Chapter 6 : Viruses and Multiple Sclerosis

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

Viruses and Multiple Sclerosis, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555817947/9781555812447_Chap06-1.gif /docserver/preview/fulltext/10.1128/9781555817947/9781555812447_Chap06-2.gif


Multiple sclerosis (MS) is a complex demyelinating disease of the central nervous system (CNS) affecting mostly young adults. A few viruses, including human herpesvirus 6 (HHV-6), are accumulating considerable and consistent support for a role in MS. The complexity and diversity of MS pathologic features in relation to the history of the disease have made the identification of a single pathogenic pathway unsuccessful and are now contributing to a new approach to the study of the disease pathogenesis. There has been a strong contribution to MS research by use of the murine experimental autoimmune encephalomyelitis (EAE) model and the demonstration of myelin-reactive T cells that has focused considerable attention on cellular immunity. Not only can viruses induce direct damage of the infected cells, but they can also trigger autoimmune reactions leading to demyelination. There are a number of demyelinating diseases following systemic infections with viruses such as mumps, varicella-zoster, influenza, and measles viruses, termed postinfectious encephalomyelitis (PIE). Other demyelinating diseases with well-defined viral etiologies are progressive multifocal leukoencephalopathy (PML), subacute sclerosing panencephalitis (SSPE), and human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The study of this unique, multifaceted disorder represents a challenging opportunity not only to better define the disease itself, but also to understand how the CNS, which once was considered an immune privileged site, reacts to infections and how one or more viral agents can cause aberrant autoimmunity.

Citation: Donati D, Jacobson S. 2002. Viruses and Multiple Sclerosis, p 99-124. In Brogden K, Guthmiller J (ed), Polymicrobial Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817947.ch6

Key Concept Ranking

Central Nervous System Diseases
Tumor Necrosis Factor alpha
Semliki forest virus
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


1. Ablashi, D. V.,, N. Balachandran,, S. F. Josephs,, C. L. Hun,, G. R. F. Krueger,, B. Kramarsky,, S. Z. Salahuddin,, and R. C. Gallo. 1991. Genomic polymorphism, growth properties, and immunologic variations in human herpesvirus-6 isolates. Virology 184:545552.
2. Ablashi, D. V.,, H. B. Eastman,, C. B. Owen,, M. M. Roman,, J. Friedman,, J. B. Zabriskie,, D. L. Peterson,, G. R. Pearson,, and J. E. Whitman. 2000. Frequent HHV-6 reactivation in multiple sclerosis (MS) and chronic fatigue syndrome (CFS) patients. J. Clin. Virol. 16:179191.
3. Akhyani, N.,, R. Berti,, M. B. Brennan,, S. S. Soldan,, J. M. Eaton,, H. F. McFarland,, and S. Jacobson. 2000. Tissue distribution and variant characterization of human herpesvirus (HHV)-6: increased prevalence of HHV-6A in patients with multiple sclerosis. J. Infect. Dis. 182:13211325.
4. Albright, A. V.,, E. Lavi,, J. B. Black,, S. Goldberg,, M. J. O’Connor,, and F. González-Scarano. 1998. The effect of human herpesvirus-6 (HHV-6) on cultured human neural cells: oligodendrocytes and microglia. J. Neurovirol. 4:486494.
5. Archelos, J. J.,, M. K. Storch,, and H. P. Hartung. 2000. The role of B cells and autoantibodies in multiple sclerosis. Ann. Neurol. 47:694706.
6. Bailey, O. T.,, A. M. Pappenheimer,, F. S. Cheever,, and J. B. Daniels. 1949. A murine hepatitis virus (JHM) causing disseminated encephalomyelitis with extensive destruction of myelin. II. Pathology. J. Exp. Med. 90:195212.
7. Bajramovic, J. J.,, H. Lassmann,, and J. M. van Noort. 1997. Expression of alphaB-crystallin in glia cells during lesional development in multiple sclerosis. J. Neuroimmunol. 78:143151.
8. Barac-Latas, V.,, G. Suchanek,, H. Breitschopf,, A. Stuehler,, H. Wege,, and H. Lassmann. 1997. Patterns of oligodendrocyte pathology in coronavirus-induced subacute demyelinating encephalomyelitis in the Lewis rat. Glia 19:112.
9. Berger, J. R.,, B. Kaszovitz,, M. J. Post,, and G. Dickinson. 1987. Progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. A review of the literature with a report of sixteen cases. Ann. Intern. Med. 107:7887.
10. Berger, J. R.,, and L. Mucke. 1988. Prolonged survival and partial recovery in AIDS-associated progressive multifocal leukoencephalopathy. Neurology 38:10601065.
11. Bergström, T. 1999. Herpesviruses—a rationale for antiviral treatment in multiple sclerosis. Antiviral Res. 41:119.
12. Bergström, T.,, O. Andersen,, and A. Vahlne. 1989. Isolation of herpes simplex type 1 during first attack of multiple sclerosis. Ann. Neurol. 26:283285.
13. Bitsch, A.,, J. Schuchardt,, S. Bunkowski,, T. Kuhlmann,, and W. Brück. 2000. Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain 123:11741183.
14. Blond, J. L.,, F. Beseme,, L. Duret,, O. Bouton,, F. Bedin,, H. Perron,, B. Mandrand,, and F. Mallet. 1999. Molecular characterization and placental expression of HERV-W, a new human endogenous retrovirus family. J. Virol. 73:11751185.
15. Blumberg, B. M.,, D. J. Mock,, J. M. Powers,, M. Ito,, J. G. Assouline,, J. V. Backer,, B. Chen,, and A. D. Goodman. 2000. The HHV6 paradox: ubiquitous commensal or insidious pathogen? A two-step in situ PCR approach. J. Clin. Virol. 16:159178.
16. Borrow, P.,, P. Tonks,, C. J. R. Welsh,, and A. A. Nash. 1992. The role of CD8+ T cells in the acute and chronic phases of Theiler’s virus-induced disease in mice. J. Gen. Virol. 73:18611865.
17. Brahic, M.,, and J.-F. Bureau. 1997. Multiple sclerosis and retroviruses. Ann. Neurol. 42:984985.
18. Bray, P. F.,, J. Luka,, P. F. Bray,, K. W. Culp,, and J. P. Schlight. 1992. Antibodies against Epstein- Barr nuclear antigen (EBNA) in multiple sclerosis CSF, and two pentapeptide sequence identities between EBNA and myelin basic protein. Neurology 42:17981804.
19. Brosnan, C. F.,, M. K. Racke,, and K. Selmaj. 1988. Hypothesis: a role of tumor necrosis factor in immune-mediated demyelination and its relevance to multiple sclerosis. J. Neuroimmunol. 18:8794.
20. Burns, J.,, A. Rosenzweig,, B. Zweiman,, and R. P. Lisak. 1983. Isolation of myelin basic protein- reactive T-cell lines from normal human blood. Cell. Immunol. 81:435440.
21. Butcher, E. C. 1991. Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity. Cell 67:10331036.
22. Caserta, M. T.,, C. Breese-Hall,, K. Schnabel,, K. McIntyre,, C. Long,, M. Costanzo,, S. Dewhurst,, R. Insel,, and L. G. Epstein. 1994. Neuroinvasion and persistence of human herpesvirus 6 in children. J. Infect. Dis. 170:15861589.
23. Cattaneo, R.,, A. Schmid,, M. A. Billeter,, R. D. Sheppard,, and S. A. Udem. 1988. Multiple viral mutations rather than host factors cause defective measles virus gene expression in a subacute sclerosing panencephalitis cell line. J. Virol. 62:13881397.
24. Cermelli, C.,, and S. Jacobson. 2000. Viruses and multiple sclerosis. Viral Immunol. 13:255267.
25. Challoner, P. B.,, K. T. Smith,, J. D. Parker,, D. L. MacLeod,, S. N. Coulter,, T. M. Rose,, E. R. Schultz,, J. L. Bennett,, R. L. Garber,, M. Chang,, P. A. Schad,, P. M. Stewart,, R. C. Nowinski,, J. P. Brown,, and G. C. Burmer. 1995. Plaque-associated expression of human herpesvirus 6 in multiple sclerosis. Proc. Natl. Acad. Sci. USA 92:74407444.
26. Chataway, J.,, R. Feakes,, F. Coraddu,, J. Gray,, J. Deans,, M. Fraser,, N. Robertson,, S. Broadley,, H. Jones,, D. Clayton,, P. Goodfellow,, S. Sawcer,, and A. Compston. 1998. The genetics of multiple sclerosis: principles, background and updated results of the United Kingdom systematic region screen. Brain 121:18691887.
27. Chesters, P. M.,, J. Heritage,, and D. Mc- Cance. 1983. Persistence of DNA sequences of BK virus and JC virus in normal human tissues and in diseased tissues. J. Infect. Dis. 147:676682.
28. Clark, D. A. 2000. Human herpesvirus 6. Rev. Med. Virol. 10:155173.
29. Clatch, R. J.,, H. L. Lipton,, and S. D. Miller. 1986. Characterization of Theiler’s murine encephalomyelitis virus (TMEV)-specific delayed type hypersensitivity responses in TMEV-induced demyelinating disease: correlation with clinical signs. J. Immunol. 136:920927.
30. Compston, A. 1994. The epidemiology of multiple sclerosis: principles, achievements, and recommendations. Ann. Neurol. 36(Suppl. 2):S211217.
31. Cone, R. W.,, R. C. Hackman,, M. L. Huang,, R. A. Bowden,, J. D. Meyers,, M. Metcalf,, J. Zeh,, R. Ashley,, and L. Corey. 1993. Human herpesvirus 6 in lung tissue from patients with pneumonitis after bone marrow transplantation. N. Engl. J. Med. 329:156161.
32. Connolly, J. H.,, I. V. Allen,, L. J. Hurwitz,, and J. H. Millar. 1967. Measles-virus antibody and antigen in subacute sclerosing panencephalitis. Lancet i:542544.
33. Corssmit, E. P.,, M. A. Leverstein-van Hall,, P. Portegies,, and P. Bakker. 1997. Severe neurological complications in association with Epstein-Barr virus infection. J. Neurovirol. 3:460464.
34. Coyle, P. K. 1985. CSF immune complexes in multiple sclerosis. Neurology 35:429432.
35. Cross, A. H.,, J. L. Trotter,, and J.-A. Lyons. 2001. B cells and antibodies in CNS demyelinating disease. J. Neuroimmunol. 112:114.
36. Dewhurst, S.,, K. McIntyre,, K. Schnabel,, and C. B. Hall. 1993. Human herpesvirus-6 (HHV-6) variant accounts for the majority of symptomatic primary HHV-6 infections in a population of U.S. infants. J. Clin. Microbiol. 31:416418.
37. Dominguez, G.,, T. R. Dambaugh,, F. R. Stamey,, S. Dewhurst,, N. Inoue,, and P. E. Pellett. 1999. Human herpesvirus 6B genome sequence: coding content and comparison with human herpesvirus 6A. J. Virol. 73:80408052.
38. Dore-Duffy, P.,, W. Newman,, R. Balabanov,, R. P. Lisak,, E. Mainolfi,, R. Rothlein,, and M. Peterson. 1995. Circulating soluble adhesion proteins in cerebrospinal fluid and serum of patients with multiple sclerosis: correlation with clinical activity. Ann. Neurol. 37:5562.
39. Drobyski, W. R.,, K. K. Knox,, D. Majewski,, and D. R. Carrigan. 1994. Brief report: fatal encephalitis due to variant B human herpesvirus- 6 infection in a bone marrow transplant recipient. N. Engl. J. Med. 330:13561360.
40. Edwards, S.,, M. Zvartau,, H. Clarke,, W. Irving,, and L. D. Blumhardt. 1998. Clinical relapses and disease activity on magnetic resonance imaging associated with viral upper respiratory tract infections in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 64:736741.
41. Erlich, S.,, J. Fleming,, S. Stohlman,, and L. Weiner. 1987. Experimental neuropathology of remote infection with a JHM virus variant (DS). Arch. Neurol. 44:24832489.
42. Ferrante, P.,, E. Omodeo-Zorini,, M. R. Zuffolato,, R. Mancuso,, R. Caldarelli-Stefano,, S. Puricelli,, M. Mediati,, L. Losciale,, and D. Caputo. 1997. Human T-cell lymphotropic virus tax and Epstein-Barr virus DNA in peripheral blood of multiple sclerosis patient during acute attack. Acta Neurol. Scand. 169 (Suppl.):7985.
43. Fritz, R. B.,, M. J. Skeen,, C. H.-J. Chen,, M. Garcia,, and I. K. Egorov. 1985. Major histocompatibility complex linked control of the immune response to myelin basic protein. J. Immunol. 134:23282332.
44. Fujinami, R. B.,, and J. E. Libbey. 1999. Endogenous retroviruses: are they the cause of multiple sclerosis? Trends Microbiol. 7:263264.
45. Fujinami, R. S.,, and M. B. A. Oldstone. 1980. Alterations in expression of measles virus polypeptides by antibody: molecular events in antibody- induced antigenic modulation. J. Immunol. 125:7885.
46. Fujinami, R. S.,, and M. B. A. Oldstone. 1985. Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity. Science 230:10431045.
47. Garson, J. A.,, P. W. Tuke,, P. Giraud,, G. Paranhos-Baccala,, and H. Perron. 1998. Detection of virion-associated MSRV-RNA in serum of patients with multiple sclerosis. Lancet 351:33.
48. Gay, F. W.,, T. J. Drye,, G. W. A. Dick,, and M. M. Esiri. 1997. The application of multifactorial cluster analysis in the staging of plaques in early multiple sclerosis. Identification and characterization of the primary demyelinating lesion. Brain 120:14611483.
49. Genain, C. P.,, M. H. Nguyen,, N. L. Letvin,, R. Pearl,, R. L. Davis,, M. Adelman,, M. B. Lees,, C. Linington,, and S. L. Hauser. 1995. Antibody facilitation of multiple sclerosis-like lesions in a nonhuman primate. J. Clin. Investig. 96:29662974.
50. Gendelman, H. E.,, G. H. Pezeshkpour,, N. J. Pressman,, J. S. Wolinsky,, R. H. Quarles,, M. J. Dobersen,, B. D. Trapp,, C. A. Kitt,, A. Aksamit,, and R. T. Johnson. 1985. A quantitation of myelin-associated glycoprotein and myelin basic protein loss in different demyelinating diseases. Ann. Neurol. 18:324328.
51. Goldberg, S. H.,, A. V. Albright,, R. P. Lisak,, and F. Gonzalez-Scarano. 1999. Polymerase chain reaction analysis of human herpesvirus 6 sequences in the sera and cerebrospinal fluid of patients with multiple sclerosis. J. Neurovirol. 5:134139.
52. Haar, S.,, M. Munch,, T. Christensen,, A. Meller-Larson,, and J. Hvas. 1997. Cluster of multiple sclerosis patients from Danish community. Lancet 349:9056.
53. Hall, C. B.,, M. T. Caserta,, K. C. Schnabel,, C. Long,, L. G. Epstein,, R. A. Insel,, and S. Dewhurst. 1998. Persistence of human herpesvirus 6 according to site and variant: possible greater neurotropism of variant A. Clin. Infect. Dis. 26:132137.
54. Hall, W. W.,, and P. W. Choppin. 1981. Measles virus proteins in the brain tissue of patients with subacute sclerosing panencephalitis. N. Engl. J. Med. 304:11521155.
55. Hilton, D. A.,, S. Love,, A. Fletcher,, and J. H. Pringle. 1994. Absence of Epstein-Barr virus RNA in multiple sclerosis as assessed by in situ hybridization. J. Neurol. Neurosurg. Psychiatry 57:975976.
56. Hofman, F. M.,, R. I. von Hanwehr,, C. A. Dinarello,, S. B. Mizel,, D. Hinton,, and J. E. Merrill. 1986. Immunoreglatory molecules and IL 2 receptors identified in multiple sclerosis brain. J. Immunol. 136:32393245.
57. Horwitz, M. S.,, L. M. Bradley,, J. Harbertson,, T. Krahl,, J. Lee,, and N. Sarvetnick. 1998. Diabetes induced by coxsackievirus: initiation by bystander damage and not molecular mimicry. Nat. Med. 4:781785.
58. Ijichi, S.,, S. Izumo,, N. Eiraku,, K. Machigashira,, R. Kubota,, M. Nagai,, N. Ikegami,, N. Kashio,, F. Umehara,, and I. Maruyama. 1993. An autoaggressive process against bystander tissues in HTLV-I infected individuals: a possible pathomechanism of HAM/TSP. Med. Hypotheses 41:572547.
59. Ishiguro, M. 1990. Meningo-encephalitis associated with HHV-6 related exanthem subitum. Acta Paediatr. Scand. 79:987989.
60. Jacobson, S. 1998. Association of human herpesvirus- 6 and multiple sclerosis: here we go again? J. Neurovirol. 4:471473.
61. Jacobson, S.,, M. L. Flerlage,, and H. F. Mc- Farland. 1985. Impaired measles virus specific cytotoxic-T cell responses in multiple sclerosis. J. Exp. Med. 162:839850.
62. Johns, T. G.,, and C. C. Bernard. 1999. The structure and function of myelin oligodendrocyte glycoprotein. J. Neurochem. 71:19.
63. Johnson, K. P.,, B. R. Brooks,, J. A. Cohen,, C. C. Ford,, J. Goldstein,, R. P. Lisak,, L. W. Myers,, H. S. Panitch,, J. W. Rose,, R. B. Schiffer, et al. 1995. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. Neurology 45:12681276.
64. Johnson, R. T. 1994. The virology of demyelinating diseases. Ann. Neurol. 36:S54S60.
65. Johnson, R. T.,, D. E. Griffin,, R. L. Hirsch,, J. S. Wolinsky,, S. Roedenbeck,, I. Lindo de Soriano,, and A. Vaisberg. 1984. Measles encephalomyelitis: clinical and immunological studies. N. Engl. J. Med. 310:137141.
66. Joshi, N.,, K. Usuku,, and S. L. Hauser. 1993. The T-cell response to myelin basic protein in familial multiple sclerosis: diversity of fine specificity restricting elements, and T-cell receptor usage. Ann. Neurol. 34:385393.
67. Karpus, W. J.,, J. G. Pope,, J. D. Peterson,, M. C. Dal Canto,, and S. D. Miller. 1995. Inhibition of Theiler’s virus-mediated demyelination by peripheral immune tolerance induction. J. Immunol. 155:947957.
68. Kastrukoff, L. F.,, A. S. Lau,, and S. U. Kim. 1987. Multifocal CNS demyelination following peripheral inoculation with herpes simplex virus type I. Ann. Neurol. 22:5259.
69. Kastrukoff, L. F.,, A. S. Lau,, G. Y. Leung,, and E. E. Thomas. 1993. Contrasting effects of immunosuppression on herpes simplex virus type I (HSV I) induced central nervous system (CNS) demyelination in mice. J. Neurol. Sci. 117:148158.
70. Katz-Levy, Y.,, K. L. Neville,, A. M. Girvin,, C. L. Vanderlugt,, J. G. Pope,, L. J. Tan,, and S. D. Miller. 1999. Endogenous presentation of self myelin epitopes by CNS-resident APCs in Theiler’s virus-infected mice. J. Clin. Investig. 104:599610.
71. Kawano, M.,, T. Seya,, I. Koni,, and H. Mabuchi. 1999. Elevated serum levels of soluble membrane cofactor protein (CD46, MCP) in patients with systemic lupus erythematosus (SLE). Clin. Exp. Immunol. 116:542546.
72. Kaye, J. F.,, N. Kerlero de Rosbo,, I. Mendel,, S. Fletcher,, M. Hoffman,, I. Yust,, and A. Ben-Nun. 2000. The central nervous systemspecific myelin oligodendrocytic basic protein (MOBP) is encephalitogenic and a potential target antigen in multiple sclerosis (MS). J. Neuroimmunol. 102:189198.
73. Kim, J.,, K. Lee,, J. Park,, M. Kim,, and W. Shin. 2000. Detection of human herpesvirus 6 variant A in peripheral blood mononuclear cells from multiple sclerosis patients. Eur. Neurol. 43:170173.
74. Kleinschmidt-DeMasters, B. K.,, C. Amlie- Lefond,, and D. H. Gilden. 1996. The patterns of varicella-zoster virus encephalitis. Hum. Pathol. 27:927938.
75. Knox, K. K.,, J. H. Brewer,, J. M. Henry,, D. J. Harrington,, and D. R. Carrigan. 2000. Human herpesvirus 6 and multiple sclerosis: systemic active infections in patients with early disease. Clin. Infect. Dis. 31:894903.
76. Knox, K. K.,, and D. R. Carrigan. 1995. Active human herpesvirus (HHV-6) infection in the central nervous system in patients with AIDS. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 9:6973.
77. Koprowski, H.,, and E. DeFreitas. 1988. HTLV-I and chronic nervous diseases: present status and a look into the future. Ann. Neurol. 23(Suppl.):166170.
78. Koprowski, H.,, E. C. DeFreitas,, M. E. Harper,, M. Sandberg-Wollheim,, W. A. Sheremata,, M. Robert-Guroff,, C. W. Saxinger,, M. B. Feinberg,, F. Wong-Staal,, and R. C. Gallo. 1985. Multiple sclerosis and human T-cell lymphotropic retroviruses. Nature 318:154160.
79. Krieg, A. M.,, M. F. Gourley,, and A. Perl. 1992. Endogenous retroviruses: potential etiologic agents in autoimmunity. FASEB J. 6:25372544.
80. Kurtzke, J. F. 1993. Epidemiologic evidence for multiple sclerosis as an infection. Clin. Microbiol. Rev. 6:382427.
81. Kurtzke, J. F. 1995. MS epidemiology worldwide. One view of current status. Acta Neurol. Scand. 161(Suppl.):2333.
82. Kurtzke, J. F.,, K. Hyllested,, and A. Heltberg. 1995. Multiple sclerosis in the Faroe islands: transmission across four epidemics. Acta Neurol. Scand. 91:321325.
83. Kyuwa, S.,, K. Yamaguchi,, Y. Toyoda,, and K. Fujiwara. 1991. Induction of self-reactive T cells after murine infection. J. Virol. 65:17891795.
84. Lafaille, J. J.,, F. V. Keere,, A. L. Hsu,, J. L. Baron,, W. Haas,, C. S. Raine,, and S. Tonegawa. 1997. Myelin basic protein specific T helper 2 (Th2) cells cause experimental autoimmune encephalomyelitis in immunodeficient hosts rather than protect them from the disease. J. Exp. Med. 186:307312.
85. Lehman, P. V.,, T. Forsthuber,, A. Miller,, and E. E. Sercarz. 1992. Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature 358:155157.
86. Leonard, J. P.,, K. E. Waldburger,, and S. J. Goldman. 1995. Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12. J. Exp. Med. 181:381386.
87. Liedtke, W.,, K. Quabeck,, D. W. Beelen,, V. Straeten,, and U. W. Schaefer. 1994. Recurrent acute inflammatory demyelinating polyradiculitis after allogeneic bone marrow transplantation. J. Neurol. Sci. 125:110111.
88. Lindert, R.-B.,, C. G. Haase,, U. Brehm,, C. Linington,, H. Wekerle,, and R. Hohfeld. 1999. Multiple sclerosis: B- and T-cell responses to the extracellular domain of the myelin oligodendrocyte glycoprotein. Brain 122:20892099.
89. Linington, C.,, M. Bradl,, H. Lassmann,, C. Brunner,, and K. Vass. 1988. Augmentation of demyelination in rat acute allergic encephalomyelitis by circulating mouse monoclonal antibodies directed against a myelin/oligodendrocyte glycoprotein. Am. J. Pathol. 130:443454.
90. Lipton, H. L.,, G. Twaddle,, and M. L. Jelachich. 1995. The predominant virus antigen burden is present in macrophages in Theiler’s murine encephalomyelitis virus-induced demyelinating disease. J. Virol. 69:25252533.
91. Locatelli, G.,, F. Santoro,, F. Veglia,, A. Gobbi,, P. Lusso,, and M. S. Malnati. 2000. Real-time quantitative PCR for human herpesvirus 6 DNA. J. Clin. Microbiol. 38:40424048.
92. Lorentzen, J. C.,, S. Issazadeh,, M. Storch,, M. I. Mustafa,, H. Lassmann,, C. Linington,, L. Klareskog,, and T. Olsson. 1995. Protracted relapsing and demyelinating experimental autoimmune encephalomyelitis in DA rats immunized with syngeneic spinal cord and incomplete Freund’s adjuvant. J. Neuroimmunol. 63:193205.
93. Lublin, F. D.,, and S. C. Reing old for the National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. 1996. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology 46:907911.
94. Lucchinetti, C.,, W. Brück,, and J. Noseworthy. 2001. Multiple sclerosis: recent developments in neuropathology, pathogenesis, magnetic resonance imaging studies and treatment. Curr. Opin. Neurol. 14:259269.
95. Lucchinetti, C.,, W. Brück,, J. Parisi,, B. Scheithauer,, M. Rodriguez,, and H. Lassmann. 1999. A quantitative analysis of oligodendrocytes in multiple sclerosis lesions. A study of 113 cases. Brain 122:22792295.
96. Lucchinetti, C.,, W. Brück,, J. Parisi,, B. Scheithauer,, M. Rodriguez,, and H. Lassmann. 2000. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann. Neurol. 47:707717.
97. Lusso, P.,, F. Di Marzo Veronese,, S. Z. Salahuddin,, D. V. Ablashi,, S. Pahwa,, K. Krohn,, and R. C. Gallo. 1988. In vitro cellular tropism of human B-lymphotropic virus (human herpesvirus 6). J. Exp. Med. 167:16591670.
98. Lycke, J.,, B. Svennerholm,, E. Hjelmquist,, L. Frisen,, G. Badr,, M. Andersson,, A. Vahlne,, and O. Andersen. 1996. Acyclovir treatment of relapsing-remitting multiple sclerosis. A randomized, placebo-controlled, doubleblind study. J. Neurol. 243:214224.
99. Madsen, L. S.,, E. C. Andersson,, L. Jansson,, M. Krogsgaard,, C. B. Andersen,, J. Engberg,, J. L. Strominger,, A. Svejgaard,, J. P. Hjorth,, R. Holmdahl,, K. W. Wucherpfennig,, and L. Fugger. 1999. A humanized model for multiple sclerosis using HLA DR2 and a human T cell receptor. Nat. Genet. 23:343347.
100. Marrie, R. A.,, C. Wolfson,, M. C. Sturkenboom,, O. Gout,, O. Heinzlef,, E. Roullet,, and L. Abenhaim. 2000. Multiple sclerosis and antecedent infections: a case-control study. Neurology 54:23072310.
101. Marschang, P.,, J. Sodroski,, R. Wurzner,, and M. P. Dierich. 1995. Decay accelerating factor (CD55) protects human immunodeficiency virus type 1 from inactivation by human complement. Eur. J. Immunol. 25:285290.
102. Martin, C.,, M. Enbom,, M. Söderström,, S. Fredrikson,, H. Dahl,, J. Lycke,, T. Bergström,, and A. Linde. 1997. Absence 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. 95:280283.
103. Mayne, M.,, J. Krishnana,, L. Metz,, A. Nath,, A. Auty,, B. M. Sahai,, and C. Power. 1998. Infrequent detection of human herpesvirus 6 DNA in peripheral mononuclear cells from multiple sclerosis patients. Ann. Neurol. 44:391394.
104. Miller, S. D.,, C. L. Vanderlugt,, W. S. Begolka,, W. Pao,, R. L. Yauch,, K. L. Neville,, Y. Katz-Levy,, A. Carrizosa,, and B. S. Kim. 1997. Persistent infection with Theiler’s virus leads to CNS autoimmunity via epitope spreading. Nat. Med. 3:11331136.
105. Mokhtarian, F.,, and P. Swoveland. 1987. Predisposition to EAE induction in resistant mice by prior infection with Semliki Forest virus. J. Immunol. 138:32643268.
106. Mokhtarian, F.,, Z. Zhang,, Y. Shi,, E. Gonzales,, and R. A. Sobel. 1999. Molecular mimicry between a viral peptide and myelin oligodendrocyte glycoprotein induces autoimmune demyelinating disease in mice. J. Neuroimmunol. 95:4354.
107. Moller, J. R.,, D. Johnson,, R. O. Brady,, W. W. Tourtellotte,, and R. H. Quarles. 1989. Antibodies to myelin-associated glycoprotein (MAG) in the cerebrospinal fluid of multiple sclerosis patients. J. Neuroimmunol. 22:5561.
108. Montefiori, D. C.,, R. J. Cornell,, J. Y. Zhou,, J. T. Zhou,, V. M. Hirschand,, and P. R. Johnson. 1994. Complement control proteins, CD46, CD55 and CD59, as common surface constituents of human and simian immunodeficiency viruses and possible targets for vaccine protection. Virology 205:8292.
109. Munch, M.,, A. Møller-Larsen,, T. Christensen,, N. Morling,, H. J. Hansen,, and S. Haar. 1997. Production of retrovirus and Epstein- Barr virus in cell lines from multiple sclerosis patients. Acta Neurol. Scand. 169(Suppl.):6569.
110. Murray, P. D.,, D. B. McGavern,, S. Sathornsumetee,, and M. Rodriguez. 2001. Spontaneous remyelination following extensive demyelination is associated with improved neurological function in a viral model of multiple sclerosis. Brain 124:14031416.
111. Nagano, I.,, S. Nakamura,, M. Yoshioka,, J. Onodera,, K. Kogure,, and Y. Itoyama. 1994. Expression of cytokines in brain lesions in subacute sclerosing panencephalitis. Neurology 44:710715.
112. Neighbour, P. A.,, A. E. Miller,, and B. R. Bloom. 1981. Interferon responses of leukocytes in multiple sclerosis. Neurology 31:561566.
113. Newcombe, J.,, S. Gahan,, and M. L. Cuzner. 1985. Serum antibodies against central nervous system proteins in human demyelinating disease. Clin. Exp. Immunol. 59:383390.
114. Norrby, E.,, H. Link,, and J. E. Olsson. 1974. Measles virus antibodies in multiple sclerosis, comparison of antibody titres in cerebrospinal fluid and serum. Arch. Neurol. 30:285292.
115. Noseworthy, J. H.,, C. Lucchinetti,, M. Rodrigez,, and B. G. Weinshenker. 2000. Multiple sclerosis. N. Engl. J. Med. 343:938952.
116. Olson, J. K.,, J. L. Croxford,, M. A. Calenoff,, M. C. Dal Canto,, and S. D. Miller. 2001. A virus-induced molecular mimicry model of multiple sclerosis. J. Clin. Investig. 108:311318.
117. Padgett, B. L.,, and D. L. Walker. 1973. Prevalence of antibodies in human sera against JC virus: an isolate from a case of progressive multifocal leukoencephalopathy. J. Infect. Dis. 127:467470.
118. Panitch, H. S.,, R. L. Hirsch,, J. Schindler,, and K. P. Johnson. 1987. Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurology 37:10971102.
119. Perron, H.,, C. Geny,, A. Laurent,, C. Mouriquand,, J. Pellat,, J. Perret,, and J. M. Seigneurin. 1989. Leptomeningeal cell line from multiple sclerosis with reverse transcriptase activity and viral particles. Res. Virol. 140:551561.
120. Perron, H.,, J. A. Garson,, F. Bedin,, F. Beseme,, G. Paranhos-Baccala,, F. Komurian- Pradel,, F. Mallet,, P. W. Tuke,, C. Voisset,, J. L. Blond,, B. Lalande,, J. M. Seigneurin,, B. Mandrand, et al. 1997. Molecular identification of a novel retrovirus repeatedly isolated from patients with multiple sclerosis. Proc. Natl. Acad. Sci. USA 94:75837588.
121. Perron, H.,, M. Suh,, B. Lalande,, B. Gratacap,, A. Laurent,, P. Stoebner,, and J. M. Seigneurin. 1993. Herpes simplex virus ICP0 and ICP4 immediate early proteins strongly enhance expression of a retrovirus harboured by a leptomeningeal cell line from a patient with multiple sclerosis. J. Gen. Virol. 74:6572.
122. Peterson, J. D.,, C. Waltenbaugh,, and S. D. Miller. 1992. IgG subclass responses in Theiler’s murine encephalomyelitis virus infection and immunization suggest a dominant role for Th1 cells in susceptible mouse strains. Immunology 75:652658.
123. Pette, M.,, K. Fujita,, B. Kitze,, J. N. Whitaker,, E. Albert,, L. Kappos,, and H. Wekerle. 1990. Myelin basic protein-specific T lymphocyte lines from MS patients and healthy individuals. Neurology 40:17701776.
124. Piddlesden, S. J.,, H. Lassmann,, F. Zimprich,, B. P. Morgan,, and C. Linington. 1993. The demyelinating potential of antibodies to myelin oligodendrocyte glycoprotein is related to their ability to fix complement. Am. J. Pathol. 143:555564.
125. Piddlesden, S. J.,, M. K. Storch,, M. Hibbs,, A. M. Freeman,, H. Lassmann,, and B. P. Morgan. 1994. Soluble recombinant complement receptor 1 inhibits inflammation and demyelination in antibody-mediated demyelinating experimental allergic encephalomyelitis. J. Immunol. 152:54775484.
126. Pinter, C.,, S. Beltrami,, D. Caputo,, P. Ferrante,, and A. Clivio. 2000. Presence of autoantibodies against complement regulatory proteins in relapsing-remitting multiple sclerosis. J. Neurovirol. 6(Suppl. 2):S42S46.
127. Pinto, A. J.,, P. S. Morahan,, M. Brinton,, D. Stewart,, and E. Gavin. 1990. Comparative therapeutic efficacy of recombinant interferons- alpha, -beta, and -gamma against alphatogavirus, bunyavirus, flavivirus, and herpesvirus infections. J. Interferon Res. 10:293298.
128. Rand, H. K.,, H. Houck,, N. D. Denslow,, and K. M. Heilman. 2000. Epstein-Barr virus nuclear antigen-1 (EBNA-1) associated oligoclonal bands in patients with multiple sclerosis. J. Neurol. Sci. 173:3239.
129. Reindl, M.,, C. Linington,, U. Brehm,, E. Dilitz,, F. Deisenhammer,, W. Poewe,, and T. Berger. 1999. Antibodies against the myelin oligodendrocyte glycoprotein and the myelin basic protein in multiple sclerosis and other neurological diseases: a comparative study. Brain 122:20472056.
130. Richardson, J. H.,, K. W. Wurcherpfennig,, and N. Endo. 1989. PCR analysis of DNA from multiple sclerosis patients for the presence of HTLV-I. Science 246:821824.
131. Rieckmann, P.,, M. Albrecht,, B. Kitze,, T. Weber,, H. Tumani,, A. Brooks,, W. Luer,, A. Helwig,, and S. Poser. 1995. Tumor necrosis factor-alpha messenger RNA expression in patients with relapsing-remitting multiple sclerosis is associated with disease activity. Ann. Neurol. 37:8288.
132. Romagnani, S. 1997. The Th1/Th2 paradigm. Immunol. Today 18:263266.
133. Ross, R. T.,, and M. Cheang. 1995. Geographic similarities between varicella and multiple sclerosis: an hypothesis on the environmental factor of multiple sclerosis. J. Clin. Epidemiol. 48:731737.
134. Rotola, A.,, E. Cassai,, M. R. Tola,, E. Granieri,, and D. Di Luca. 1999. Human herpesvirus 6 is latent in peripheral blood of patients with relapsing-remitting multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 67:529531.
135. Rudick, R. A.,, R. M. Ransohoff,, J. C. Lee,, R. Peppler,, M. Yu,, P. M. Mathisen,, and V. K. Tuohy. 1998. In vivo effects of interferon beta-1a on immunosuppressive cytokines in multiple sclerosis. Neurology 50:12941300.
136. Sadovnick, A. D.,, P. A. Baird,, and R. H. Ward. 1988. Multiple sclerosis: updated risks for relatives. Am. J. Med. Genet. 29:533541.
137. Sadovnick, A. D.,, and G. C. Ebers. 1993. Epidemiology of multiple sclerosis: a critical overview. Can. J. Neurol. Sci. 20:1729.
138. Salahuddin, S. Z.,, D. V. Ablashi,, P. D. Markham,, S. F. Josephs,, S. Sturzenegger,, M. Kaplan,, G. Halligan,, P. Biberfeld,, F. Wong-Staal,, B. Kramarsky,, and R. C. Gallo. 1986. Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science 234:596601.
139. Sanders, V. J.,, S. Felisan,, A. Waddel,, and W. W. Tourtellotte. 1996. Detection of herpesviridae in postmortem multiple sclerosis brain tissue and controls by polymerase chain reaction. J. Neurovirol. 2:249258.
140. Santoro, F.,, P. E. Kennedy,, G. Locatelli,, M. S. Malnati,, E. A. Berger,, and P. Lusso. 1999. CD46 is a cellular receptor for human herpesvirus 6. Cell 99:817827.
141. Scolding, N. J.,, B. P. Morgan,, and D. A. S. Compston. 1998. The expression of complement regulatory proteins by adult human oligodendrocytes. J. Neuroimmunol. 84:6975.
142. Secchiero, P.,, D. R. Carrigan,, Y. Asano,, L. Benedetti,, R. W. Crowley,, A. L. Komaroff,, R. C. Gallo,, and P. Lusso. 1995. Detection of human herpesvirus 6 in plasma of children with primary infection and immunosuppressed patients by polymerase chain reaction. J. Infect. Dis. 171:273280.
143. Segal, B. M.,, B. K. Dwyer,, E. M. Shevach. 1998. An interleukin (IL)-10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease. J. Exp. Med. 187:537546.
144.. Selmaj, K.,, and C. S. Raine. 1988. Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro. Ann. Neurol. 23:339346.
145. Sibley, W. A.,, C. R. Bamford,, and K. Clark. 1985. Clinical viral infections and multiple sclerosis. Lancet i:13131315.
146. Sindic, C. J. M.,, P. Monteyne,, and E. C. Laterre. 1994. The intrathecal synthesis of virus-specific oligoclonal IgG in multiple sclerosis. J. Neuroimmunol. 54:7580.
147. Soderberg-Naucler, C. S.,, S. Larsson,, and E. Moller. 1996. A novel mechanism for virusinduced autoimmunity in humans. Immunol. Rev. 152:175192.
148. Soldan, S. S.,, R. Berti,, N. Salem,, P. Secchiero,, L. Flamand,, P. A. Calabresi,, M. B. Brennan,, H. W. Maloni,, H. F. McFarland,, H.-C. Lin,, M. Patnaik,, and S. Jacobson. 1997. Association of human herpesvirus 6 (HHV- 6) with multiple sclerosis: increased IgM response to HHV-6 early antigen and detection of serum HHV-6 DNA. Nat. Med. 3:13941397.
149. Soldan, S. S.,, A. Fogdell-Hahn,, M. B. Brennan,, B. B. Mittleman,, C. Ballerini,, L. Massacesi,, T. Seya,, H. F. McFarland,, and S. Jacobson. 2001. Elevated serum and CSF levels of soluble HHV-6 receptor, membrane cofactor protein, in patients with multiple sclerosis. Ann. Neurol. 50:486493.
150. Soldan, S. S.,, and S. Jacobson. 2001. Role of viruses in the etiology and pathogenesis of multiple sclerosis. Adv. Virus Res. 56:513551.
151. Soldan, S. S.,, T. P. Leist,, K. N. Juhng,, H. F. McFarland,, and S. Jacobson. 2000. Increased lymphoproliferative response to human herpesvirus type 6A variant in multiple sclerosis patients. Ann. Neurol. 47:306316.
152. Sorensen, P. S.,, B. Wanscher,, C. V. Jensen,, K. Schreiber,, M. Blinkenberg,, M. Ravnborg,, H. Kirsmeier,, V. A. Larsen,, and M. L. Lee. 1998. Intravenous immunoglobulin G reduces MRI activity in relapsing remitting multiple sclerosis. Neurology 50:12731281.
153. Spear, G. T.,, N. S. Lurain,, C. J. Parker,, M. Ghassemi,, G. H. Payne,, and M. Saifuddin. 1995. Host cell-derived complement control proteins CD55 and CD59 are incorporated into the virions of two unrelated enveloped viruses, human T cell leukemia/lymphoma virus type I (HTLVI) and human cytomegalovirus (HCMV). J. Immunol..
154.. Stohlman, S. A.,, and D. R. Hinton. 2001. Viral induced demyelination. Brain Pathol. 11:92106.
155. Storch, M. K.,, S. Piddlesden,, M. Haltia,, M. Iivainen,, P. Morgan,, and H. Lassmann. 1998. Multiple sclerosis: in situ evidence for antibody- and complement-mediated demyelination. Ann. Neurol. 43:465471.
156. Sumaya, C. V.,, L. W. Myers,, G. W. Ellison,, and Y. Ench. 1985. Increased prevalence and titres of Epstein-Barr virus antibodies in patients with multiple sclerosis. Ann. Neurol. 17:371377.
157. Sun, N.,, D. Grzybicki,, R. Castro,, S. Murphy,, and S. Perlman. 1995. Activation of astrocytes in the spinal cord of mice chronically infected with a neurotropic coronavirus. Virology 213:482493.
158. Theiler, M. 1937. Spontaneous encephalomyelitis of mice, a new virus disease. J. Exp. Med. 65:705719.
159. Thoua, N.-M.,, J. M. van Noort,, D. Baker,, A. Bose,, A. C. van Sechel,, M. J. B. van Stipdonk,, P. J. Travers,, and S. Amor. 2000. Encephalitogenic and immunogenic potential of the stress protein αB-crystallin in Biozzi ABH (H2Ag7) mice. J. Neuroimmunol. 104:4757.
160. Thuoy, V. K.,, M. Yu,, L. Yin,, J. A. Kawczak,, and P. Kinkel. 1999. Spontaneous regression of primary autoreactivity during chronic progression of experimental autoimmune encephalomyelitis and multiple sclerosis. J. Exp. Med. 189:10331042.
161. Vahlne, A.,, S. Edström,, P. Hanner,, O. Andersen,, B. Svennerholm,, and E. Lycke. 1985. Possible association of herpes simplex virus with demyelinating disease. Scand. J. Infect. Dis. 47:1621.
162. Vanguri, P.,, B. Silverman,, L. Koski,, and M. L. Shin. 1982. Complement activation by isolated myelin: activation of the classical pathway in the absence of myelin-specific antibodies. Proc. Natl. Acad. Sci. USA 79:32903294.
163. Van Noort, M. J.,, J. J. Bajramovic,, A. C. Plomp,, and M. J. B. Stipdonk. 2000. Mistaken self, a novel model that links microbial infections with myelin-directed autoimmunity in multiple sclerosis. J. Neuroimmunol. 105:4657.
164. van Noort, M. J.,, A. C. van Sechel,, J. J. Bajramovic,, M. El Ouagmiri,, C. H. Polman,, H. Lassmann,, and R. Ravid. 1995. The small heat-shock protein αB-crystallin as candidate autoantigen in multiple sclerosis. Nature 375:798801.
165. Van Sechel, A. C.,, J. J. Bajramovic,, M. J. B. van Stipdonk,, C. Persoon-Deen,, S. B. Geutskens,, and J. M. van Noort. 1999. EBV-induced expression and HLA-DR-restricted presentation by human B cells of αB-crystallin, a candidate autoantigen in multiple sclerosis. J. Immunol. 162:129135.
166. Wandinger, K. P.,, W. Jabs,, A. Siekhaus,, S. Bubel,, P. Trillenberg,, H. J. Wagner,, K. Wessel,, H. Kirchner,, and H. Hennig. 2000. Association between clinical disease activity and Epstein-Barr virus reactivation in MS. Neurology 55:178184.
167. Wang, F. Z.,, H. Dahl,, P. Ljungman,, and A. Linde. 1999. Lymphoproliferative responses to human herpesvirus-6 variant A and variant B in healthy adults. J. Med. Virol. 57:134139.
168. Warren, K. G.,, and I. Catz. 1994. Relative frequency of autoantibodies to myelin basic protein and proteolipid protein in optic neuritis and multiple sclerosis cerebrospinal fluid. J. Neurol. Sci. 121:6673.
169. Warrington, A. E.,, K. Asakura,, A. J. Bieber,, B. Ciric,, V. Van Keulen,, S. V. Kaveri,, R. A. Kyle,, L. R. Pease,, and M. Rodriguez. 2000. Human monoclonal antibodies reactive to oligodendrocytes promote remyelination in a model of multiple sclerosis. Proc. Natl. Acad. Sci. USA 97:68206825.
170. Watanabe, R.,, H. Wege,, and V. ter Meulen. 1987. Comparative analysis of coronavirus JHMinduced demyelinating encephalomyelitis in Lewis and Brown Norway rats. Lab. Investig. 57:375383.
171. Weerth, S.,, T. Berger,, H. Lassmann,, and C. Linington. 1999. Encephalitogenic and neuritogenic T cell responses to the myelin-associated glycoprotein (MAG) in the Lewis rat. J. Neuroimmunol. 95:157164.
172. Wekerle, H.,, K. Kojima,, J. Lannes-Vieira,, H. Lassmann,, and C. Linington. 1994. Animal models. Ann. Neurol. 36(Suppl.):S47S53.
173. Williamson, J. S. P.,, and S. A. Stohlman. 1990. Effective clearance of mouse hepatitis virus from the central nervous system requires both CD4+ and CD8+ T cells. J. Virol. 64:38173823.
174. Windhangen, A.,, J. Newcombe,, F. Dangond,, C. Strand,, M. N. Woodroofe,, M. L. Cuzner,, and D. A. Hafler. 1995. Expression of costimulatory molecules B7-1 (CD80), B7-2 (CD86), and interleukin 12 cytokine in multiple sclerosis lesions. J. Exp. Med. 182:19851996.
175. Wisniewski, H. M.,, and B. R. Bloom. 1975. Primary demyelination as a non-specific consequence of a cell-mediated immune reaction. J. Exp. Med. 141:346359.
176. Wu, G. F.,, and S. Perlman. 1999. Macrophage infiltration, but not apoptosis, is correlated with immune-mediated demyelination following murine infection with a neurotropic coronavirus. J. Virol. 73:87718780.
177. Wucherpfennig, K. W.,, and J. L. Strominger. 1995. Molecular mimicry in T cellmediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell 80:695705.
178. Xue, S.,, N. Sun,, N. van Roijen,, and S. Perlman. 1999. Depletion of blood-borne macrophages does not reduce demyelination in mice infected with a neurotropic coronavirus. J. Virol. 73:63276334.
179. Zhang, J.,, S. Markovic-Plese,, B. Lacet,, J. Raus,, H. L. Weiner,, and D. A. Hafler. 1994. Increased frequency of interleukin 2-responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis. J. Exp. Med. 179:973984.
180. Zheng, L.,, M. A. Calenoff,, and M. C. Dal Canto. 2001. Astrocytes, not microglia, are the main cells responsible for viral persistence in Theiler’s murine encephalomyelitis virus infection leading to demyelination. J. Neuroimmunol. 118:256267.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error