Journal of Neuroimmunology
Volume 225, Issue 1 , Pages 5-12 , 25 August 2010

Orchestrating innate immune responses in multiple sclerosis: Molecular players

  • Marta Fernández
    • ,
  • Xavier Montalban
    • ,
  • Manuel Comabella

      Affiliations

    • Corresponding Author InformationCorresponding author. Unitat de Neuroimmunologia Clínica, CEM-Cat. Edif. EUI 2ª planta, Hospital Universitari Vall d'Hebron, Pg. Vall d'Hebron 119-129 08035 Barcelona, Spain. Tel.: +34 932746834; fax: +34 932746084.

Received 30 March 2010 ,Accepted 3 May 2010.

References 

  1. Argaw AT, Zhang Y, Snyder BJ, Zhao ML, Kopp N, Lee SC, et al. IL-1beta regulates blood-brain barrier permeability via reactivation of the hypoxia-angiogenesis program. J. Immunol. 2006;177:5574–5584
  2. Arnett HA, Mason J, Marino M, Suzuki K, Matsushima GK, Ting JP. TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nat. Neurosci. 2001;4:1116–1122
  3. Barnett MH, Parratt JD, Cho ES, Prineas JW. Immunoglobulins and complement in postmortem multiple sclerosis tissue. Ann. Neurol. 2009;65:32–46
  4. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441:235–238
  5. Bitsch A, Kuhlmann T, Da Costa C, Bunkowski S, Polak T, Brück W. Tumour necrosis factor alpha mRNA expression in early multiple sclerosis lesions: correlation with demyelinating activity and oligodendrocyte pathology. Glia. 2000;29:366–375
  6. Boos L, Campbell IL, Ames R, Wetsel RA, Barnum SR. Deletion of the complement anaphylatoxin C3a receptor attenuates, whereas ectopic expression of C3a in the brain exacerbates, experimental autoimmune encephalomyelitis. J. Immunol. 2004;173:4708–4714
  7. Boos LA, Szalai AJ, Barnum SR. Murine complement C4 is not required for experimental autoimmune encephalomyelitis. Glia. 2005;49:158–160
  8. Breij EC, Brink BP, Veerhuis R, van den Berg C, Vloet R, Yan R, et al. Homogeneity of active demyelinating lesions in established multiple sclerosis. Ann. Neurol. 2008;63:16–25
  9. Brinkmann V, Geiger T, Alkan S, Heusser CH. Interferon alpha increases the frequency of interferon gamma-producing human CD4+ T cells. J Exp Med. 1993;178:1655–1663
  10. Calida DM, Constantinescu C, Purev E, Zhang GX, Ventura ES, Lavi E, et al. Cutting edge: C3, a key component of complement activation, is not required for the development of myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis in mice. J. Immunol. 2001;166:723–726
  11. Christophi GP, Panos M, Hudson CA, Christophi RL, Gruber RC, Mersich AT, et al. Macrophages of multiple sclerosis patients display deficient SHP-1 expression and enhanced inflammatory phenotype. Lab. Invest. 2009;89:742–759
  12. Claudio L, Martiney JA, Brosnan CF. Ultrastructural studies of the blood-retina barrier after exposure to interleukin-1 beta or tumor necrosis factor-alpha. Lab. Invest. 1994;70:850–861
  13. Comabella M, Lünemann JD, Río J, Sánchez A, López C, Julià E, et al. A type I interferon signature in monocytes is associated with poor response to interferon-beta in multiple sclerosis. Brain. 2009;132(Pt 12):3353–3365Dec
  14. Eugster HP, Frei K, Kopf M, Lassmann H, Fontana A. IL-6-deficient mice resist myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. Eur. J. Immunol. 1998;28:2178–2187
  15. Eugster HP, Frei K, Bachmann R, Bluethmann H, Lassmann H, Fontana A. Severity of symptoms and demyelination in MOG-induced EAE depends on TNFR1. Eur. J. Immunol. 1999;29:626–632
  16. Freeman HJ, Flak B. Demyelination-like syndrome in Crohn's disease after infliximab therapy. Can. J. Gastroenterol. 2005;19:313–316
  17. Frei K, Fredrikson S, Fontana A, Link H. Interleukin-6 is elevated in plasma in multiple sclerosis. J. Neuroimmunol. 1991;31:147–153
  18. Gay FW, Drye TJ, Dick GW, Esiri MM. The application of multifactorial cluster analysis in the staging of plaques in early multiple sclerosis. Identification and characterization of the primary demyelinating lesion. Brain. 1997;120:1461–1483
  19. Goverman J. Autoimmune T cell responses in the central nervous system. Nat. Rev. Immunol. 2009;9:393–407
  20. Hauser SL, Doolittle TH, Lincoln R, Brown RH, Dinarello CA. Cytokine accumulations in CSF of multiple sclerosis patients: frequent detection of interleukin-1 and tumor necrosis factor but not interleukin-6. Neurology. 1990;40:1735–1739
  21. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Müller-Newen G, Schaper F. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem. J. 2003;374:1–20
  22. Ingram G, Hakobyan S, Robertson NP, Morgan BP. Complement in multiple sclerosis: its role in disease and potential as a biomarker. Clin. Exp. Immunol. 2009;155:128–139
  23. Kalie E, Jaitin DA, Podoplelova Y, Piehler J, Schreiber G. The stability of the ternary interferon-receptor complex rather than the affinity to the individual subunits dictates differential biological activities. J. Biol. Chem. 2008;283:32925–32936
  24. Kameda T, Dobashi H, Kittaka K, Susaki K, Hosomi N, Deguchi K, et al. A case of rheumatoid arthritis complicated by demyelination in both cerebral cortex and spinal cord during etanercept therapy. Mod. Rheumatol. 2008;18:399–402
  25. Kappos L, Traboulsee A, Constantinescu C, Erälinna JP, Forrestal F, Jongen P, et al. Long-term subcutaneous interferon beta-1a therapy in patients with relapsing–remitting MS. Neurology. 2006;67:944–953
  26. Korn T, Mitsdoerffer M, Croxford AL, Awasthi A, Dardalhon VA, Galileos G, et al. IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells. Proc. Natl. Acad. Sci. U.S.A. 2008;105:18460–18465
  27. Lampropoulou V, Hoehlig K, Roch T, Neves P, Calderón Gómez E, Sweenie CH, et al. TLR-activated B cells suppress T cell-mediated autoimmunity. J. Immunol. 2008;180:4763–4773
  28. Le Bon A, Schiavoni G, D'Agostino G, Gresser I, Belardelli F, Tough DF. Type I interferons potently enhance humoral immunity and can promote isotype switching by stimulating dendritic cells in vivo. Immunity. 2001;14:461–470
  29. Li Q, Huang D, Nacion K, Bu H, Lin F. Augmenting DAF levels in vivo ameliorates experimental autoimmune encephalomyelitis. Mol. Immunol. 2009;46:2885–2891
  30. Linington C, Morgan BP, Scolding NJ, Wilkins P, Piddlesden S, Compston DA. The role of complement in the pathogenesis of experimental allergic encephalomyelitis. Brain. 1989;112:895–911
  31. Linker RA, Lühder F, Kallen KJ, Lee DH, Engelhardt B, Rose-John S, et al. IL-6 transsignalling modulates the early effector phase of EAE and targets the blood-brain barrier. J. Neuroimmunol. 2008;205:64–72
  32. Liu J, Miwa T, Hilliard B, Chen Y, Lambris JD, Wells AD, et al. The complement inhibitory protein DAF (CD55) suppresses T cell immunity in vivo. J. Exp. Med. 2005;201:567–577
  33. Lucchinetti C, Brück W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann. Neurol. 2000;47:707–717
  34. Lumsden CE. The immunogenesis of the multiple sclerosis plaque. Brain Res. 1971;28:365–390
  35. Maimone D, Gregory S, Arnason BG, Reder AT. Cytokine levels in the cerebrospinal fluid and serum of patients with multiple sclerosis. J. Neuroimmunol. 1991;32:67–74
  36. Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet. 1999;354:1932–1939
  37. Malmeström C, Andersson BA, Haghighi S, Lycke J. IL-6 and CCL2 levels in CSF are associated with the clinical course of MS: implications for their possible immunopathogenic roles. J. Neuroimmunol. 2006;175:176–182
  38. Marta M, Andersson A, Isaksson M, Kämpe O, Lobell A. Unexpected regulatory roles of TLR4 and TLR9 in experimental autoimmune encephalomyelitis. Eur. J. Immunol. 2008;38:565–575
  39. Matsuki T, Nakae S, Sudo K, Horai R, Iwakura Y. Abnormal T cell activation caused by the imbalance of the IL-1/IL-1R antagonist system is responsible for the development of experimental autoimmune encephalomyelitis. Int. Immunol. 2006;18:399–407
  40. McCoy MK, Tansey MG. TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J. Neuroinflammation. 2008;5:45
  41. McLaughlin KA, Wucherpfennig KW. B cells and autoantibodies in the pathogenesis of multiple sclerosis and related inflammatory demyelinating diseases. Adv. Immunol. 2008;98:121–149
  42. Mead RJ, Singhrao SK, Neal JW, Lassmann H, Morgan BP. The membrane attack complex of complement causes severe demyelination associated with acute axonal injury. J. Immunol. 2002;168:458–465
  43. Mendel I, Katz A, Kozak N, Ben-Nun A, Revel M. Interleukin-6 functions in autoimmune encephalomyelitis: a study in gene-targeted mice. Eur. J. Immunol. 1998;28:1727–1737
  44. Michalopoulou M, Nikolaou C, Tavernarakis A, Alexandri NM, Rentzos M, Chatzipanagiotou S, et al. Soluble interleukin-6 receptor (sIL-6R) in cerebrospinal fluid of patients with inflammatory and non inflammatory neurological diseases. Immunol. Lett. 2004;94:183–189
  45. Mollnes TE, Vandvik B, Lea T, Vartdal F. Intrathecal complement activation in neurological diseases evaluated by analysis of the terminal complement complex. J. Neurol. Sci. 1987;78:17–28
  46. Nataf S, Carroll SL, Wetsel RA, Szalai AJ, Barnum SR. Attenuation of experimental autoimmune demyelination in complement-deficient mice. J. Immunol. 2000;165:5867–5873
  47. Navikas V, Matusevicius D, Söderström M, Fredrikson S, Kivisäkk P, Ljungdahl A, et al. Increased interleukin-6 mRNA expression in blood and cerebrospinal fluid mononuclear cells in multiple sclerosis. J. Neuroimmunol. 1996;64:63–69
  48. Okuda Y, Sakoda S, Fujimura H, Saeki Y, Kishimoto T, Yanagihara T. IL-6 plays a crucial role in the induction phase of myelin oligodendrocyte glucoprotein 35–55 induced experimental autoimmune encephalomyelitis. J. Neuroimmunol. 1999;101:188–196
  49. O'Neill LA. ‘Fine tuning’ TLR signaling. Nat. Immunol. 2008;9:459–461
  50. Padberg F, Feneberg W, Schmidt S, Schwarz MJ, Körschenhausen D, Greenberg BD, et al. CSF and serum levels of soluble interleukin-6 receptors (sIL-6R and sgp130), but not of interleukin-6 are altered in multiple sclerosis. J. Neuroimmunol. 1999;99:218–223
  51. Padberg F, Haase CG, Feneberg W, Schwarz MJ, Hampel H. No association between anti-myelin oligodendrocyte glycoprotein antibodies and serum/cerebrospinal fluid levels of the soluble interleukin-6 receptor complex in multiple sclerosis. Neurosci. Lett. 2001;305:13–16
  52. Paty DW, Li DK. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group. Neurology. 1993;43:662–667
  53. Perez L, Alvarez-Cermeño JC, Rodriguez C, Roldán E, Brieva JA. B cells capable of spontaneous IgG secretion in cerebrospinal fluid from patients with multiple sclerosis: dependency on local IL-6 production. Clin. Exp. Immunol. 1995;101:449–452
  54. Piddlesden S, Lassmann H, Laffafian I, Morgan BP, Linington C. Antibody-mediated demyelination in experimental allergic encephalomyelitis is independent of complement membrane attack complex formation. Clin. Exp. Immunol. 1991;83:245–250
  55. Piddlesden SJ, Storch MK, Hibbs M, Freeman AM, Lassmann H, Morgan BP. Soluble recombinant complement receptor 1 inhibits inflammation and demyelination in antibody-mediated demyelinating experimental allergic encephalomyelitis. J. Immunol. 1994;152:5477–5484
  56. Prinz M, Garbe F, Schmidt H, Mildner A, Gutcher I, Wolter K, et al. Innate immunity mediated by TLR9 modulates pathogenicity in an animal model of multiple sclerosis. J. Clin. Invest. 2006;116(2):456–464
  57. Quintana A, Müller M, Frausto RF, Ramos R, Getts DR, Sanz E, et al. Site-specific production of IL-6 in the central nervous system retargets and enhances the inflammatory response in experimental autoimmune encephalomyelitis. J. Immunol. 2009;183:2079–2088
  58. Radvanyi LG, Banerjee A, Weir M, Messner H. Low levels of interferon-alpha induce CD86 (B7.2) expression and accelerates dendritic cell maturation from human peripheral blood mononuclear cells. Scand. J. Immunol. 1999;50:499–509
  59. Reiman R, Gerard C, Campbell IL, Barnum SR. Disruption of the C5a receptor gene fails to protect against experimental allergic encephalomyelitis. Eur. J. Immunol. 2002;32:1157–1163
  60. Ruddle NH, Bergman CM, McGrath KM, Lingenheld EG, Grunnet ML, Padula SJ, et al. An antibody to lymphotoxin and tumor necrosis factor prevents transfer of experimental allergic encephalomyelitis. J. Exp. Med. 1990;172:1193–1200
  61. Rus H, Cudrici C, David S, Niculescu F. The complement system in central nervous system diseases. Autoimmunity. 2006;39:395–402
  62. Rus H, Cudrici C, Niculescu F, Shin ML. Complement activation in autoimmune demyelination: dual role in neuroinflammation and neuroprotection. J. Neuroimmunol. 2006;180:9–16
  63. Russo R, Siviglia E, Gliozzi M, Amantea D, Paoletti A, Berliocchi L, et al. Evidence implicating matrix metalloproteinases in the mechanism underlying accumulation of IL-1beta and neuronal apoptosis in the neocortex of HIV/gp120-exposed rats. Int. Rev. Neurobiol. 2007;82:407–421
  64. Samoilova EB, Horton JL, Hilliard B, Liu TS, Chen Y. IL-6-deficient mice are resistant to experimental autoimmune encephalomyelitis: roles of IL-6 in the activation and differentiation of autoreactive T cells. J. Immunol. 1998;161:6480–6486
  65. Sanders ME, Koski CL, Robbins D, Shin ML, Frank MM, Joiner KA. Activated terminal complement in cerebrospinal fluid in Guillain–Barré syndrome and multiple sclerosis. J. Immunol. 1986;136:4456–4459
  66. Scolding NJ, Morgan BP, Compston DAJ. The expression of complement regulatory proteins by adult human oligodendrocytes. J. Neuroimmunol. 1998;84:69–75
  67. Sellebjerg F, Jaliashvili I, Christiansen M, Garred P. Intrathecal activation of the complement system and disability in multiple sclerosis. J. Neurol. Sci. 1998;157:168–174
  68. Selmaj K, Raine CS, Cross AH. Anti-tumor necrosis factor therapy abrogates autoimmune demyelination. Ann. Neurol. 1991;30:694–700
  69. Shrikant P, Chung IY, Ballestas ME, Benveniste EN. Regulation of intercellular adhesion molecule-1 gene expression by tumor necrosis factor-alpha, interleukin-1 beta, and interferon-gamma in astrocytes. J. Neuroimmunol. 1994;51:209–220
  70. Silverman BA, Carney DF, Johnston CA, Vanguri P, Shin ML. Isolation of membrane attack complex of complement from myelin membranes treated with serum complement. J. Neurochem. 1984;42:1024–1029
  71. Simi A, Lerouet D, Pinteaux E, Brough D. Mechanisms of regulation for interleukin-1beta in neurodegenerative disease. Neuropharmacology. 2007;52:1563–1569
  72. Sjöberg AP, Trouw LA, Blom AM. Complement activation and inhibition: a delicate balance. Trends Immunol. 2009;30:83–90
  73. Smith SS, Ludwig M, Wohler JE, Bullard DC, Szalai AJ, Barnum SR. Deletion of both ICAM-1 and C3 enhances severity of experimental autoimmune encephalomyelitis compared to C3-deficient mice. Neurosci. Lett. 2008;442:158–160
  74. Sospedra M, Martin R. Immunology of multiple sclerosis. Annu. Rev. Immunol. 2005;23:683–747
  75. Szalai AJ, Hu X, Adams JE, Barnum SR. Complement in experimental autoimmune encephalomyelitis revisited: C3 is required for development of maximal disease. Mol. Immunol. 2007;44:3132–3136
  76. Takeda K, Akira S. Toll-like receptors in innate immunity. Int. Immunol. 2005;17:1–14
  77. Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu. Rev. Immunol. 2003;21:335–376
  78. Tegla CA, Cudrici C, Rus V, Ito T, Vlaicu S, Singh A, et al. Neuroprotective effects of the complement terminal pathway during demyelination: implications for oligodendrocyte survival. J. Neuroimmunol. 2009;213:3–11
  79. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurology. 1999;53(3):457–465
  80. Thomas CW, Weinshenker BG, Sandborn WJ. Demyelination during anti-tumor necrosis factor alpha therapy with infliximab for Crohn's disease. Inflamm. Bowel Dis. 2004;10:28–31
  81. Touil T, Fitzgerald D, Zhang GX, Rostami A, Gran B. Cutting edge: TLR3 stimulation suppresses experimental autoimmune encephalomyelitis by inducing endogenous IFN-beta. J. Immunol. 2006;177:7505–7509
  82. Tran GT, Hodgkinson SJ, Carter N, Killingsworth M, Spicer ST, Hall BM. Attenuation of experimental allergic encephalomyelitis in complement component 6-deficient rats is associated with reduced complement C9 deposition, P-selectin expression, and cellular infiltrate in spinal cords. J. Immunol. 2002;168:4293–4300
  83. Urich E, Gutcher I, Prinz M, Becher B. Autoantibody-mediated demyelination depends on complement activation but not activatory Fc-receptors. Proc. Natl Acad. Sci. USA. 2006;103:18697–18702
  84. Vanguri P, Shin ML. Activation of complement by myelin: identification of C1-binding proteins of human myelin from central nervous tissue. J. Neurochem. 1986;46:1535–1541
  85. Vanguri P, Koski CL, Silverman B, Shin ML. Complement activation by isolated myelin: activation of the classical pathway in the absence of myelin-specific antibodies. Proc. Natl Acad. Sci. USA. 1982;79:3290–3294
  86. Walport MJ. Complement. First of two parts. N Engl J. Med. 2001;344:1058–1066
  87. Weerth SH, Rus H, Shin ML, Raine CS. Complement C5 in experimental autoimmune encephalomyelitis (EAE) facilitates remyelination and prevents gliosis. Am. J. Pathol. 2003;163:1069–1080
  88. Weinberg AD, Montler R. Modulation of TNF receptor family members to inhibit autoimmune disease. Curr. Drug Targets Inflamm. Allergy. 2005;4:195–203
  89. Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J. Med. 1999;340:253–259
  90. Wing MG, Zajicek J, Seilly DJ, Compston DA, Lachmann PJ. Oligodendrocytes lack glycolipid anchored proteins which protect them against complement lysis. Restoration of resistance to lysis by incorporation of CD59. Immunology. 1992;76:140–145
  91. Wren DR, Noble M. Oligodendrocytes and oligodendrocyte/type-2 astrocyte progenitor cells of adult rats are specifically susceptible to the lytic effects of complement in absence of antibody. Proc. Natl Acad. Sci. USA. 1989;86:9025–9029

PII: S0165-5728(10)00198-0

doi: 10.1016/j.jneuroim.2010.05.014

Journal of Neuroimmunology
Volume 225, Issue 1 , Pages 5-12 , 25 August 2010

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