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The Human Microbiome in Multiple Sclerosis: Pathogenic or Protective Constituents?

Published online by Cambridge University Press:  02 December 2014

Christopher Power*
Affiliation:
Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Joseph M. Antony
Affiliation:
Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Kristofor K. Ellestad
Affiliation:
Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
André Deslauriers
Affiliation:
Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Rakesh Bhat
Affiliation:
Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Farshid Noorbakhsh
Affiliation:
Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
*
Division of Neurology, HMRC 6-11, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada.
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Abstract:

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The human microbiome is comprised of commensal and pathogenic microorganisms, which exert diverse effects in close proximity to the site of intection as well as in remote tissues through immune-mediated mechanisms. Multiple infectious agents have been implicated in the pathogenesis of multiple sclerosis (MS) with variable findings depending on the agent, techniques, and disease phenotype. Herein, the contributions of individual infectious agents to MS and their effects on the immune and nervous systems are reviewed, focusing on herpes viruses, coronaviruses, retroviruses, and synchronic infections. While infectious agents are often assumed to be pathogenic, their effects might also be beneficial to the host in the long-term, depending on age and the type of immunogen/pathogen exposure, as proposed by the hygiene hypothesis. The human microbiome has potential impact on future diagnostic and therapeutic issues in MS.

Résumé:

RÉSUMÉ:

Le microbiome humain est composé d'agents microbiens commensaux et pathogènes, qui produisent différents effets tant à proximité de leur lieu d'infection qu'à distance, au moyen de mécanismes à médiation immunitaire. Plusieurs agents infectieux ont été impliqués dans la pathogenèse de la sclérose en plaques (SP). Les observations sont différentes selon l'agent, les techniques utilisées et le phénotype de la maladie. Nous revoyons ici la contribution de certains agents infectieux dans la SP et leurs effets sur le système immunitaire et le système nerveux, particulièrement les virus de l'herpès, les coronavirus, les rétrovirus et les infections synchrones. Bien qu'on présume souvent que les agents infectieux soient pathogènes, leurs effets pourraient également être bénéfiques à l'hôte à long terme, selon l'âge et le type d'exposition à un agent immunogène/pathogène, tel que proposé par “l'hypothèse de l'hygiène”. À l'avenir, le microbiome humain pourrait avoir un impact sur certains aspects diagnostiques et thérapeutiques dans la SP.

Type
Research Article
Copyright
Copyright © Canadian Neurological Sciences Federation 2010

References

1. Virgin, HW, Wherry, EJ, R, Ahmed. Redefining chronic viral infection. Cell. 2009 Jul 10;138(1):3050.CrossRefGoogle ScholarPubMed
2. Abraham, C, Cho, JH. Inflammatory bowel disease. N Engl J Med. 2009 Nov 19;361(21):2066–78.CrossRefGoogle ScholarPubMed
3. Colmegna, I, Garry, RF. Role of endogenous retroviruses in autoimmune diseases. Infect Dis Clin North Am. 2006 Dec;20(4):913–29.CrossRefGoogle ScholarPubMed
4. Rieger, F, Pierig, R, Cifuentes-Diaz, C, et al. New perspectives in multiple sclerosis: retroviral involvement and glial cell death. Pathol Biol (Paris). 2000 Feb;48(1):1524.Google ScholarPubMed
5. Kivity, S, Agmon-Levin, N, Blank, M, Shoenfeld, Y. Infections and autoimmunity--friends or foes? Trends Immunol. 2009 Aug;30(8):409–14.CrossRefGoogle ScholarPubMed
6. Inglis, TJ. Principia aetiologica: taking causality beyond Koch’s postulates. J Med Microbiol. 2007 Nov;56(Pt 11):1419–22.CrossRefGoogle ScholarPubMed
7. Blank, M, Krause, I, Magrini, L, et al. Overlapping humoral autoimmunity links rheumatic fever and the antiphospholipid syndrome. Rheumatology (Oxford). 2006 Jul;45(7):833–41.CrossRefGoogle ScholarPubMed
8. Holmes, C, Cunningham, C, Zotova, E, et al. Systemic inflammation and disease progression in Alzheimer disease. Neurology. 2009 Sep 8;73(10):768–74.CrossRefGoogle ScholarPubMed
9. Mazmanian, SK, Round, JL, Kasper, DL. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature. 2008 May 29;453(7195):620–5.CrossRefGoogle ScholarPubMed
10. Holmoy, T, Hestvik, AL. Multiple sclerosis: immunopathogenesis and controversies in defining the cause. Curr Opin Infect Dis. 2008 Jun;21(3):271–8.CrossRefGoogle ScholarPubMed
11. Frohman, EM, Racke, MK, Raine, CS. Multiple sclerosis--the plaque and its pathogenesis. N Engl J Med. 2006 Mar 2;354(9):942–55.CrossRefGoogle ScholarPubMed
12. Paty, DW. MRI as a method to reveal in-vivo pathology in MS. J Neural Transm Suppl. 1997;49:211–7.Google ScholarPubMed
13. Polman, CH, Reingold, SC, Barkhof, F, et al. Ethics of placebocontrolled clinical trials in multiple sclerosis: a reassessment. Neurology. 2008 Mar 25;70(13 Pt 2):1134–40.CrossRefGoogle ScholarPubMed
14. Lucchinetti, CF, Bruck, W, Rodriguez, M, Lassmann, H. Distinct patterns of multiple sclerosis pathology indicates heterogeneity on pathogenesis. Brain Pathol. 1996 Jul;6(3):259–74.CrossRefGoogle ScholarPubMed
15. Trapp, BD, Peterson, J, Ransohoff, RM, Rudick, R, Mork, S, Bo, L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998 Jan 29;338(5):278–85.CrossRefGoogle ScholarPubMed
16. Markovic-Plese, S, McFarland, HF. Immunopathogenesis of the multiple sclerosis lesion. Curr Neurol Neurosci Rep. 2001 May;1(3):257–62.CrossRefGoogle ScholarPubMed
17. Biswas, PS, Rouse, BT. Early events in HSV keratitis--setting the stage for a blinding disease. Microbes Infect. 2005 Apr;7(4):799810.CrossRefGoogle ScholarPubMed
18. Bo, L. The histopathology of grey matter demyelination in multiple sclerosis. Acta Neurol Scand Suppl. 2009(189):51–7.CrossRefGoogle ScholarPubMed
19. Ferguson, B, Matyszak, MK, Esiri, MM, Perry, VH. Axonal damage in acute multiple sclerosis lesions. Brain. 1997 Mar;120 (Pt 3):393–9.CrossRefGoogle ScholarPubMed
20. Sospedra, M, Martin, R. Immunology of multiple sclerosis. Annu Rev Immunol. 2005;23:683–747.CrossRefGoogle ScholarPubMed
21. Rodriguez, M. Effectors of demyelination and remyelination in the CNS: implications for multiple sclerosis. Brain Pathol. 2007 Apr;17(2):219–29.CrossRefGoogle ScholarPubMed
22. Noseworthy, JH. Progress in determining the causes and treatment of multiple sclerosis. Nature. 1999 Jun 24;399(6738 Suppl): A40–7.CrossRefGoogle ScholarPubMed
23. Mbopi-Keou, FX, Robinson, NJ, Mayaud, P, Belec, L, Brown, DW. Herpes simplex virus type 2 and heterosexual spread of human immunodeficiency virus infection in developing countries: hypotheses and research priorities. Clin Microbiol Infect. 2003 Mar;9(3):161–71.CrossRefGoogle ScholarPubMed
24. Nair, A, Frederick, TJ, Miller, SD. Astrocytes in multiple sclerosis: a product of their environment. Cell Mol Life Sci. 2008 Sep;65(17):2702–20.CrossRefGoogle ScholarPubMed
25. Owens, GP, Burgoon, MP, Anthony, J, Kleinschmidt-DeMasters, BK, Gilden, DH. The immunoglobulin G heavy chain repertoire in multiple sclerosis plaques is distinct from the heavy chain repertoire in peripheral blood lymphocytes. Clin Immunol. 2001 Feb;98(2):258–63.CrossRefGoogle ScholarPubMed
26. Antel, J. Multiple sclerosis--emerging concepts of disease pathogenesis. J Neuroimmunol. 1999 Jul 1;98(1):45–8.CrossRefGoogle ScholarPubMed
27. Ffrench-Constant, C, Kiernan, BW, Milner, R, Scott-Drew, S. Developmental studies of oligodendrocyte precursor cell migration and their implications for transplantation as therapy for multiple sclerosis. Eye. 1994;8 ( Pt 2):221–3.CrossRefGoogle ScholarPubMed
28. Barnett, MH, Prineas, JW. Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol. 2004 Apr;55(4):458–68.CrossRefGoogle ScholarPubMed
29. Bruck, W, Lucchinetti, C, Lassmann, H. The pathology of primary progressive multiple sclerosis. Mult Scler. 2002 Apr;8(2):93–7.CrossRefGoogle ScholarPubMed
30. Ransohoff, RM. Mechanisms of inflammation in MS tissue: adhesion molecules and chemokines. J Neuroimmunol. 1999 Jul 1;98(1):5768.CrossRefGoogle Scholar
31. Yong, VW, Power, C, Forsyth, P, Edwards, DR. Metalloproteinases in biology and pathology of the nervous system. Nat Rev Neurosci. 2001 Jul;2(7):502–11.CrossRefGoogle ScholarPubMed
32. Bonetti, B, Raine, CS. Multiple sclerosis: oligodendrocytes display cell death-related molecules in situ but do not undergo apoptosis. Ann Neurol. 1997 Jul;42(1):7484.CrossRefGoogle Scholar
33. Lander, ES, Linton, LM, Birren, B, et al. Initial sequencing and analysis of the human genome. Nature. 2001 Feb 15;409(6822): 860921.Google ScholarPubMed
34. Hohlfeld, R. The prospects for neuroprotection in MS. Int MS J. 2003 Dec;10(4):103–5.Google ScholarPubMed
35. Beretich, BD, Beretich, TM. Explaining multiple sclerosis prevalence by ultraviolet exposure: a geospatial analysis. Mult Scler. 2009 Aug;15(8):891–8.CrossRefGoogle ScholarPubMed
36. Dyment, DA, Yee, IM, Ebers, GC, Sadovnick, AD. Multiple sclerosis in stepsiblings: recurrence risk and ascertainment. J Neurol Neurosurg Psychiatry. 2006 Feb;77(2):258–9.CrossRefGoogle ScholarPubMed
37. Brudek, T, Christensen, T, Hansen, HJ, Bobecka, J, Moller-Larsen, A. Simultaneous presence of endogenous retrovirus and herpes virus antigens has profound effect on cell-mediated immune responses: implications for multiple sclerosis. AIDS Res Hum Retroviruses. 2004 Apr;20(4):415–23.CrossRefGoogle ScholarPubMed
38. Oksenberg, JR, Barcellos, LF. Multiple sclerosis genetics: leaving no stone unturned. Genes Immun. 2005 Aug;6(5):375–87.CrossRefGoogle ScholarPubMed
39. Johnson, RT. Viral Infections of the Nervous System. 2nd ed. Philadelphia: Lippincott-Raven; 1998.Google Scholar
40. Giovannoni, G, Cutter, GR, Lunemann, J, et al. Infectious causes of multiple sclerosis. Lancet Neurol. 2006 Oct;5(10):887–94.CrossRefGoogle ScholarPubMed
41. Johnson, RT. Viral infections of the nervous system. 1998:133–68.Google Scholar
42. Booss, J, Esiri, MM. Viral encephalitis in humans. 2003:4160.Google Scholar
43. Gilden, D, Cohrs, RJ, Mahalingam, R, Nagel, MA. Varicella zoster virus vasculopathies: diverse clinical manifestations, laboratory features, pathogenesis, and treatment. Lancet Neurol. 2009 Aug; 8(8):731–40.CrossRefGoogle ScholarPubMed
44. Volpi, A. Epstein-Barr virus and human herpesvirus type 8 infections of the central nervous system. Herpes. 2004 Jun;11 Suppl 2:120A–7A.Google ScholarPubMed
45. Soldan, SS, Berti, R, Salem, N, et al. Association of human herpes virus 6 (HHV-6) with multiple sclerosis: increased IgM response to HHV-6 early antigen and detection of serum HHV-6 DNA. Nat Med. 1997 Dec;3(12):1394–7.CrossRefGoogle ScholarPubMed
46. Alvarez-Lafuente, R, Martin-Estefania, C, de Las Heras, V, et al. Active human herpesvirus 6 infection in patients with multiple sclerosis. Arch Neurol. 2002 Jun;59(6):929–33.CrossRefGoogle ScholarPubMed
47. Tejada-Simon, MV, Zang, YC, Hong, J, Rivera, VM, Killian, JM, Zhang, JZ. Detection of viral DNA and immune responses to the human herpesvirus 6 101-kilodalton virion protein in patients with multiple sclerosis and in controls. J Virol. 2002 Jun;76(12):6147–54.CrossRefGoogle Scholar
48. Fotheringham, J, Jacobson, S. Human herpesvirus 6 and multiple sclerosis: potential mechanisms for virus-induced disease. Herpes. 2005 Jun;12(1):49.Google ScholarPubMed
49. Marrie, RA, Wolfson, C. Multiple sclerosis and varicella zoster virus infection: a review. Epidemiol Infect. 2001 Oct;127(2):315–25.CrossRefGoogle ScholarPubMed
50. Ross, RT, Nicolle, LE, Cheang, M. The varicella zoster virus: a pilot trial of a potential therapeutic agent in multiple sclerosis. J Clin Epidemiol. 1997 Jan;50(1):63–8.CrossRefGoogle ScholarPubMed
51. Sotelo, J, Martinez-Palomo, A, Ordonez, G, Pineda, B. Varicellazoster virus in cerebrospinal fluid at relapses of multiple sclerosis. Ann Neurol. 2008 Mar;63(3):303–11.CrossRefGoogle ScholarPubMed
52. Burgoon, MP, Cohrs, RJ, Bennett, JL, et al. Varicella zoster virus is not a disease-relevant antigen in multiple sclerosis. Ann Neurol. 2009 Apr;65(4):474–9.CrossRefGoogle Scholar
53. Bagert, BA. Epstein-Barr virus in multiple sclerosis. Curr Neurol Neurosci Rep. 2009 Sep;9(5):405–10.CrossRefGoogle ScholarPubMed
54. Ramagopalan, SV, Valdar, W, Dyment, DA, et al. Association of infectious mononucleosis with multiple sclerosis. A populationbased study. Neuroepidemiology. 2009;32(4):257–62.CrossRefGoogle ScholarPubMed
55. Gilden, DH. Infectious causes of multiple sclerosis. Lancet Neurol. 2005 Mar;4(3):195202.CrossRefGoogle ScholarPubMed
56. Sargsyan, SA, Shearer, AJ, Ritchie, AM, et al. Absence of Epstein-Barr virus in the brain and CSF of patients with multiple sclerosis. Neurology. 2010 Apr 6;74(14):1127–35.CrossRefGoogle ScholarPubMed
57. Serafini, B, Rosicarelli, B, Franciotta, D, et al. Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J Exp Med. 2007 Nov 26;204(12):2899–912.CrossRefGoogle ScholarPubMed
58. Templeton, SP, Perlman, S. Pathogenesis of acute and chronic central nervous system infection with variants of mouse hepatitis virus, strain JHM. Immunol Res. 2007;39(1–3):160–72.CrossRefGoogle ScholarPubMed
59. Arbour, N, Day, R, Newcombe, J, Talbot, PJ. Neuroinvasion by human respiratory coronaviruses. J Virol. 2000 Oct;74(19):8913–21.CrossRefGoogle ScholarPubMed
60. Boucher, A, Desforges, M, Duquette, P, Talbot, PJ. Long-term human coronavirus-myelin cross-reactive T-cell clones derived from multiple sclerosis patients. Clin Immunol. 2007 Jun;123(3): 258–67.CrossRefGoogle ScholarPubMed
61. Do Carmo, S, Jacomy, H, Talbot, PJ, Rassart, E. Neuroprotective effect of apolipoprotein D against human coronavirus OC43-induced encephalitis in mice. J Neurosci. 2008 Oct 8;28(41): 10330–8.CrossRefGoogle ScholarPubMed
62. Patrick, MK, Johnston, JB, Power, C. Lentiviral neuropathogenesis: comparative neuroinvasion, neurotropism, neurovirulence, and host neurosusceptibility. J Virol. 2002;76(16):7923–31.CrossRefGoogle ScholarPubMed
63. Boisse, L, Gill, MJ, Power, C. HIV infection of the central nervous system: clinical features and neuropathogenesis. Neurol Clin. 2008 Aug;26(3):799819, x.CrossRefGoogle ScholarPubMed
64. Azoulay-Cayla, A. [Is multiple sclerosis a disease of viral origin?]. Pathol Biol (Paris). 2000;48(1):414.Google ScholarPubMed
65. Little, PF. Structure and function of the human genome. Genome Res. 2005 Dec;15(12):1759–66.CrossRefGoogle ScholarPubMed
66. Blond, JL, Beseme, F, Duret, L, et al. Molecular characterization and placental expression of HERV-W, a new human endogenous retrovirus family. J Virol. 1999 Feb;73(2):1175–85.CrossRefGoogle ScholarPubMed
67. Armbruester, V, Sauter, M, Krautkraemer, E, et al. A novel gene from the human endogenous retrovirus K expressed in transformed cells. Clin Cancer Res. 2002 Jun;8(6):1800–7.Google ScholarPubMed
68. O’Reilly, RL, Singh, SM. Retroviruses and schizophrenia revisited. Am J Med Genet. 1996 Feb 16;67(1):1924.3.0.CO;2-N>CrossRefGoogle ScholarPubMed
69. York, DF, Vigne, R, Verwoerd, DW, Querat, G. Nucleotide sequence of the jaagsiekte retrovirus, an exogenous and endogenous type D and B retrovirus of sheep and goats. J Virol. 1992 Aug;66(8):4930–9.CrossRefGoogle Scholar
70. Conrad, B, Weissmahr, RN, Boni, J, Arcari, R, Schupbach, J, Mach, B. A human endogenous retroviral superantigen as candidate autoimmune gene in type I diabetes. Cell. 1997;90(2):303–13.CrossRefGoogle ScholarPubMed
71. Portis, JL. Perspectives on the role of endogenous human retroviruses in autoimmune diseases. Virology. 2002;296(1):15.CrossRefGoogle ScholarPubMed
72. David, A. Wilkinson DLMaJ-ACL. Endogenous Human Retroviruses. In: Levy, JA, editor. The Retroviridae. New York: Plenum Press; 1994. p. 535.Google Scholar
73. Johnston, JB, Silva, C, Holden, J, Warren, KG, Clark, AW, Power, C. Monocyte activation and differentiation augment human endogenous retrovirus expression: implications for inflammatory brain diseases. Ann Neurol. 2001 Oct;50(4):434–42.CrossRefGoogle ScholarPubMed
74. Voisset, C, Bouton, O, Bedin, F, et al. Chromosomal distribution and coding capacity of the human endogenous retrovirus HERV-W family. AIDS Res Hum Retroviruses. 2000 May 20;16(8): 731–40.CrossRefGoogle ScholarPubMed
75. Antony, JM, van Marle, G, Opii, W, et al. Human endogenous retrovirus glycoprotein-mediated induction of redox reactants causes oligodendrocyte death and demyelination. Nat Neurosci. 2004 Oct;7(10):1088–95.CrossRefGoogle ScholarPubMed
76. Perron, H, Garson, JA, Bedin, F, et al. Molecular identification of a novel retrovirus repeatedly isolated from patients with multiple sclerosis. The Collaborative Research Group on Multiple Sclerosis. Proc Natl Acad Sci U S A. 1997;94(14):7583–8.CrossRefGoogle ScholarPubMed
77. Mirsattari, SM, Johnston, JB, McKenna, R, et al. Aboriginals with multiple sclerosis: HLA types and predominance of neuromyelitis optica. Neurology. 2001 Feb 13;56(3):317–23.CrossRefGoogle ScholarPubMed
78. Bastian, FO. Spiroplasma as a candidate agent for the transmissible spongiform encephalopathies. J Neuropathol Exp Neurol. 2005 Oct;64(10):833–8.CrossRefGoogle ScholarPubMed
79. Serra, C, Mameli, G, Arru, G, Sotgiu, S, Rosati, G, Dolei, A. In vitro modulation of the multiple sclerosis (MS)-associated retrovirus by cytokines: implications for MS pathogenesis. J Neurovirol. 2003 Dec;9(6):637–43.Google ScholarPubMed
80. Rolland, A, Jouvin-Marche, E, Saresella, M, et al. Correlation between disease severity and in vitro cytokine production mediated by MSRV (multiple sclerosis associated retroviral element) envelope protein in patients with multiple sclerosis. J Neuroimmunol. 2005 Mar;160(1–2):195-203.CrossRefGoogle ScholarPubMed
81. Rolland, A, Jouvin-Marche, E, Viret, C, Faure, M, Perron, H, Marche, PN. The Envelope Protein of a Human Endogenous Retrovirus-W Family Activates Innate Immunity through CD14/TLR4 and Promotes Th1-Like Responses. J Immunol. 2006 Jun 15;176(12):7636–44.CrossRefGoogle ScholarPubMed
82. Mameli, G, Astone, V, Arru, G, et al. Brains and peripheral blood mononuclear cells of multiple sclerosis (MS) patients hyperexpress MS-associated retrovirus/HERV-W endogenous retrovirus, but not human herpesvirus 6. J Gen Virol. 2007 Jan; 88(Pt 1):264–74.CrossRefGoogle Scholar
83. Christensen, T. Association of human endogenous retroviruses with multiple sclerosis and possible interactions with herpes viruses. Rev Med Virol. 2005 May-Jun;15(3):179211.CrossRefGoogle ScholarPubMed
84. Antony, JM, Ellestad, KK, Hammond, R, et al. The human endogenous retrovirus envelope glycoprotein, syncytin-1, regulates neuroinflammation and its receptor expression in multiple sclerosis: a role for endoplasmic reticulum chaperones in astrocytes. J Immunol. 2007 Jul 15;179(2):1210–24.CrossRefGoogle ScholarPubMed
85. Mameli, G, Poddighe, L, Astone, V, et al. Novel reliable real-time PCR for differential detection of MSRVenv and syncytin-1 in RNA and DNA from patients with multiple sclerosis. J Virol Methods. 2009 Oct;161(1):98106.CrossRefGoogle ScholarPubMed
86. Ruprecht, K. [Multiple sclerosis and Epstein-Barr virus : new developments and perspectives]. Nervenarzt. 2008 Apr;79(4): 399407.CrossRefGoogle Scholar
87. Clausen, J. Endogenous retroviruses and MS: using ERVs as disease markers. Int MS J. 2003 Apr;10(1):22–8.Google ScholarPubMed
88. Akiba, S, Koriyama, C, Herrera-Goepfert, R, Eizuru, Y. Epstein-Barr virus associated gastric carcinoma: epidemiological and clinicopathological features. Cancer Sci. 2008 Feb;99(2): 195201.CrossRefGoogle ScholarPubMed
89. Christensen, T, Tonjes, RR, zur Megede, J, Boller, K, Moller-Larsen, A. Reverse transcriptase activity and particle production in Blymphoblastoid cell lines established from lymphocytes of patients with multiple sclerosis. AIDS Res Hum Retroviruses. 1999 Feb 10;15(3):285–91.CrossRefGoogle Scholar
90. Christensen, T, Pedersen, L, Sorensen, PD, Moller-Larsen, A. A transmissible human endogenous retrovirus. AIDS Res Hum Retroviruses. 2002 Aug 10;18(12):861–6.CrossRefGoogle ScholarPubMed
91. Christensen, T, Dissing Sorensen, P, Riemann, H, et al. Molecular characterization of HERV-H variants associated with multiple sclerosis. Acta Neurol Scand. 2000;101(4):22938.CrossRefGoogle ScholarPubMed
92. Alvarez-Lafuente, R, Garcia-Montojo, M, De Las Heras, V, et al. Herpesviruses and human endogenous retroviral sequences in the cerebrospinal fluid of multiple sclerosis patients. Mult Scler. 2008 Jun;14(5):595601.CrossRefGoogle ScholarPubMed
93. Brudek, T, Luhdorf, P, Christensen, T, Hansen, HJ, Moller-Larsen, A. Activation of endogenous retrovirus reverse transcriptase in multiple sclerosis patient lymphocytes by inactivated HSV-1HHV-6 and VZV. J Neuroimmunol. 2007 Jul;187(1–2):147–55.CrossRefGoogle ScholarPubMed
94. Brudek, T, Christensen, T, Hansen, HJ, Petersen, T, Moller-Larsen, A. Synergistic immune responses induced by endogenous retrovirus and herpesvirus antigens result in increased production of inflammatory cytokines in multiple sclerosis patients. Scand J Immunol. 2008 Mar;67(3):295303.CrossRefGoogle ScholarPubMed
95. Moyes, DL, Goris, G, Ban, M, et al. HERV-K113 is not associated with multiple sclerosis in a large family-based study. AIDS Res Hum Retroviruses. 2008 Mar;24(3):363–5.CrossRefGoogle ScholarPubMed
96. Paty, DW, Hashimoto, SA, Ebers, GC. Management of Multiple Sclerosis and interpretation of Clinical Trials; 1998.Google Scholar
97. Edwards, S, Zvartau, M, Clarke, H, Irving, W, Blumhardt, LD. Clinical relapses and disease activity on magnetic resonance imaging associated with viral upper respiratory tract infections in multiple sclerosis. J Neurol Neurosurg Psychiatry. 1998 Jun;64(6):736–41.CrossRefGoogle ScholarPubMed
98. Sibley, WA, Bamford, CR, Clark, K. Clinical viral infections and multiple sclerosis. Lancet. 1985 Jun 8;1(8441):1313–5.CrossRefGoogle ScholarPubMed
99. Buljevac, D, Flach, HZ, Hop, WC, et al. Prospective study on the relationship between infections and multiple sclerosis exacerbations. Brain. 2002 May;125(Pt 5):952–60.CrossRefGoogle ScholarPubMed
100. Wandinger, K, Jabs, W, Siekhaus, A, et al. Association between clinical disease activity and Epstein-Barr virus reactivation in MS. Neurology. 2000 Jul 25;55(2):178–84.CrossRefGoogle ScholarPubMed
101. Auer, DP, Schumann, EM, Kumpfel, T, Gossl, C, Trenkwalder, C. Seasonal fluctuations of gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis. Ann Neurol. 2000 Feb;47(2):276–7.3.0.CO;2-1>CrossRefGoogle ScholarPubMed
102. Rovaris, M, Comi, G, Sormani, MP, Wolinsky, JS, Ladkani, D, Filippi, M. Effects of seasons on magnetic resonance imaging--measured disease activity in patients with multiple sclerosis. Ann Neurol. 2001 Mar;49(3):415–6.CrossRefGoogle ScholarPubMed
103. Killestein, J, Rep, MH, Meilof, JF, et al. Seasonal variation in immune measurements and MRI markers of disease activity in MS. Neurology. 2002 Apr 9;58(7):1077–80.CrossRefGoogle ScholarPubMed
104. Jin, Y, de Pedro-Cuesta, J, Soderstrom, M, Stawiarz, L, Link, H. Seasonal patterns in optic neuritis and multiple sclerosis: a metaanalysis. J Neurol Sci. 2000 Dec 1;181(1–2):5664.CrossRefGoogle ScholarPubMed
105. DeStefano, F, Verstraeten, T, Jackson, LA, et al. Vaccinations and risk of central nervous system demyelinating diseases in adults. Arch Neurol. 2003 Apr;60(4):504–9.CrossRefGoogle ScholarPubMed
106. Hernan, MA, Jick, SS, Olek, MJ, Jick, H. Recombinant hepatitis Bvaccine and the risk of multiple sclerosis: a prospective study. Neurology. 2004 Sep 14;63(5):838–42.CrossRefGoogle Scholar
107. Miller, AE, Morgante, LA, Buchwald, LY, et al. A multicenter, randomized, double-blind, placebo-controlled trial of influenza immunization in multiple sclerosis. Neurology. 1997 Feb;48(2): 312–4.CrossRefGoogle ScholarPubMed
108. Confavreux, C, Suissa, S, Saddier, P, Bourdes, V, Vukusic, S. Vaccinations and the risk of relapse in multiple sclerosis. Vaccines in Multiple Sclerosis Study Group. N Engl J Med. 2001 Feb 1;344(5):319–26.CrossRefGoogle ScholarPubMed
109. Ristori, G, Buzzi, MG, Sabatini, U, et al. Use of Bacille Calmette-Guerin (BCG) in multiple sclerosis. Neurology. 1999 Oct 22;53 (7):1588–9.CrossRefGoogle ScholarPubMed
110. Paolillo, A, Buzzi, MG, Giugni, E, et al. The effect of Bacille Calmette-Guerin on the evolution of new enhancing lesions to hypointense T1 lesions in relapsing remitting MS. J Neurol. 2003 Feb;250(2):247–8.CrossRefGoogle ScholarPubMed
111. Correale, J, Farez, M, Razzitte, G. Helminth infections associated with multiple sclerosis induce regulatory B cells. Ann Neurol. 2008 Aug;64(2):187–99.CrossRefGoogle ScholarPubMed
112. La Flamme, AC, Ruddenklau, K, Backstrom, BT. Schistosomiasis decreases central nervous system inflammation and alters the progression of experimental autoimmune encephalomyelitis. Infect Immun. 2003 Sep;71(9):49965004.CrossRefGoogle ScholarPubMed
113. Brocke, S, Gaur, A, Piercy, C, et al. Induction of relapsing paralysis in experimental autoimmune encephalomyelitis by bacterial superantigen. Nature. 1993 Oct 14;365(6447):642–4.CrossRefGoogle ScholarPubMed
114. Ellestad, KK, Tsutsui, S, Noorbakhsh, F, et al. Early life exposure to lipopolysaccharide suppresses experimental autoimmune encephalomyelitis by promoting tolerogenic dendritic cells and regulatory T cells. J Immunol. 2009 Jul 1;183(1):298309.CrossRefGoogle ScholarPubMed