Molecular Neurobiology

, Volume 54, Issue 5, pp 3911–3923 | Cite as

Viruses and Multiple Sclerosis: From Mechanisms and Pathways to Translational Research Opportunities

  • Alexios-Fotios A. Mentis
  • Efthimios Dardiotis
  • Nikolaos Grigoriadis
  • Efthimia Petinaki
  • Georgios M. Hadjigeorgiou
Article

Abstract

Viruses are directly or indirectly implicated in multiple sclerosis (MS). Here, we review the evidence on the virus-related pathophysiology of MS, introduce common experimental models, and explore the ways in which viruses cause demyelination. By emphasizing knowledge gaps, we highlight future research directions for effective MS diagnostics and therapies: (i) identifying biomarkers for at-risk individuals, (ii) searching for direct evidence of specific causative viruses, (iii) establishing the contribution of host genetic factors and viruses, and (iv) investigating the contribution of immune regulation at extra-CNS sites. Research in these areas is likely to be facilitated by the application of high-throughput technologies, the development of systems-based bioinformatic approaches, careful selection of experimental models, and the acquisition of high-quality clinical material for tissue-based research.

Keywords

Multiple sclerosis Virus Sequencing Molecular mimicry Epitope spreading Bystander activation 

Notes

Acknowledgements

A.-F.A.M. has been supported through an educational scholarship from the Onassis Public Benefit Foundation. The latter played no role in the design of the study, collection or/and interpretation of data, or writing of the review article.

References

  1. 1.
    Kingwell EMJ, Jetté N, Pringsheim T, Makhani N, Morrow SA, Fisk JD, Evans C, Béland SG et al (2013) Incidence and prevalence of multiple sclerosis in Europe. BMC Neurol 13:128PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Grytten N, Torkildsen O, Myhr KM (2015) Time trends in the incidence and prevalence of multiple sclerosis in Norway during eight decades. Acta Neurol Scand 132(199):29–36. doi: 10.1111/ane.12428 PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Salomon JA, Vos T, Hogan DR, Gagnon M, Naghavi M, Mokdad A, Begum N, Shah R et al (2012) Common values in assessing health outcomes from disease and injury: disability weights measurement study for the Global Burden of Disease Study 2010. Lancet 380(9859):2129–2143. doi: 10.1016/s0140-6736(12)61680-8 PubMedCrossRefGoogle Scholar
  4. 4.
    Eskandarieh S, Heydarpour P, Minagar A, Pourmand S, Sahraian MA (2016) Multiple sclerosis epidemiology in East Asia, South East Asia and South Asia: A systematic review. Neuroepidemiology 46(3):209–221. doi: 10.1159/000444019 PubMedCrossRefGoogle Scholar
  5. 5.
    Leray E, Moreau T, Fromont A, Edan G (2016) Epidemiology of multiple sclerosis. Rev Neurol 172(1):3–13. doi: 10.1016/j.neurol.2015.10.006 PubMedCrossRefGoogle Scholar
  6. 6.
    DeSalvo K, Galvez E (2015) Connecting health and care for the nation: a shared nationwide interoperability roadmap—version 1.0. Health IT Buzz.Google Scholar
  7. 7.
    MS Ao (Atlas of MS) (2013) Mapping multiple sclerosis around the world. Multiple Sclerosis International Federation, LondonGoogle Scholar
  8. 8.
    Paul Browne DC, Angood C, Tremlett H, Baker C, Taylor BV, Thompson AJ (2014) Atlas of multiple sclerosis 2013: a growing global problem with widespread inequity. Neurology 83(11):1022–1024PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG (2000) Multiple sclerosis. N Engl J Med 343(13):938–952. doi: 10.1056/NEJM200009283431307 PubMedCrossRefGoogle Scholar
  10. 10.
    Babbe H, Roers A, Waisman A, Lassmann H, Goebels N, Hohlfeld R, Friese M, Schroder R et al (2000) Clonal expansions of CD8(+) T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction. J Exp Med 192(3):393–404PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Saxena A, Martin-Blondel G, Mars LT, Liblau RS (2011) Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis. FEBS Lett 585(23):3758–3763. doi: 10.1016/j.febslet.2011.08.047 PubMedCrossRefGoogle Scholar
  12. 12.
    Lublin F (2005) History of modern multiple sclerosis therapy. J Neurol 254(4):493500 252 Suppl 3:iii3-iii9 Google Scholar
  13. 13.
    Benson T, Grieve G (2016) Principles of health interoperability: SNOMED CT, HL7 and FHIR. Springer, LondonCrossRefGoogle Scholar
  14. 14.
    Tselis A (2011) Evidence for viral etiology of multiple sclerosis. Semin Neurol 31(3):307–316. doi: 10.1055/s-0031-1287656 PubMedCrossRefGoogle Scholar
  15. 15.
    Belbasis L, Bellou V, Evangelou E, Ioannidis JPA, Tzoulaki I (2015) Environmental risk factors and multiple sclerosis: an umbrella review of systematic reviews and meta-analyses. The Lancet Neurology 14(3):263–273. doi: 10.1016/s1474-4422(14)70267-4 PubMedCrossRefGoogle Scholar
  16. 16.
    Dendrou CA, Fugger L, Friese MA (2015) Immunopathology of multiple sclerosis. Nat Rev Immunol 15(9):545–558. doi: 10.1038/nri3871 PubMedCrossRefGoogle Scholar
  17. 17.
    Bashinskaya VV, Kulakova OG, Boyko AN, Favorov AV, Favorova OO (2015) A review of genome-wide association studies for multiple sclerosis: classical and hypothesis-driven approaches. Hum Genet 134(11–12):1143–1162. doi: 10.1007/s00439-015-1601-2 PubMedCrossRefGoogle Scholar
  18. 18.
    Baranzini SE, Mudge J, van Velkinburgh JC, Khankhanian P, Khrebtukova I, Miller NA, Zhang L, Farmer AD et al (2010) Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis. Nature 464(7293):1351–1356. doi: 10.1038/nature08990 PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Brodin P, Jojic V, Gao T, Bhattacharya S, Angel CJ, Furman D, Shen-Orr S, Dekker CL et al (2015) Variation in the human immune system is largely driven by non-heritable influences. Cell 160(1–2):37–47. doi: 10.1016/j.cell.2014.12.020 PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Owens GP, Gilden D, Burgoon MP, Yu X, Bennett JL (2011) Viruses and multiple sclerosis. Neuroscientist 17(6):659–676. doi: 10.1177/1073858411386615 PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Mattes FM, JEM, Emery VC, Clark DA, GriYths PD (2000) Histopathological detection of owl’s eye inclusions. J Clin Pathol 53:612–614PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Libbey JE, Cusick MF, Fujinami RS (2014) Role of pathogens in multiple sclerosis. Int Rev Immunol 33(4):266–283. doi: 10.3109/08830185.2013.823422 PubMedCrossRefGoogle Scholar
  23. 23.
    Baltimore D (1971) Expression of animal virus genomes. Bacteriol Rev 35(3):235–241PubMedPubMedCentralGoogle Scholar
  24. 24.
    Andrews J (2016) Precision medicine: analytics, data science and EHRs in the new age. Healthcare IT NewsGoogle Scholar
  25. 25.
    Virtanen JO, Jacobson S (2012) Viruses and multiple sclerosis. CNS Neurol Disord Drug Targets 11(5):528–544PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Roots BI (2008) The phylogeny of invertebrates and the evolution of myelin. Neuron Glia Biol 4(2):101–109. doi: 10.1017/S1740925X0900012X PubMedCrossRefGoogle Scholar
  27. 27.
    Travis J (2009) Origins. On the origin of the immune system. Science 324(5927):580–582. doi: 10.1126/science.324_580 PubMedCrossRefGoogle Scholar
  28. 28.
    Fang Y, Lei X, Li X, Chen Y, Xu F, Feng X, Wei S, Li Y (2014) A novel model of demyelination and remyelination in a GFP-transgenic zebrafish. Biol Open 4(1):62–68. doi: 10.1242/bio.201410736 PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Amor S, Groome N, Linington C, Morris MM, Dornmair K, Gardinier MV, Matthieu JM, Baker D (1994) Identification of epitopes of myelin oligodendrocyte glycoprotein for the induction of experimental allergic encephalomyelitis in SJL and Biozzi AB/H mice. J Immunol 153(10):4349–4356PubMedGoogle Scholar
  30. 30.
    Fazakerley JK, Amor S, Webb HE (1983) Reconstitution of Semliki forest virus infected mice, induces immune mediated pathological changes in the CNS. Clin Exp Immunol 52(1):115–120PubMedPubMedCentralGoogle Scholar
  31. 31.
    Mokhtarian F, Huan CM, Roman C, Raine CS (2003) Semliki Forest virus-induced demyelination and remyelination—involvement of B cells and anti-myelin antibodies. J Neuroimmunol 137(1–2):19–31PubMedCrossRefGoogle Scholar
  32. 32.
    Tsunoda I, Fujinami RS (2010) Neuropathogenesis of Theiler’s murine encephalomyelitis virus infection, an animal model for multiple sclerosis. J NeuroImmune Pharmacol 5(3):355–369. doi: 10.1007/s11481-009-9179-x PubMedCrossRefGoogle Scholar
  33. 33.
    Das Sarma J, Kenyon LC, Hingley ST, Shindler KS (2009) Mechanisms of primary axonal damage in a viral model of multiple sclerosis. J Neurosci 29(33):10272–10280. doi: 10.1523/JNEUROSCI.1975-09.2009 PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Shindler KS, Kenyon LC, Dutt M, Hingley ST, Das Sarma J (2008) Experimental optic neuritis induced by a demyelinating strain of mouse hepatitis virus. J Virol 82(17):8882–8886. doi: 10.1128/JVI.00920-08 PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Blair TC, Manoharan M, Rawlings-Rhea SD, Tagge I, Kohama SG, Hollister-Smith J, Ferguson B, Woltjer RL et al (2016) Immunopathology of Japanese macaque encephalomyelitis is similar to multiple sclerosis. J Neuroimmunol 291:1–10. doi: 10.1016/j.jneuroim.2015.11.026 PubMedCrossRefGoogle Scholar
  36. 36.
    Kipp M, van der Star B, Vogel DY, Puentes F, van der Valk P, Baker D, Amor S (2012) Experimental in vivo and in vitro models of multiple sclerosis: EAE and beyond. Mult Scler Relat Disord 1(1):15–28. doi: 10.1016/j.msard.2011.09.002 PubMedCrossRefGoogle Scholar
  37. 37.
    Procaccini C, De Rosa V, Pucino V, Formisano L, Matarese G (2015) Animal models of multiple sclerosis. Eur J Pharmacol 759:182–191. doi: 10.1016/j.ejphar.2015.03.042 PubMedCrossRefGoogle Scholar
  38. 38.
    Krishnamoorthy G, Lassmann H, Wekerle H, Holz A (2006) Spontaneous opticospinal encephalomyelitis in a double-transgenic mouse model of autoimmune T cell/B cell cooperation. J Clin Invest 116(9):2385–2392. doi: 10.1172/JCI28330 PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Ousman SS, Tomooka BH, van Noort JM, Wawrousek EF, O’Connor KC, Hafler DA, Sobel RA, Robinson WH et al (2007) Protective and therapeutic role for alphaB-crystallin in autoimmune demyelination. Nature 448(7152):474–479. doi: 10.1038/nature05935 PubMedCrossRefGoogle Scholar
  40. 40.
    Mastronardi FG, Ackerley CA, Arsenault L, Roots BI, Moscarello MA (1993) Demyelination in a transgenic mouse: a model for multiple sclerosis. J Neurosci Res 36(3):315–324. doi: 10.1002/jnr.490360309 PubMedCrossRefGoogle Scholar
  41. 41.
    Blakemore WF, Franklin RJ (2008) Remyelination in experimental models of toxin-induced demyelination. Curr Top Microbiol Immunol 318:193–212PubMedGoogle Scholar
  42. 42.
    Franklin RJ, Crang AJ, Blakemore WF (1993) The reconstruction of an astrocytic environment in glia-deficient areas of white matter. J Neurocytol 22(5):382–396PubMedCrossRefGoogle Scholar
  43. 43.
    Kipp M, Clarner T, Dang J, Copray S, Beyer C (2009) The cuprizone animal model: new insights into an old story. Acta Neuropathol 118(6):723–736. doi: 10.1007/s00401-009-0591-3 PubMedCrossRefGoogle Scholar
  44. 44.
    Mothe AJ, Tator CH (2008) Transplanted neural stem/progenitor cells generate myelinating oligodendrocytes and Schwann cells in spinal cord demyelination and dysmyelination. Exp Neurol 213(1):176–190. doi: 10.1016/j.expneurol.2008.05.024 PubMedCrossRefGoogle Scholar
  45. 45.
    Baker D, Amor S (2015) Mouse models of multiple sclerosis: lost in translation? Curr Pharm Des 21(18):2440–2452PubMedCrossRefGoogle Scholar
  46. 46.
    Lassmann H, Bradl M (2016) Multiple sclerosis: experimental models and reality. Acta Neuropathol. doi: 10.1007/s00401-016-1631-4 Google Scholar
  47. 47.
    Gilli F, Li L, Pachner AR (2016) The immune response in the CNS in Theiler’s virus induced demyelinating disease switches from an early adaptive response to a chronic innate-like response. J Neuro-Oncol 22(1):66–79. doi: 10.1007/s13365-015-0369-4 Google Scholar
  48. 48.
    Benner B, Martorell AJ, Mahadevan P, Najm FJ, Tesar PJ, Freundt EC (2016) Depletion of Olig2 in oligodendrocyte progenitor cells infected by Theiler’s murine encephalomyelitis virus. J Neuro-Oncol 22(3):336–348. doi: 10.1007/s13365-015-0402-7 Google Scholar
  49. 49.
    Kang HS, Myoung J, So EY, Bahk YY, Kim BS (2016) Transgenic expression of non-structural genes of Theiler’s virus suppresses initial viral replication and pathogenesis of demyelination. J Neuroinflammation 13(1):133. doi: 10.1186/s12974-016-0597-4 PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Stavrou S, Feng Z, Lemon SM, Roos RP (2010) Different strains of Theiler’s murine encephalomyelitis virus antagonize different sites in the type I interferon pathway. J Virol 84(18):9181–9189. doi: 10.1128/JVI.00603-10 PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Estep RD, Hansen SG, Rogers KS, Axthelm MK, Wong SW (2013) Genomic characterization of Japanese macaque rhadinovirus, a novel herpesvirus isolated from a nonhuman primate with a spontaneous inflammatory demyelinating disease. J Virol 87(1):512–523. doi: 10.1128/JVI.02194-12 PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Grigoriadis N, Hadjigeorgiou GM (2006) Virus-mediated autoimmunity in multiple sclerosis. J Autoimmune Dis 3:1. doi: 10.1186/1740-2557-3-1 PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Wortman MJ, Lundberg PS, Dagdanova AV, Venkataraman P, Daniel DC, Johnson EM (2016) Opportunistic DNA recombination with Epstein-Barr virus at sites of control region rearrangements mediating JC virus Neurovirulence. J Infect Dis 213(9):1436–1443. doi: 10.1093/infdis/jiv755 PubMedCrossRefGoogle Scholar
  54. 54.
    Kweder H, Ainouze M, Brunel J, Gerlier D, Manet E, Buckland R (2015) Measles virus: identification in the M protein primary sequence of a potential molecular marker for subacute sclerosing panencephalitis. Adv Virol 2015:769837. doi: 10.1155/2015/769837 PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Behan PO, Chaudhuri A (2014) EAE is not a useful model for demyelinating disease. Mult Scler Relat Disord 3(5):565–574. doi: 10.1016/j.msard.2014.06.003 PubMedCrossRefGoogle Scholar
  56. 56.
    Smyk DS, Alexander AK, Walker M, Walker M (2014) Acute disseminated encephalomyelitis progressing to multiple sclerosis: are infectious triggers involved? Immunol Res 60(1):16–22. doi: 10.1007/s12026-014-8499-y PubMedCrossRefGoogle Scholar
  57. 57.
    Di Ruscio A, Patti F, Welner RS, Tenen DG, Amabile G (2015) Multiple sclerosis: getting personal with induced pluripotent stem cells. Cell Death Dis 6:e1806. doi: 10.1038/cddis.2015.179 PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Song B, Sun G, Herszfeld D, Sylvain A, Campanale NV, Hirst CE, Caine S, Parkington HC et al (2012) Neural differentiation of patient specific iPS cells as a novel approach to study the pathophysiology of multiple sclerosis. Stem Cell Res 8(2):259–273. doi: 10.1016/j.scr.2011.12.001 PubMedCrossRefGoogle Scholar
  59. 59.
    Pamies D, Barreras P, Block K, Makri G, Kumar A, Wiersma D, Smirnova L, Zhang C et al (2016) A human brain microphysiological system derived from induced pluripotent stem cells to study neurological diseases and toxicity. ALTEX. doi: 10.14573/altex.1609122 PubMedCentralGoogle Scholar
  60. 60.
    Marro BS, Blanc CA, Loring JF, Cahalan MD, Lane TE (2014) Promoting remyelination: utilizing a viral model of demyelination to assess cell-based therapies. Expert Rev Neurother 14(10):1169–1179. doi: 10.1586/14737175.2014.955854 PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Li X, Zhang Y, Yan Y, Ciric B, Ma CG, Chin J, Curtis M, Rostami A et al (2016) LINGO-1-fc-transduced neural stem cells are effective therapy for chronic stage experimental autoimmune encephalomyelitis. Mol Neurobiol. doi: 10.1007/s12035-016-9994-z PubMedCentralGoogle Scholar
  62. 62.
    Voulgari-Kokota A, Fairless R, Karamita M, Kyrargyri V, Tseveleki V, Evangelidou M, Delorme B, Charbord P et al (2012) Mesenchymal stem cells protect CNS neurons against glutamate excitotoxicity by inhibiting glutamate receptor expression and function. Exp Neurol 236(1):161–170. doi: 10.1016/j.expneurol.2012.04.011 PubMedCrossRefGoogle Scholar
  63. 63.
    Hoftberger R, Leisser M, Bauer J, Lassmann H (2015) Autoimmune encephalitis in humans: how closely does it reflect multiple sclerosis ? Acta Neuropathol Commun 3:80. doi: 10.1186/s40478-015-0260-9 PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Zhao Z-S, Granucci F, Yeh L, Schaffer PA, Cantor H (1998) Molecular mimicry by herpes simplex virus-type 1: autoimmune disease after viral infection. Science 279:1344–1347PubMedCrossRefGoogle Scholar
  65. 65.
    Cusick MF, Libbey JE, Fujinami RS (2013) Multiple sclerosis: autoimmunity and viruses. Curr Opin Rheumatol 25(4):496–501. doi: 10.1097/BOR.0b013e328362004d PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Lindsey JW, deGannes SL, Pate KA, Zhao X (2016) Antibodies specific for Epstein-Barr virus nuclear antigen-1 cross-react with human heterogeneous nuclear ribonucleoprotein L. Mol Immunol 69:7–12. doi: 10.1016/j.molimm.2015.11.007 PubMedCrossRefGoogle Scholar
  67. 67.
    Mameli G, Cossu D, Cocco E, Masala S, Frau J, Marrosu MG, Sechi LA (2014) Epstein-Barr virus and Mycobacterium avium subsp. paratuberculosis peptides are cross recognized by anti-myelin basic protein antibodies in multiple sclerosis patients. J Neuroimmunol 270(1–2):51–55. doi: 10.1016/j.jneuroim.2014.02.013 PubMedCrossRefGoogle Scholar
  68. 68.
    Gabibov AG, Belogurov AA Jr, Lomakin YA, Zakharova MY, Avakyan ME, Dubrovskaya VV, Smirnov IV, Ivanov AS et al (2011) Combinatorial antibody library from multiple sclerosis patients reveals antibodies that cross-react with myelin basic protein and EBV antigen. FASEB J 25(12):4211–4221. doi: 10.1096/fj.11-190769 PubMedCrossRefGoogle Scholar
  69. 69.
    Lomakin YA, Zakharova MY, Belogurov AA, Bykova NA, Dronina MA, Tupikin AE, Knorre VD, Boyko AN et al (2013) Polyreactive monoclonal autoantibodies. Acta Nat 5(4):94–104Google Scholar
  70. 70.
    Moise L, Beseme S, Tassone R, Liu R, Kibria F, Terry F, Martin W, De Groot AS (2016) T cell epitope redundancy: cross-conservation of the TCR face between pathogens and self and its implications for vaccines and autoimmunity. Expert Rev Vaccines 15(5):607–617. doi: 10.1586/14760584.2016.1123098 PubMedCrossRefGoogle Scholar
  71. 71.
    Zheng MM, Zhang XH (2014) Cross-reactivity between human cytomegalovirus peptide 981-1003 and myelin oligodendroglia glycoprotein peptide 35-55 in experimental autoimmune encephalomyelitis in Lewis rats. Biochem Biophys Res Commun 443(3):1118–1123. doi: 10.1016/j.bbrc.2013.12.122 PubMedCrossRefGoogle Scholar
  72. 72.
    Carter CJ (2012) Epstein-Barr and other viral mimicry of autoantigens, myelin and vitamin D-related proteins and of EIF2B, the cause of vanishing white matter disease: massive mimicry of multiple sclerosis relevant proteins by the Synechococcus phage. Immunopharmacol Immunotoxicol 34(1):21–35. doi: 10.3109/08923973.2011.572262 PubMedCrossRefGoogle Scholar
  73. 73.
    Chan YK, Gack MU (2016) Viral evasion of intracellular DNA and RNA sensing. Nat Rev Microbiol 14(6):360–373. doi: 10.1038/nrmicro.2016.45 PubMedCrossRefGoogle Scholar
  74. 74.
    Broccolo F, Fusetti L, Ceccherini-Nelli L (2013) Possible role of human herpesvirus 6 as a trigger of autoimmune disease. ScientificWorldJournal 2013:867389. doi: 10.1155/2013/867389 PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    t Hart BA, Hintzen RQ, Laman JD (2009) Multiple sclerosis—a response-to-damage model. Trends Mol Med 15(6):235–244. doi: 10.1016/j.molmed.2009.04.001 CrossRefGoogle Scholar
  76. 76.
    Kakalacheva K, Munz C, Lunemann JD (2011) Viral triggers of multiple sclerosis. Biochim Biophys Acta 1812(2):132–140. doi: 10.1016/j.bbadis.2010.06.012 PubMedCrossRefGoogle Scholar
  77. 77.
    McCoy L, Tsunoda I, RS F (2006) Multiple sclerosis and virus induced immune responses-autoimmunity can be primed by molecular mimicry and augmented by bystander activation. Autoimmunity 39(1):9–19PubMedCrossRefGoogle Scholar
  78. 78.
    Sanderson NS, Zimmermann M, Eilinger L, Gubser C, Schaeren-Wiemers N, Lindberg RL, Dougan SK, Ploegh HL et al (2017) Cocapture of cognate and bystander antigens can activate autoreactive B cells. Proc Natl Acad Sci U S A. doi: 10.1073/pnas.1614472114 Google Scholar
  79. 79.
    Fujinami RS, von Herrath MG, Christen U, Whitton JL (2006) Molecular mimicry, bystander activation, or viral persistence: infections and autoimmune disease. Clin Microbiol Rev 19(1):80–94. doi: 10.1128/CMR.19.1.80-94.2006 PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    McMahon EJBS, Castenada CV, Waldner H, Miller SD (2005) Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis. Nat Med 11(3):335–339PubMedCrossRefGoogle Scholar
  81. 81.
    MGv H, Fujinami RS, Whitton JL (2003) Microorganisms and autoimmunity: making the barren field fertile. Nature ReviewsMicrobiology 1:151–156Google Scholar
  82. 82.
    Merkler D, Horvath E, Bruck W, Zinkernagel RM, Del la Torre JC, Pinschewer DD (2006) “Viral deja vu” elicits organ-specific immune disease independent of reactivity to self. J Clin Invest 116(5):1254–1263. doi: 10.1172/JCI27372 PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D et al (2015) Structural and functional features of central nervous system lymphatic vessels. Nature 523(7560):337–341. doi: 10.1038/nature14432 PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Palanichamy A, Apeltsin L, Kuo TC, Sirota M, Wang S, Pitts SJ, Sundar PD, Telman D et al (2014) Immunoglobulin class-switched B cells form an active immune axis between CNS and periphery in multiple sclerosis. Sci Transl Med 6(248):248ra106. doi: 10.1126/scitranslmed.3008930 PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, Wiig H, Alitalo K (2015) A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med 212(7):991–999. doi: 10.1084/jem.20142290 PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Iijima N, Iwasaki A (2016) Access of protective antiviral antibody to neuronal tissues requires CD4 T-cell help. Nature 533(7604):552–556. doi: 10.1038/nature17979 PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Stern JN, Yaari G, Vander Heiden JA, Church G, Donahue WF, Hintzen RQ, Huttner AJ, Laman JD et al (2014) B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes. Sci Transl Med 6(248):248ra107. doi: 10.1126/scitranslmed.3008879 PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Engelhardt B, Carare RO, Bechmann I, Flugel A, Laman JD, Weller RO (2016) Vascular, glial, and lymphatic immune gateways of the central nervous system. Acta Neuropathol 132(3):317–338. doi: 10.1007/s00401-016-1606-5 PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Pfeiffer JK, Virgin HW (2016) Viral immunity. Transkingdom control of viral infection and immunity in the mammalian intestine. Science 351(6270). doi: 10.1126/science.aad5872
  90. 90.
    Berer K, Krishnamoorthy G (2014) Microbial view of central nervous system autoimmunity. FEBS Lett 588(22):4207–4213. doi: 10.1016/j.febslet.2014.04.007 PubMedCrossRefGoogle Scholar
  91. 91.
    Berer K, Mues M, Koutrolos M, Rasbi ZA, Boziki M, Johner C, Wekerle H, Krishnamoorthy G (2011) Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479(7374):538–541. doi: 10.1038/nature10554 PubMedCrossRefGoogle Scholar
  92. 92.
    Lee YK, Menezes JS, Umesaki Y, Mazmanian SK (2011) Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 108(Suppl 1):4615–4622. doi: 10.1073/pnas.1000082107 PubMedCrossRefGoogle Scholar
  93. 93.
    Berer K, Krishnamoorthy G (2012) Commensal gut flora and brain autoimmunity: a love or hate affair? Acta Neuropathol 123(5):639–651. doi: 10.1007/s00401-012-0949-9 PubMedCrossRefGoogle Scholar
  94. 94.
    Chen J, Chia N, Kalari KR, Yao JZ, Novotna M, Soldan MM, Luckey DH, Marietta EV et al (2016) Multiple sclerosis patients have a distinct gut microbiota compared to healthy controls. Sci Rep 6:28484. doi: 10.1038/srep28484 PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Jangi S, Gandhi R, Cox LM, Li N, von Glehn F, Yan R, Patel B, Mazzola MA et al (2016) Alterations of the human gut microbiome in multiple sclerosis. Nat Commun 7:12015. doi: 10.1038/ncomms12015 PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Mielcarz DW, Kasper LH (2015) The gut microbiome in multiple sclerosis. Curr Treat Options Neurol 17(4):344. doi: 10.1007/s11940-015-0344-7 PubMedCrossRefGoogle Scholar
  97. 97.
    Westall FC (2006) Molecular mimicry revisited: gut bacteria and multiple sclerosis. J Clin Microbiol 44(6):2099–2104. doi: 10.1128/JCM.02532-05 PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Norman JM, Handley SA, Baldridge MT, Droit L, Liu CY, Keller BC, Kambal A, Monaco CL et al (2015) Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell 160(3):447–460. doi: 10.1016/j.cell.2015.01.002 PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Reyes A, Haynes M, Hanson N, Angly FE, Heath AC, Rohwer F, Gordon JI (2010) Viruses in the faecal microbiota of monozygotic twins and their mothers. Nature 466(7304):334–338. doi: 10.1038/nature09199 PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Modi SR, Lee HH, Spina CS, Collins JJ (2013) Antibiotic treatment expands the resistance reservoir and ecological network of the phage metagenome. Nature 499(7457):219–222. doi: 10.1038/nature12212 PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Young GR, Eksmond U, Salcedo R, Alexopoulou L, Stoye JP, Kassiotis G (2012) Resurrection of endogenous retroviruses in antibody-deficient mice. Nature 491(7426):774–778. doi: 10.1038/nature11599 PubMedPubMedCentralGoogle Scholar
  102. 102.
    Emmer A, Staege MS, Kornhuber ME (2014) The retrovirus/superantigen hypothesis of multiple sclerosis. Cell Mol Neurobiol 34(8):1087–1096. doi: 10.1007/s10571-014-0100-7 PubMedCrossRefGoogle Scholar
  103. 103.
    Lill CM (2014) Recent advances and future challenges in the genetics of multiple sclerosis. Front Neurol 5:130. doi: 10.3389/fneur.2014.00130 PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Ramagopalan SV, Dyment DA, Cader MZ, Morrison KM, Disanto G, Morahan JM, Berlanga-Taylor AJ, Handel A et al (2011) Rare variants in the CYP27B1 gene are associated with multiple sclerosis. Ann Neurol 70(6):881–886. doi: 10.1002/ana.22678 PubMedCrossRefGoogle Scholar
  105. 105.
    Sanders KA, Benton MC, Lea RA, Maltby VE, Agland S, Griffin N, Scott RJ, Tajouri L et al (2016) Next-generation sequencing reveals broad down-regulation of microRNAs in secondary progressive multiple sclerosis CD4+ T cells. Clin Epigenetics 8(1):87. doi: 10.1186/s13148-016-0253-y PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Perlejewski K, Bukowska-Osko I, Nakamura S, Motooka D, Stokowy T, Ploski R, Rydzanicz M, Zakrzewska-Pniewska B et al (2016) Metagenomic analysis of cerebrospinal fluid from patients with multiple sclerosis. Adv Exp Med Biol. doi: 10.1007/5584_2016_25 Google Scholar
  107. 107.
    Jovel J, Okeefe S, Patterson J, Bording-Jorgensen M, Wang W, Mason AL, Warren KG, Wong GK-S (2016) Cerebrospinal fluid in a small cohort of patients with multiple sclerosis was generally free of microbial DNA. Front Cell Infect Microbiol 6:198PubMedGoogle Scholar
  108. 108.
    Rounds WH, Salinas EA, Wilks TB 2nd, Levin MK, Ligocki AJ, Ionete C, Pardo CA, Vernino S et al (2015) MSPrecise: a molecular diagnostic test for multiple sclerosis using next generation sequencing. Gene 572(2):191–197. doi: 10.1016/j.gene.2015.07.011 PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Branton WG, Lu JQ, Surette MG, Holt RA, Lind J, Laman JD, Power C (2016) Brain microbiota disruption within inflammatory demyelinating lesions in multiple sclerosis. Sci Rep 6:37344. doi: 10.1038/srep37344 PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Kriesel JD, Hobbs MR, Jones BB, Milash B, Nagra RM, Fischer KF (2012) Deep sequencing for the detection of virus-like sequences in the brains of patients with multiple sclerosis: detection of GBV-C in human brain. PLoS One 7(3):e31886. doi: 10.1371/journal.pone.0031886 PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Han MH, Hwang SI, Roy DB, Lundgren DH, Price JV, Ousman SS, Fernald GH, Gerlitz B et al (2008) Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets. Nature 451(7182):1076–1081. doi: 10.1038/nature06559 PubMedCrossRefGoogle Scholar
  112. 112.
    Koopman FA, Chavan SS, Miljko S, Grazio S, Sokolovic S, Schuurman PR, Mehta AD, Levine YA et al (2016) Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci U S A 113(29):8284–8289. doi: 10.1073/pnas.1605635113 PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Wiles TJ, Jemielita M, Baker RP, Schlomann BH, Logan SL, Ganz J, Melancon E, Eisen JS et al (2016) Host gut motility promotes competitive exclusion within a model intestinal microbiota. PLoS Biol 14(7):e1002517. doi: 10.1371/journal.pbio.1002517 PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Ulusoy A, Phillips RJ, Helwig M, Klinkenberg M, Powley TL, Di Monte DA (2016) Brain-to-stomach transfer of alpha-synuclein via vagal preganglionic projections. Acta Neuropathol. doi: 10.1007/s00401-016-1661-y PubMedGoogle Scholar
  115. 115.
    Zintzaras E, Doxani C, Mprotsis T, Schmid CH, Hadjigeorgiou GM (2012) Network analysis of randomized controlled trials in multiple sclerosis. Clin Ther 34 (4):857–869 e859. doi: 10.1016/j.clinthera.2012.02.018 PubMedCrossRefGoogle Scholar
  116. 116.
    Tsivgoulis G, Katsanos AH, Grigoriadis N, Hadjigeorgiou GM, Heliopoulos I, Papathanasopoulos P, Kilidireas C, Voumvourakis K et al, Helani (2015) The effect of disease modifying therapies on disease progression in patients with relapsing-remitting multiple sclerosis: a systematic review and meta-analysis. PLoS One 10(12):e0144538. doi: 10.1371/journal.pone.0144538
  117. 117.
    Thompson AJ (2017) Challenge of progressive multiple sclerosis therapy. Curr Opin Neurol. doi: 10.1097/WCO.0000000000000453 PubMedGoogle Scholar
  118. 118.
    Curtin F, Perron H, Faucard R, Porchet H, Lang AB (2015) Treatment against human endogenous retrovirus: a possible personalized medicine approach for multiple sclerosis. Mol Diagn Ther 19(5):255–265. doi: 10.1007/s40291-015-0166-z PubMedCrossRefGoogle Scholar
  119. 119.
    Perron H, Garson JA, Bedin F, Beseme F, Paranhos-Baccala G, Komurian-Pradel F, Mallet F, Tuke PW et al (1997) 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 94(14):7583–7588PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Alexios-Fotios A. Mentis
    • 1
    • 2
  • Efthimios Dardiotis
    • 3
  • Nikolaos Grigoriadis
    • 4
  • Efthimia Petinaki
    • 1
  • Georgios M. Hadjigeorgiou
    • 3
  1. 1.Department of MicrobiologyUniversity Hospital of Larissa, University of ThessalyLarissaGreece
  2. 2.The Johns Hopkins University, AAPBaltimoreUSA
  3. 3.Department of NeurologyUniversity Hospital of Larissa, University of ThessalyLarissaGreece
  4. 4.B’ Department of Neurology, Laboratory of Experimental Neurology and NeuroimmunologyAHEPA University Hospital, Aristotle University of ThessalonikiThessalonikiGreece

Personalised recommendations