gadeberg P, Hansen HJ, Malmeström C, Andersen O et alA randomized, double-blind, placebo-controlled MRI study of anti-herpes virus therapy in MS. Neurology 2002; 58: 31–36.
155. Mei YP, Zhu XF, Zhou JM, Huang H, Deng R, Zeng YX. siRNA targeting LMP1-induced apoptosis in EBV-positive lymphoma cells is associated with inhibition of telomerase activity and expression. Cancer Lett 2006; 232: 189–198.
156. Li N, Thompson S, Schultz DC, Zhu W, Jiang H, Luo C et alDiscovery of selective inhibitors against EBNA1 via high throughput in silico virtual screening. PLoS ONE 2010; 5: e10126.
157. Procko E, Berguig GY, Shen BW, Song Y, Frayo S, Convertine AJ et alA computationally designed inhibitor of an Epstein-Barr viral Bcl-2 protein induces apoptosis in infected cells. Cell 2014; 157: 1644–1656.
158. Savoldo B, Goss JA, Hammer MM, Zhang L, Lopez T, Gee AP et alTreatment of solid organ transplant recipients with autologous Epstein Barr virus-specific cytotoxic T lymphocytes (CTLs). Blood 2006; 108: 2942–2949.
159. Smith C, Tsang J, Beagley L, Chua D, Lee V, Li V et alEffective treatment of metastatic forms of Epstein-Barr virus-associated nasopharyngeal carcinoma with a novel adenovirus-based adoptive immunotherapy. Cancer Res 2012; 72: 1116–1125.