Skip to main content

Advertisement

SpringerLink
Log in

Biomarker Studies in Multiple Sclerosis: From Proteins to Noncoding RNAs

  • Overview
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Multiple sclerosis (MS) is a neuroimmunological disorder characterized by central nervous system demyelination, axonal injury and loss. Considering the complexity of its aetiopathogenesis, early diagnosis of MS and individualized management are challenging in clinical practice. As the pathophysiologic and pharmacological indicators, studies on biomarkers in MS are useful for early prediction and diagnosis, monitoring of disease activity and predicting treatment response. In this review, we will summarize recent development of biomarker studies in MS from protein molecules to noncoding RNAs.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Dhib-Jalbut S (2007) Pathogenesis of myelin/oligodendrocyte damage in multiple sclerosis. Neurology 68(22 Suppl. 3):S13–S21

    CAS  PubMed  Google Scholar 

  2. Billiau A (1996) Interferon-gamma in autoimmunity. Cytokine Growth Factor Rev 7(1):25–34

    CAS  PubMed  Google Scholar 

  3. Panitch HS, Hirsch RL, Haley AS, Johnson KP (1987) Exacerbations of multiple sclerosis in patients treated with gamma interferon. Lancet 1(8538):893–895

    CAS  PubMed  Google Scholar 

  4. Beck J, Rondot P, Catinot L, Falcoff E, Kirchner H, Wietzerbin J (1988) Increased production of interferon gamma and tumor necrosis factor precedes clinical manifestation in multiple sclerosis: do cytokines trigger off exacerbations? Acta Neurol Scand 78(4):318–323

    CAS  PubMed  Google Scholar 

  5. Becher B, Giacomini PS, Pelletier D, McCrea E, Prat A, Antel JP (1999) Interferon-gamma secretion by peripheral blood T-cell subsets in multiple sclerosis: correlation with disease phase and interferon-beta therapy. Ann Neurol 45(2):247–250

    CAS  PubMed  Google Scholar 

  6. Valenzuela RM, Costello K, Chen M, Said A, Johnson KP, Dhib-Jalbut S (2007) Clinical response to glatiramer acetate correlates with modulation of IFN-gamma and IL-4 expression in multiple sclerosis. Mult Scler 13(6):754–762

    CAS  PubMed  Google Scholar 

  7. Graber JJ, Ford D, Zhan M, Francis G, Panitch H, Dhib-Jalbut S (2007) Cytokine changes during interferon-beta therapy in multiple sclerosis: correlations with interferon dose and MRI response. J Neuroimmunol 185(1–2):168–174

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Tzartos JS, Friese MA, Craner MJ, Palace J, Newcombe J, Esiri MM, Fugger L (2008) Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol 172(1):146–155

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Graber JJ, Allie SR, Mullen KM, Jones MV, Wang T, Krishnan C, Kaplin AI, Nath A, Kerr DA, Calabresi PA (2008) Interleukin-17 in transverse myelitis and multiple sclerosis. J Neuroimmunol 196(1–2):124–132

    CAS  PubMed  Google Scholar 

  10. Matusevicius D, Kivisakk P, He B, Kostulas N, Ozenci V, Fredrikson S, Link H (1999) Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult Scler 5(2):101–104

    CAS  PubMed  Google Scholar 

  11. Durelli L, Conti L, Clerico M, Boselli D, Contessa G, Ripellino P, Ferrero B, Eid P, Novelli F (2009) T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-beta. Ann Neurol 65(5):499–509

    CAS  PubMed  Google Scholar 

  12. Alexander JS, Harris MK, Wells SR, Mills G, Chalamidas K, Ganta VC, McGee J, Jennings MH, Gonzalez-Toledo E, Minagar A (2010) Alterations in serum MMP-8, MMP-9, IL-12p40 and IL-23 in multiple sclerosis patients treated with interferon-beta1b. Mult Scler 16(7):801–809

    CAS  PubMed  Google Scholar 

  13. Axtell RC, de Jong BA, Boniface K, van der Voort LF, Bhat R, De Sarno P, Naves R, Han M, Zhong F, Castellanos JG, Mair R, Christakos A, Kolkowitz I, Katz L, Killestein J, Polman CH, de Waal MR, Steinman L, Raman C (2010) T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis. Nat Med 16(4):406–412

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Chen M, Chen G, Nie H, Zhang X, Niu X, Zang YC, Skinner SM, Zhang JZ, Killian JM, Hong J (2009) Regulatory effects of IFN-beta on production of osteopontin and IL-17 by CD4+ T Cells in MS. Eur J Immunol 39(9):2525–2536

    CAS  PubMed  Google Scholar 

  15. Kurtuncu M, Tuzun E, Turkoglu R, Petek-Balci B, Icoz S, Pehlivan M, Birisik O, Ulusoy C, Shugaiv E, Akman-Demir G, Eraksoy M (2012) Effect of short-term interferon-beta treatment on cytokines in multiple sclerosis: significant modulation of IL-17 and IL-23. Cytokine 59(2):400–402

    CAS  PubMed  Google Scholar 

  16. Comabella M, Balashov K, Issazadeh S, Smith D, Weiner HL, Khoury SJ (1998) Elevated interleukin-12 in progressive multiple sclerosis correlates with disease activity and is normalized by pulse cyclophosphamide therapy. J Clin Invest 102(4):671–678

    CAS  PubMed Central  PubMed  Google Scholar 

  17. Fassbender K, Ragoschke A, Rossol S, Schwartz A, Mielke O, Paulig A, Hennerici M (1998) Increased release of interleukin-12p40 in MS: association with intracerebral inflammation. Neurology 51(3):753–758

    CAS  PubMed  Google Scholar 

  18. Makhlouf K, Weiner HL, Khoury SJ (2001) Increased percentage of IL-12+ monocytes in the blood correlates with the presence of active MRI lesions in MS. J Neuroimmunol 119(1):145–149

    CAS  PubMed  Google Scholar 

  19. van Boxel-Dezaire AH, Hoff SC, van Oosten BW, Verweij CL, Drager AM, Ader HJ, van Houwelingen JC, Barkhof F, Polman CH, Nagelkerken L (1999) Decreased interleukin-10 and increased interleukin-12p40 mRNA are associated with disease activity and characterize different disease stages in multiple sclerosis. Ann Neurol 45(6):695–703

    PubMed  Google Scholar 

  20. Losy J, Michalowska-Wender G, Wender M (2002) Interleukin 12 and interleukin 10 are affected differentially by treatment of multiple sclerosis with glatiramer acetate (Copaxone). Folia Neuropathol 40(4):173–175

    CAS  PubMed  Google Scholar 

  21. Orbach R, Gurevich M, Achiron A (2014) Interleukin-12p40 in the spinal fluid as a biomarker for clinically isolated syndrome. Mult Scler 20(1):35–42

    PubMed  Google Scholar 

  22. Vaknin-Dembinsky A, Balashov K, Weiner HL (2006) IL-23 is increased in dendritic cells in multiple sclerosis and down-regulation of IL-23 by antisense oligos increases dendritic cell IL-10 production. J Immunol 176(12):7768–7774

    CAS  PubMed  Google Scholar 

  23. Wen SR, Liu GJ, Feng RN, Gong FC, Zhong H, Duan SR, Bi S (2012) Increased levels of IL-23 and osteopontin in serum and cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol 244(1–2):94–96

    CAS  PubMed  Google Scholar 

  24. Vaknin-Dembinsky A, Brass SD, Gandhi R, Weiner HL (2008) Membrane bound IL-15 is increased on CD14 monocytes in early stages of MS. J Neuroimmunol 195(1–2):135–139

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Kremlev SG, Gaurnier-Hausser AL, Del VL, Perez-Liz G, Dimitrov S, Tuszynski G (2008) Angiocidin promotes pro-inflammatory cytokine production and antigen presentation in multiple sclerosis. J Neuroimmunol 194(1–2):132–142

    CAS  PubMed  Google Scholar 

  26. Baranzini SE, Elfstrom C, Chang SY, Butunoi C, Murray R, Higuchi R, Oksenberg JR (2000) Transcriptional analysis of multiple sclerosis brain lesions reveals a complex pattern of cytokine expression. J Immunol 165(11):6576–6582

    CAS  PubMed  Google Scholar 

  27. Schneider R, Mohebiany AN, Ifergan I, Beauseigle D, Duquette P, Prat A, Arbour N (2011) B cell-derived IL-15 enhances CD8 T cell cytotoxicity and is increased in multiple sclerosis patients. J Immunol 187(8):4119–4128

    CAS  PubMed  Google Scholar 

  28. Saikali P, Antel JP, Pittet CL, Newcombe J, Arbour N (2010) Contribution of astrocyte-derived IL-15 to CD8 T cell effector functions in multiple sclerosis. J Immunol 185(10):5693–5703

    CAS  PubMed  Google Scholar 

  29. Baslund B, Tvede N, Danneskiold-Samsoe B, Larsson P, Panayi G, Petersen J, Petersen LJ, Beurskens FJ, Schuurman J, van de Winkel JG, Parren PW, Gracie JA, Jongbloed S, Liew FY, McInnes IB (2005) Targeting interleukin-15 in patients with rheumatoid arthritis: a proof-of-concept study. Arthritis Rheum 52(9):2686–2692

    CAS  PubMed  Google Scholar 

  30. Shimizu Y, Ota K, Ikeguchi R, Kubo S, Kabasawa C, Uchiyama S (2013) Plasma osteopontin levels are associated with disease activity in the patients with multiple sclerosis and neuromyelitis optica. J Neuroimmunol 263(1–2):148–151

    CAS  PubMed  Google Scholar 

  31. Chiocchetti A, Comi C, Indelicato M, Castelli L, Mesturini R, Bensi T, Mazzarino MC, Giordano M, D’Alfonso S, Momigliano-Richiardi P, Liguori M, Zorzon M, Amoroso A, Trojano M, Monaco F, Leone M, Magnani C, Dianzani U (2005) Osteopontin gene haplotypes correlate with multiple sclerosis development and progression. J Neuroimmunol 163(1–2):172–178

    CAS  PubMed  Google Scholar 

  32. Comabella M, Pericot I, Goertsches R, Nos C, Castillo M, Blas NJ, Rio J, Montalban X (2005) Plasma osteopontin levels in multiple sclerosis. J Neuroimmunol 158(1–2):231–239

    CAS  PubMed  Google Scholar 

  33. Vogt MH, Floris S, Killestein J, Knol DL, Smits M, Barkhof F, Polman CH, Nagelkerken L (2004) Osteopontin levels and increased disease activity in relapsing-remitting multiple sclerosis patients. J Neuroimmunol 155(1–2):155–160

    CAS  PubMed  Google Scholar 

  34. Braitch M, Nunan R, Niepel G, Edwards LJ, Constantinescu CS (2008) Increased osteopontin levels in the cerebrospinal fluid of patients with multiple sclerosis. Arch Neurol 65(5):633–635

    PubMed  Google Scholar 

  35. Kivisakk P, Healy BC, Francois K, Gandhi R, Gholipour T, Egorova S, Sevdalinova V, Quintana F, Chitnis T, Weiner HL, Khoury SJ (2014) Evaluation of circulating osteopontin levels in an unselected cohort of patients with multiple sclerosis: relevance for biomarker development. Mult Scler 20(4):438–444

    PubMed  Google Scholar 

  36. Bornsen L, Khademi M, Olsson T, Sorensen PS, Sellebjerg F (2011) Osteopontin concentrations are increased in cerebrospinal fluid during attacks of multiple sclerosis. Mult Scler 17(1):32–42

    PubMed  Google Scholar 

  37. Romme CJ, Bornsen L, Hesse D, Krakauer M, Sorensen PS, Sondergaard HB, Sellebjerg F (2012) Cellular sources of dysregulated cytokines in relapsing-remitting multiple sclerosis. J Neuroinflamm 9:215

    Google Scholar 

  38. Bartosik-Psujek H, Stelmasiak Z (2006) The interleukin-10 levels as a potential indicator of positive response to interferon beta treatment of multiple sclerosis patients. Clin Neurol Neurosurg 108(7):644–647

    PubMed  Google Scholar 

  39. Hesse D, Krakauer M, Lund H, Sondergaard HB, Limborg SJ, Sorensen PS, Sellebjerg F (2011) Disease protection and interleukin-10 induction by endogenous interferon-beta in multiple sclerosis? Eur J Neurol 18(2):266–272

    CAS  PubMed  Google Scholar 

  40. Zhang L, Yuan S, Cheng G, Guo B (2011) Type I IFN promotes IL-10 production from T cells to suppress Th17 cells and Th17-associated autoimmune inflammation. PLoS One 6(12):e28432

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Wang H, Wang K, Zhong X, Dai Y, Qiu W, Wu A, Hu X (2012) Notable increased cerebrospinal fluid levels of soluble interleukin-6 receptors in neuromyelitis optica. Neuroimmunomodulation 19(5):304–308

    PubMed  Google Scholar 

  42. Uzawa A, Mori M, Arai K, Sato Y, Hayakawa S, Masuda S, Taniguchi J, Kuwabara S (2010) Cytokine and chemokine profiles in neuromyelitis optica: significance of interleukin-6. Mult Scler 16(12):1443–1452

    CAS  PubMed  Google Scholar 

  43. Sellebjerg F, Krakauer M, Hesse D, Ryder LP, Alsing I, Jensen PE, Koch-Henriksen N, Svejgaard A, Soelberg SP (2009) Identification of new sensitive biomarkers for the in vivo response to interferon-beta treatment in multiple sclerosis using DNA-array evaluation. Eur J Neurol 16(12):1291–1298

    CAS  PubMed  Google Scholar 

  44. Brettschneider J, Czerwoniak A, Senel M, Fang L, Kassubek J, Pinkhardt E, Lauda F, Kapfer T, Jesse S, Lehmensiek V, Ludolph AC, Otto M, Tumani H (2010) The chemokine CXCL13 is a prognostic marker in clinically isolated syndrome (CIS). PLoS One 5(8):e11986

    PubMed Central  PubMed  Google Scholar 

  45. Khademi M, Kockum I, Andersson ML, Iacobaeus E, Brundin L, Sellebjerg F, Hillert J, Piehl F, Olsson T (2011) Cerebrospinal fluid CXCL13 in multiple sclerosis: a suggestive prognostic marker for the disease course. Mult Scler 17(3):335–343

    CAS  PubMed  Google Scholar 

  46. Linden M, Khademi M, Lima BI, Piehl F, Jagodic M, Kockum I, Olsson T (2013) Multiple sclerosis risk genotypes correlate with an elevated cerebrospinal fluid level of the suggested prognostic marker CXCL13. Mult Scler 19(7):863–870

    CAS  PubMed  Google Scholar 

  47. Ingram G, Hakobyan S, Hirst CL, Harris CL, Pickersgill TP, Cossburn MD, Loveless S, Robertson NP, Morgan BP (2010) Complement regulator factor H as a serum biomarker of multiple sclerosis disease state. Brain 133(Pt 6):1602–1611

    PubMed  Google Scholar 

  48. Ingram G, Hakobyan S, Hirst CL, Harris CL, Loveless S, Mitchell JP, Pickersgill TP, Robertson NP, Morgan BP (2012) Systemic complement profiling in multiple sclerosis as a biomarker of disease state. Mult Scler 18(10):1401–1411

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Kumanogoh A, Shikina T, Suzuki K, Uematsu S, Yukawa K, Kashiwamura S, Tsutsui H, Yamamoto M, Takamatsu H, Ko-Mitamura EP, Takegahara N, Marukawa S, Ishida I, Morishita H, Prasad DV, Tamura M, Mizui M, Toyofuku T, Akira S, Takeda K, Okabe M, Kikutani H (2005) Nonredundant roles of Sema4A in the immune system: defective T cell priming and Th1/Th2 regulation in Sema4A-deficient mice. Immunity 22(3):305–316

    CAS  PubMed  Google Scholar 

  50. Koda T, Okuno T, Takata K, Honorat JA, Kinoshita M, Tada S, Moriya M, Sakoda S, Mochizuki H, Kumanogoh A, Nakatsuji Y (2014) Sema4A inhibits the therapeutic effect of IFN-beta in EAE. J Neuroimmunol 268(1–2):43–49

    CAS  PubMed  Google Scholar 

  51. Nakatsuji Y, Okuno T, Moriya M, Sugimoto T, Kinoshita M, Takamatsu H, Nojima S, Kimura T, Kang S, Ito D, Nakagawa Y, Toyofuku T, Takata K, Nakano M, Kubo M, Suzuki S, Matsui-Hasumi A, Uto-Konomi A, Ogata A, Mochizuki H, Sakoda S, Kumanogoh A (2012) Elevation of Sema4A implicates Th cell skewing and the efficacy of IFN-beta therapy in multiple sclerosis. J Immunol 188(10):4858–4865

    CAS  PubMed  Google Scholar 

  52. Eng LF, Vanderhaeghen JJ, Bignami A, Gerstl B (1971) An acidic protein isolated from fibrous astrocytes. Brain Res 28(2):351–354

    CAS  PubMed  Google Scholar 

  53. Axelsson M, Malmestrom C, Nilsson S, Haghighi S, Rosengren L, Lycke J (2011) Glial fibrillary acidic protein: a potential biomarker for progression in multiple sclerosis. J Neurol 258(5):882–888

    CAS  PubMed  Google Scholar 

  54. Misu T, Takano R, Fujihara K, Takahashi T, Sato S, Itoyama Y (2009) Marked increase in cerebrospinal fluid glial fibrillar acidic protein in neuromyelitis optica: an astrocytic damage marker. J Neurol Neurosurg Psychiatry 80(5):575–577

    CAS  PubMed  Google Scholar 

  55. Storoni M, Petzold A, Plant GT (2011) The use of serum glial fibrillary acidic protein measurements in the diagnosis of neuromyelitis optica spectrum optic neuritis. PLoS One 6(8):e23489

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Teunissen CE, Iacobaeus E, Khademi M, Brundin L, Norgren N, Koel-Simmelink MJ, Schepens M, Bouwman F, Twaalfhoven HA, Blom HJ, Jakobs C, Dijkstra CD (2009) Combination of CSF N-acetylaspartate and neurofilaments in multiple sclerosis. Neurology 72(15):1322–1329

    CAS  PubMed  Google Scholar 

  57. Salzer J, Svenningsson A, Sundstrom P (2010) Neurofilament light as a prognostic marker in multiple sclerosis. Mult Scler 16(3):287–292

    CAS  PubMed  Google Scholar 

  58. Gunnarsson M, Malmestrom C, Axelsson M, Sundstrom P, Dahle C, Vrethem M, Olsson T, Piehl F, Norgren N, Rosengren L, Svenningsson A, Lycke J (2011) Axonal damage in relapsing multiple sclerosis is markedly reduced by natalizumab. Ann Neurol 69(1):83–89

    CAS  PubMed  Google Scholar 

  59. Norgren N, Sundstrom P, Svenningsson A, Rosengren L, Stigbrand T, Gunnarsson M (2004) Neurofilament and glial fibrillary acidic protein in multiple sclerosis. Neurology 63(9):1586–1590

    CAS  PubMed  Google Scholar 

  60. Kuhle J, Leppert D, Petzold A, Regeniter A, Schindler C, Mehling M, Anthony DC, Kappos L, Lindberg RL (2011) Neurofilament heavy chain in CSF correlates with relapses and disability in multiple sclerosis. Neurology 76(14):1206–1213

    CAS  PubMed  Google Scholar 

  61. Breij EC, Heijnen P, van der Goes A, Teunissen CE, Polman CH, Dijkstra CD (2006) Myelin flow cytometry assay detects enhanced levels of antibodies to human whole myelin in a subpopulation of multiple sclerosis patients. J Neuroimmunol 176(1–2):106–114

    CAS  PubMed  Google Scholar 

  62. Tintore M, Rovira A, Rio J, Tur C, Pelayo R, Nos C, Tellez N, Perkal H, Comabella M, Sastre-Garriga J, Montalban X (2008) Do oligoclonal bands add information to MRI in first attacks of multiple sclerosis? Neurology 70(13 Pt 2):1079–1083

    CAS  PubMed  Google Scholar 

  63. Jarius S, Aboul-Enein F, Waters P, Kuenz B, Hauser A, Berger T, Lang W, Reindl M, Vincent A, Kristoferitsch W (2008) Antibody to aquaporin-4 in the long-term course of neuromyelitis optica. Brain 131(Pt 11):3072–3080

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Jarius S, Wildemann B (2010) AQP4 antibodies in neuromyelitis optica: diagnostic and pathogenetic relevance. Nat Rev Neurol 6(7):383–392

    CAS  PubMed  Google Scholar 

  65. Kim SM, Waters P, Woodhall M, Kim JY, Kim JE, Yang JW, Kim JS, Sung JJ, Park KS, Lee KW (2013) Utility of aquaporin-4 antibody assay in patients with neuromyelitis optica spectrum disorders. Mult Scler 19(8):1060–1067

    PubMed  Google Scholar 

  66. Srivastava R, Aslam M, Kalluri SR, Schirmer L, Buck D, Tackenberg B, Rothhammer V, Chan A, Gold R, Berthele A, Bennett JL, Korn T, Hemmer B (2012) Potassium channel KIR4.1 as an immune target in multiple sclerosis. N Engl J Med 367(2):115–123

    CAS  PubMed  Google Scholar 

  67. Reindl M, Linington C, Brehm U, Egg R, Dilitz E, Deisenhammer F, Poewe W, Berger T (1999) Antibodies against the myelin oligodendrocyte glycoprotein and the myelin basic protein in multiple sclerosis and other neurological diseases: a comparative study. Brain 122(Pt 11):2047–2056

    PubMed  Google Scholar 

  68. Schmidt S, Haase CG, Bezman L, Moser H, Schmidt M, Kohler W, Linington C, Klockgether T (2001) Serum autoantibody responses to myelin oligodendrocyte glycoprotein and myelin basic protein in X-linked adrenoleukodystrophy and multiple sclerosis. J Neuroimmunol 119(1):88–94

    CAS  PubMed  Google Scholar 

  69. Antel JP, Bar-Or A (2003) Do myelin-directed antibodies predict multiple sclerosis? N Engl J Med 349(2):107–109

    CAS  PubMed  Google Scholar 

  70. Rauer S, Euler B, Reindl M, Berger T (2006) Antimyelin antibodies and the risk of relapse in patients with a primary demyelinating event. J Neurol Neurosurg Psychiatry 77(6):739–742

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Berger T, Rubner P, Schautzer F, Egg R, Ulmer H, Mayringer I, Dilitz E, Deisenhammer F, Reindl M (2003) Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event. N Engl J Med 349(2):139–145

    CAS  PubMed  Google Scholar 

  72. Kuhle J, Pohl C, Mehling M, Edan G, Freedman MS, Hartung HP, Polman CH, Miller DH, Montalban X, Barkhof F, Bauer L, Dahms S, Lindberg R, Kappos L, Sandbrink R (2007) Lack of association between antimyelin antibodies and progression to multiple sclerosis. N Engl J Med 356(4):371–378

    CAS  PubMed  Google Scholar 

  73. Zhou D, Srivastava R, Nessler S, Grummel V, Sommer N, Bruck W, Hartung HP, Stadelmann C, Hemmer B (2006) Identification of a pathogenic antibody response to native myelin oligodendrocyte glycoprotein in multiple sclerosis. Proc Natl Acad Sci USA 103(50):19057–19062

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Lalive PH, Menge T, Delarasse C, Della GB, Pham-Dinh D, Villoslada P, von Budingen HC, Genain CP (2006) Antibodies to native myelin oligodendrocyte glycoprotein are serologic markers of early inflammation in multiple sclerosis. Proc Natl Acad Sci USA 103(7):2280–2285

    CAS  PubMed Central  PubMed  Google Scholar 

  75. O’Connor KC, McLaughlin KA, De Jager PL, Chitnis T, Bettelli E, Xu C, Robinson WH, Cherry SV, Bar-Or A, Banwell B, Fukaura H, Fukazawa T, Tenembaum S, Wong SJ, Tavakoli NP, Idrissova Z, Viglietta V, Rostasy K, Pohl D, Dale RC, Freedman M, Steinman L, Buckle GJ, Kuchroo VK, Hafler DA, Wucherpfennig KW (2007) Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein. Nat Med 13(2):211–217

    PubMed Central  PubMed  Google Scholar 

  76. McLaughlin KA, Chitnis T, Newcombe J, Franz B, Kennedy J, McArdel S, Kuhle J, Kappos L, Rostasy K, Pohl D, Gagne D, Ness JM, Tenembaum S, O’Connor KC, Viglietta V, Wong SJ, Tavakoli NP, de Seze J, Idrissova Z, Khoury SJ, Bar-Or A, Hafler DA, Banwell B, Wucherpfennig KW (2009) Age-dependent B cell autoimmunity to a myelin surface antigen in pediatric multiple sclerosis. J Immunol 183(6):4067–4076

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Bjartmar C, Trapp BD (2001) Axonal and neuronal degeneration in multiple sclerosis: mechanisms and functional consequences. Curr Opin Neurol 14(3):271–278

    CAS  PubMed  Google Scholar 

  78. Mathey EK, Derfuss T, Storch MK, Williams KR, Hales K, Woolley DR, Al-Hayani A, Davies SN, Rasband MN, Olsson T, Moldenhauer A, Velhin S, Hohlfeld R, Meinl E, Linington C (2007) Neurofascin as a novel target for autoantibody-mediated axonal injury. J Exp Med 204(10):2363–2372

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Derfuss T, Parikh K, Velhin S, Braun M, Mathey E, Krumbholz M, Kumpfel T, Moldenhauer A, Rader C, Sonderegger P, Pollmann W, Tiefenthaller C, Bauer J, Lassmann H, Wekerle H, Karagogeos D, Hohlfeld R, Linington C, Meinl E (2009) Contactin-2/TAG-1-directed autoimmunity is identified in multiple sclerosis patients and mediates gray matter pathology in animals. Proc Natl Acad Sci USA 106(20):8302–8307

    CAS  PubMed Central  PubMed  Google Scholar 

  80. van der Voort LF, Gilli F, Bertolotto A, Knol DL, Uitdehaag BM, Polman CH, Killestein J (2010) Clinical effect of neutralizing antibodies to interferon beta that persist long after cessation of therapy for multiple sclerosis. Arch Neurol 67(4):402–407

    PubMed  Google Scholar 

  81. Polman CH, Bertolotto A, Deisenhammer F, Giovannoni G, Hartung HP, Hemmer B, Killestein J, McFarland HF, Oger J, Pachner AR, Petkau J, Reder AT, Reingold SC, Schellekens H, Sorensen PS (2010) Recommendations for clinical use of data on neutralising antibodies to interferon-beta therapy in multiple sclerosis. Lancet Neurol 9(7):740–750

    CAS  PubMed  Google Scholar 

  82. Salama HH, Hong J, Zang YC, El-Mongui A, Zhang J (2003) Blocking effects of serum reactive antibodies induced by glatiramer acetate treatment in multiple sclerosis. Brain 126(Pt 12):2638–2647

    PubMed  Google Scholar 

  83. Teitelbaum D, Brenner T, Abramsky O, Aharoni R, Sela M, Arnon R (2003) Antibodies to glatiramer acetate do not interfere with its biological functions and therapeutic efficacy. Mult Scler 9(6):592–599

    CAS  PubMed  Google Scholar 

  84. Brenner T, Arnon R, Sela M, Abramsky O, Meiner Z, Riven-Kreitman R, Tarcik N, Teitelbaum D (2001) Humoral and cellular immune responses to Copolymer 1 in multiple sclerosis patients treated with Copaxone. J Neuroimmunol 115(1–2):152–160

    CAS  PubMed  Google Scholar 

  85. Karussis D, Teitelbaum D, Sicsic C, Brenner T (2010) Long-term treatment of multiple sclerosis with glatiramer acetate: natural history of the subtypes of anti-glatiramer acetate antibodies and their correlation with clinical efficacy. J Neuroimmunol 220(1–2):125–130

    CAS  PubMed  Google Scholar 

  86. Calabresi PA, Giovannoni G, Confavreux C, Galetta SL, Havrdova E, Hutchinson M, Kappos L, Miller DH, O’Connor PW, Phillips JT, Polman CH, Radue EW, Rudick RA, Stuart WH, Lublin FD, Wajgt A, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA (2007) The incidence and significance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL. Neurology 69(14):1391–1403

    CAS  PubMed  Google Scholar 

  87. Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, Lee S, Plavina T, Scanlon JV, Sandrock A, Bozic C (2012) Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 366(20):1870–1880

    CAS  PubMed  Google Scholar 

  88. Uccelli A, Ginocchio F, Mancardi GL, Bassetti M (2011) Primary varicella zoster infection associated with fingolimod treatment. Neurology 76(11):1023–1024

    PubMed  Google Scholar 

  89. Sola P, Mandrioli J, Simone AM, Ferraro D, Bedin R, Annecca R, Venneri MG, Nichelli PF, Merelli E (2011) Primary progressive versus relapsing-onset multiple sclerosis: presence and prognostic value of cerebrospinal fluid oligoclonal IgM. Mult Scler 17(3):303–311

    CAS  PubMed  Google Scholar 

  90. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297

    CAS  PubMed  Google Scholar 

  91. Wu H, Neilson JR, Kumar P, Manocha M, Shankar P, Sharp PA, Manjunath N (2007) miRNA profiling of naive, effector and memory CD8 T cells. PLoS One 2(10):e1020

    PubMed Central  PubMed  Google Scholar 

  92. Neilson JR, Zheng GX, Burge CB, Sharp PA (2007) Dynamic regulation of miRNA expression in ordered stages of cellular development. Genes Dev 21(5):578–589

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Keller A, Leidinger P, Lange J, Borries A, Schroers H, Scheffler M, Lenhof HP, Ruprecht K, Meese E (2009) Multiple sclerosis: microRNA expression profiles accurately differentiate patients with relapsing-remitting disease from healthy controls. PLoS One 4(10):e7440

    PubMed Central  PubMed  Google Scholar 

  94. Gandhi R, Healy B, Gholipour T, Egorova S, Musallam A, Hussain MS, Nejad P, Patel B, Hei H, Khoury S, Quintana F, Kivisakk P, Chitnis T, Weiner HL (2013) Circulating microRNAs as biomarkers for disease staging in multiple sclerosis. Ann Neurol 73(6):729–740

    CAS  PubMed  Google Scholar 

  95. Fayyad-Kazan H, Rouas R, Fayyad-Kazan M, Badran R, El ZN, Lewalle P, Najar M, Hamade E, Jebbawi F, Merimi M, Romero P, Burny A, Badran B, Martiat P (2012) MicroRNA profile of circulating CD4-positive regulatory T cells in human adults and impact of differentially expressed microRNAs on expression of two genes essential to their function. J Biol Chem 287(13):9910–9922

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Cox MB, Cairns MJ, Gandhi KS, Carroll AP, Moscovis S, Stewart GJ, Broadley S, Scott RJ, Booth DR, Lechner-Scott J (2010) MicroRNAs miR-17 and miR-20a inhibit T cell activation genes and are under-expressed in MS whole blood. PLoS One 5(8):e12132

    PubMed Central  PubMed  Google Scholar 

  97. Lindberg RL, Hoffmann F, Mehling M, Kuhle J, Kappos L (2010) Altered expression of miR-17-5p in CD4+ lymphocytes of relapsing-remitting multiple sclerosis patients. Eur J Immunol 40(3):888–898

    CAS  PubMed  Google Scholar 

  98. De Santis G, Ferracin M, Biondani A, Caniatti L, Rosaria TM, Castellazzi M, Zagatti B, Battistini L, Borsellino G, Fainardi E, Gavioli R, Negrini M, Furlan R, Granieri E (2010) Altered miRNA expression in T regulatory cells in course of multiple sclerosis. J Neuroimmunol 226(1–2):165–171

    PubMed  Google Scholar 

  99. Tsuchida A, Ohno S, Wu W, Borjigin N, Fujita K, Aoki T, Ueda S, Takanashi M, Kuroda M (2011) miR-92 is a key oncogenic component of the miR-17-92 cluster in colon cancer. Cancer Sci 102(12):2264–2271

    CAS  PubMed  Google Scholar 

  100. Petrocca F, Vecchione A, Croce CM (2008) Emerging role of miR-106b-25/miR-17-92 clusters in the control of transforming growth factor beta signaling. Cancer Res 68(20):8191–8194

    CAS  PubMed  Google Scholar 

  101. Waschbisch A, Atiya M, Linker RA, Potapov S, Schwab S, Derfuss T (2011) Glatiramer acetate treatment normalizes deregulated microRNA expression in relapsing remitting multiple sclerosis. PLoS One 6(9):e24604

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Junker A, Krumbholz M, Eisele S, Mohan H, Augstein F, Bittner R, Lassmann H, Wekerle H, Hohlfeld R, Meinl E (2009) MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47. Brain 132(Pt 12):3342–3352

    PubMed  Google Scholar 

  103. Huang B, Zhao J, Lei Z, Shen S, Li D, Shen GX, Zhang GM, Feng ZH (2009) miR-142-3p restricts cAMP production in CD4+ CD25− T cells and CD4+ CD25+ TREG cells by targeting AC9 mRNA. EMBO Rep 10(2):180–185

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Lu LF, Boldin MP, Chaudhry A, Lin LL, Taganov KD, Hanada T, Yoshimura A, Baltimore D, Rudensky AY (2010) Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell 142(6):914–929

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Paraboschi EM, Solda G, Gemmati D, Orioli E, Zeri G, Benedetti MD, Salviati A, Barizzone N, Leone M, Duga S, Asselta R (2011) Genetic association and altered gene expression of mir-155 in multiple sclerosis patients. Int J Mol Sci 12(12):8695–8712

    CAS  PubMed Central  PubMed  Google Scholar 

  106. Du C, Liu C, Kang J, Zhao G, Ye Z, Huang S, Li Z, Wu Z, Pei G (2009) MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nat Immunol 10(12):1252–1259

    CAS  PubMed  Google Scholar 

  107. Murugaiyan G, Beynon V, Mittal A, Joller N, Weiner HL (2011) Silencing microRNA-155 ameliorates experimental autoimmune encephalomyelitis. J Immunol 187(5):2213–2221

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Guerau-de-Arellano M, Smith KM, Godlewski J, Liu Y, Winger R, Lawler SE, Whitacre CC, Racke MK, Lovett-Racke AE (2011) Micro-RNA dysregulation in multiple sclerosis favours pro-inflammatory T-cell-mediated autoimmunity. Brain 134(Pt 12):3578–3589

    PubMed  Google Scholar 

  109. Sievers C, Meira M, Hoffmann F, Fontoura P, Kappos L, Lindberg RL (2012) Altered microRNA expression in B lymphocytes in multiple sclerosis: towards a better understanding of treatment effects. Clin Immunol 144(1):70–79

    CAS  PubMed  Google Scholar 

  110. Chen CZ, Li L, Lodish HF, Bartel DP (2004) MicroRNAs modulate hematopoietic lineage differentiation. Science 303(5654):83–86

    CAS  PubMed  Google Scholar 

  111. Jima DD, Zhang J, Jacobs C, Richards KL, Dunphy CH, Choi WW, Au WY, Srivastava G, Czader MB, Rizzieri DA, Lagoo AS, Lugar PL, Mann KP, Flowers CR, Bernal-Mizrachi L, Naresh KN, Evens AM, Gordon LI, Luftig M, Friedman DR, Weinberg JB, Thompson MA, Gill JI, Liu Q, How T, Grubor V, Gao Y, Patel A, Wu H, Zhu J, Blobe GC, Lipsky PE, Chadburn A, Dave SS (2010) Deep sequencing of the small RNA transcriptome of normal and malignant human B cells identifies hundreds of novel microRNAs. Blood 116(23):e118–e127

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Lucas RM, Ponsonby AL, Dear K, Valery P, Pender MP, Burrows JM, Burrows SR, Chapman C, Coulthard A, Dwyer DE, Dwyer T, Kilpatrick T, Lay ML, McMichael AJ, Taylor BV, van der Mei IA, Williams D (2011) Current and past Epstein–Barr virus infection in risk of initial CNS demyelination. Neurology 77(4):371–379

    CAS  PubMed  Google Scholar 

  113. Gupta SK, Bang C, Thum T (2010) Circulating microRNAs as biomarkers and potential paracrine mediators of cardiovascular disease. Circ Cardiovasc Genet 3(5):484–488

    CAS  PubMed  Google Scholar 

  114. Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O’Briant KC, Allen A, Lin DW, Urban N, Drescher CW, Knudsen BS, Stirewalt DL, Gentleman R, Vessella RL, Nelson PS, Martin DB, Tewari M (2008) Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA 105(30):10513–10518

    CAS  PubMed Central  PubMed  Google Scholar 

  115. Ma R, Jiang T, Kang X (2012) Circulating microRNAs in cancer: origin, function and application. J Exp Clin Cancer Res 31:38

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Siegel SR, Mackenzie J, Chaplin G, Jablonski NG, Griffiths L (2012) Circulating microRNAs involved in multiple sclerosis. Mol Biol Rep 39(5):6219–6225

    CAS  PubMed  Google Scholar 

  117. Mercer TR, Dinger ME, Sunkin SM, Mehler MF, Mattick JS (2008) Specific expression of long noncoding RNAs in the mouse brain. Proc Natl Acad Sci USA 105(2):716–721

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Ponjavic J, Oliver PL, Lunter G, Ponting CP (2009) Genomic and transcriptional co-localization of protein-coding and long non-coding RNA pairs in the developing brain. PLoS Genet 5(8):e1000617

    PubMed Central  PubMed  Google Scholar 

  119. Guttman M, Amit I, Garber M, French C, Lin MF, Feldser D, Huarte M, Zuk O, Carey BW, Cassady JP, Cabili MN, Jaenisch R, Mikkelsen TS, Jacks T, Hacohen N, Bernstein BE, Kellis M, Regev A, Rinn JL, Lander ES (2009) Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458(7235):223–227

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Lin D, Pestova TV, Hellen CU, Tiedge H (2008) Translational control by a small RNA: dendritic BC1 RNA targets the eukaryotic initiation factor 4A helicase mechanism. Mol Cell Biol 28(9):3008–3019

    CAS  PubMed Central  PubMed  Google Scholar 

  121. Khalil AM, Faghihi MA, Modarresi F, Brothers SP, Wahlestedt C (2008) A novel RNA transcript with antiapoptotic function is silenced in fragile X syndrome. PLoS One 3(1):e1486

    PubMed Central  PubMed  Google Scholar 

  122. Faghihi MA, Modarresi F, Khalil AM, Wood DE, Sahagan BG, Morgan TE, Finch CE, St LGR, Kenny PJ, Wahlestedt C (2008) Expression of a noncoding RNA is elevated in Alzheimer’s disease and drives rapid feed-forward regulation of beta-secretase. Nat Med 14(7):723–730

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Daughters RS, Tuttle DL, Gao W, Ikeda Y, Moseley ML, Ebner TJ, Swanson MS, Ranum LP (2009) RNA gain-of-function in spinocerebellar ataxia type 8. PLoS Genet 5(8):e1000600

    PubMed Central  PubMed  Google Scholar 

  124. Doi H, Okamura K, Bauer PO, Furukawa Y, Shimizu H, Kurosawa M, Machida Y, Miyazaki H, Mitsui K, Kuroiwa Y, Nukina N (2008) RNA-binding protein TLS is a major nuclear aggregate-interacting protein in huntingtin exon 1 with expanded polyglutamine-expressing cells. J Biol Chem 283(10):6489–6500

    CAS  PubMed  Google Scholar 

  125. Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CA, Devon RS, St CD, Muir WJ, Blackwood DH, Porteous DJ (2000) Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet 9(9):1415–1423

    CAS  PubMed  Google Scholar 

  126. Martinez R, Martin-Subero JI, Rohde V, Kirsch M, Alaminos M, Fernandez AF, Ropero S, Schackert G, Esteller M (2009) A microarray-based DNA methylation study of glioblastoma multiforme. Epigenetics 4(4):255–264

    CAS  PubMed  Google Scholar 

  127. Pang KC, Dinger ME, Mercer TR, Malquori L, Grimmond SM, Chen W, Mattick JS (2009) Genome-wide identification of long noncoding RNAs in CD8+ T cells. J Immunol 182(12):7738–7748

    CAS  PubMed  Google Scholar 

  128. Yu D, Tan AH, Hu X, Athanasopoulos V, Simpson N, Silva DG, Hutloff A, Giles KM, Leedman PJ, Lam KP, Goodnow CC, Vinuesa CG (2007) Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA. Nature 450(7167):299–303

    CAS  PubMed  Google Scholar 

  129. Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ, De Jager PL, de Bakker PI, Gabriel SB, Mirel DB, Ivinson AJ, Pericak-Vance MA, Gregory SG, Rioux JD, McCauley JL, Haines JL, Barcellos LF, Cree B, Oksenberg JR, Hauser SL (2007) Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 357(9):851–862

    CAS  PubMed  Google Scholar 

  130. Zhang N, He YW (2005) An essential role for c-FLIP in the efficient development of mature T lymphocytes. J Exp Med 202(3):395–404

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Sharief MK (2000) Increased cellular expression of the caspase inhibitor FLIP in intrathecal lymphocytes from patients with multiple sclerosis. J Neuroimmunol 111(1–2):203–209

    CAS  PubMed  Google Scholar 

  132. Semra YK, Seidi OA, Sharief MK (2001) Overexpression of the apoptosis inhibitor FLIP in T cells correlates with disease activity in multiple sclerosis. J Neuroimmunol 113(2):268–274

    CAS  PubMed  Google Scholar 

  133. Vigneau S, Rohrlich PS, Brahic M, Bureau JF (2003) Tmevpg1, a candidate gene for the control of Theiler’s virus persistence, could be implicated in the regulation of gamma interferon. J Virol 77(10):5632–5638

    CAS  PubMed Central  PubMed  Google Scholar 

  134. Goris A, Heggarty S, Marrosu MG, Graham C, Billiau A, Vandenbroeck K (2002) Linkage disequilibrium analysis of chromosome 12q14-15 in multiple sclerosis: delineation of a 118-kb interval around interferon-gamma (IFNG) that is involved in male versus female differential susceptibility. Genes Immun 3(8):470–476

    CAS  PubMed  Google Scholar 

  135. Silverberg MS, Cho JH, Rioux JD, McGovern DP, Wu J, Annese V, Achkar JP, Goyette P, Scott R, Xu W, Barmada MM, Klei L, Daly MJ, Abraham C, Bayless TM, Bossa F, Griffiths AM, Ippoliti AF, Lahaie RG, Latiano A, Pare P, Proctor DD, Regueiro MD, Steinhart AH, Targan SR, Schumm LP, Kistner EO, Lee AT, Gregersen PK, Rotter JI, Brant SR, Taylor KD, Roeder K, Duerr RH (2009) Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study. Nat Genet 41(2):216–220

    CAS  PubMed Central  PubMed  Google Scholar 

  136. Collier SP, Collins PL, Williams CL, Boothby MR, Aune TM (2012) Cutting edge: influence of Tmevpg1, a long intergenic noncoding RNA, on the expression of Ifng by Th1 cells. J Immunol 189(5):2084–2088

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by National Natural Science Foundation, China (Grant Number: 81301024); Hunan Natural Science Foundation (Grant Number: 14JJ2021); Hunan Natural Science Foundation (Grant Number: 14JJ3033).

Author information

Authors and Affiliations

  1. Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, China

    Xiao-Fang Liu, Yue-Bei Luo, Zhao-Hui Luo & Huan Yang

Authors
  1. Xiao-Fang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yue-Bei Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhao-Hui Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Huan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Huan Yang.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, XF., Luo, YB., Luo, ZH. et al. Biomarker Studies in Multiple Sclerosis: From Proteins to Noncoding RNAs. Neurochem Res 39, 1661–1674 (2014). https://doi.org/10.1007/s11064-014-1386-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-014-1386-z

Keywords

Search

Navigation