• X. Montalban
Part of the Topics in Neuroscience book series (TOPNEURO)


Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Three major clinical courses have been identified in MS: relapsing-remitting MS (RRMS), characterized by exacerbations with subsequent total or partial remission of symptoms; secondary progressive MS (SPMS), in which progression follows an initial RRMS phase; and primary progressive MS (PPMS), a progressive form without relapses or remissions [1]. Although by definition PPMS is clinically different from the relapsing forms, in the past, the SPMS and PPMS forms were grouped together as “chronic progressive” (CPMS) MS. However, in the first magnetic resonance imaging (MRI) study in which PPMS was specifically investigated, it was shown that patients with PPMS, despite marked disability, had fewer and smaller gadolinium-enhancing cerebral MRI lesions than patients with SPMS [2, 3]. Furthermore, a more recent study of a large cohort of PPMS patients from six European centres has shown clear differences in MRI appearances between PPMS and SPMS [4]. Few papers have addressed the pathological differences between PPMS and the relapsing forms; inflammation, though less marked, is also obviously present in PPMS lesions [5]. Although a small number of patients with PPMS could have a distinct pathological pattern, the samples studied are small, and some cases of PPMS are indistinguishable from RR forms of MS [6]. While MS is generally associated with the haplotype A3-B7-DR2 (15)-DQw6, this occurs predominantly with the RR form of the disease.


Multiple Sclerosis Experimental Autoimmune Encephalomyelitis Experimental Allergic Encephalomyelitis Multiple Sclerosis Lesion Progressive Multiple Sclerosis 
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  1. 1.
    Lublin FD, Reingold SC (1996) Defining the clinical course of multiple sclerosis: results of an international survey. Neurology 46:907–910PubMedGoogle Scholar
  2. 2.
    Thompson AJ, Miller DH, MacManus DG, McDonald WI (1990) Patterns of disease activity in multiple sclerosis: a clinical and magnetic resonance imaging study. Br Med J 300:631–634CrossRefGoogle Scholar
  3. 3.
    Thompson AJ, Polman CH, Miller DH et al (1997) Primary progressive multiple sclerosis. Brain 120:1085–1096PubMedCrossRefGoogle Scholar
  4. 4.
    Stevenson VL, Miller DH, Rovaris M et al (1999) Primary progressive and transitional progressive multiple sclerosis: a clinical and MRI cross sectional study. Neurology 52:839–845PubMedGoogle Scholar
  5. 5.
    Revesz T, Kidd D, Thompson AJ et al (1994) A comparison of the pathology of primary and secondary progressive multiple sclerosis. Brain 117:759–765PubMedCrossRefGoogle Scholar
  6. 6.
    Lucchinetti C, Bruck W, Parisi J et al (2000). Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 47:707–717PubMedCrossRefGoogle Scholar
  7. 7.
    Pirttila T, Nurmikko T (1995) CSF oligoclonal bands, MRI, and the diagnosis of multiple sclerosis. Acta Neurol Scand 92:468–71PubMedCrossRefGoogle Scholar
  8. 8.
    Acarin N, Rio J, Fernandez AL et al (1996) Different antiganglioside antibody pattern between relapsing-remitting and progressive MS. Acta Neurol Scand 93:99–103PubMedCrossRefGoogle Scholar
  9. 9.
    Sadatipour BT, Greer JM, Pender MP (1998) Increased circulating antiganglioside antibodies in primary and secondary progressive multiple sclerosis. Ann Neurol 44:980–983PubMedCrossRefGoogle Scholar
  10. 10.
    Giovannoni G, Lai M, Thorpe J et al (1997) Longitudinal study of soluble adhesion molecules in multiple sclerosis: correlation with gadolinium enhanced magnetic resonance imaging. Neurology 48:1557–1565PubMedGoogle Scholar
  11. 11.
    Giovannoni G, Thorpe JW, Kidd D et al (1996) Soluble E-selectin in multiple sclerosis: raised concentrations in patients with primary progressive disease. J Neurol Neurosurg Psychiatry 60:20–26PubMedCrossRefGoogle Scholar
  12. 12.
    McDonnell GV, McMillan SA, Douglas JP et al (1999) Serum soluble adhesion molecules in multiple sclerosis: raised sVCAM-1, sICAM-1 and sE-selectin in primary progressive disease. J Neurol 246:87–92PubMedCrossRefGoogle Scholar
  13. 13.
    Durán I, Martinez-Caceres EM, Rio J et al (1999) Immunological profile of patients with primary progressive multiple sclerosis. Expression of adhesion molecules. Brain 122:2297–2307PubMedCrossRefGoogle Scholar
  14. 14.
    Durán I, Martínez-Cáceres E, Barberà N et al (1998) Immunological profile of primary progressive multiple sclerosis. Mult Scler 4:348CrossRefGoogle Scholar
  15. 15.
    Killestein J, Den Drijver BF, Van der Graaff WL et al (2001) Intracellular cytokine profile in T-cells subsets of multiple sclerosis patients: different fetures in primary progressive disease. Mult Scler 7:145–150PubMedGoogle Scholar
  16. 16.
    Durán I, Martinez-Caceres EM, Brieva L et al (2001) Similar pro- and anti-inflammatory cytokine production in the different clinical forms of multiple sclerosis. Mult Scler 7:151–156PubMedGoogle Scholar
  17. 17.
    Beck J, Rondot P, Catinot L et al (1988) Increased production of interferon gamma and tumor necrosis factor precedes clinical manifestations in multiple sclerosis: do cytokines trigger off exacerbations? Acta Neurol Scand 78:318–323PubMedCrossRefGoogle Scholar
  18. 18.
    Chofflon M, Juillard C, Juillard P et al (1992) Tumor necrosis factor a production as a possible predictor of relapse in patients with multiple sclerosis. Eur Cytokine Netw 3:523–531PubMedGoogle Scholar
  19. 19.
    Issazadeh S, Ljungdahl A, Hojeberg B et al (1995) Cytokine production in the central nervous system of Lewis rats with experimental autoimmune encephalomyelitis: dynamics of mRNA expression for interleukin-10, interleukin-12, cytolysin, tumor necrosis factor alpha and tumor necrosis factor beta. J Neuroimmunol 61:205–212PubMedCrossRefGoogle Scholar
  20. 20.
    Issazadeh S, Lorentzen JC, Mustafa MI et al (1996) Cytokines in relapsing experimental autoimmune encephalomyelitis in DA rats: persistent mRNA expression of proinflammatory cytokines and absent expression of interleukin-10 and transforming growth factor-beta. J Neuroimmunol 69:103–115PubMedCrossRefGoogle Scholar
  21. 21.
    Panitch HS, Hirsch RL, Haley AS, Johnson KP (1987) Exacerbations of multiple sclerosis in patients treated with gamma-interferon. Lancet 1:893–896PubMedCrossRefGoogle Scholar
  22. 22.
    Trinchieri G (1995) Interleukin 12: a proinflammatory cytokine with immunoregula-tory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol 13:251–276PubMedCrossRefGoogle Scholar
  23. 23.
    Correale J, McMillan M, Li S et al (1997) Antigen presentation by autoreactive prote-olipid protein peptide-specific T cell clones from chronic progressive multiple sclerosis patients: roles of co-stimulatory B7 molecules and IL-12. J Neuroimmunol 72:27–43PubMedCrossRefGoogle Scholar
  24. 24.
    Comabella M, Balashov K, Issazadeh S et al (1998) Elevated interleukin-12 in progressive multiple sclerosis correlates with disease activity and is normalized by pulse cyclophosphamide therapy. J Clin Invest 102:671–678PubMedCrossRefGoogle Scholar
  25. 25.
    Houssiau FA, Coulie PG, Van Snick J (1989) Distinct roles of IL-1 and IL-6 human T cell activation. J Immunol 143:2520–2524PubMedGoogle Scholar
  26. 26.
    Martmez-Cdceres EM, Rio J, Barrau M et al (1998) Amelioration of flu-like symptoms at the onset of IFNß-lb therapy in multiple sclerosis by low oral steroid use is related to a decrease in IL-6 induction. Ann Neurol 44:682–685CrossRefGoogle Scholar
  27. 27.
    Cash E, Minty A, Ferrara P et al (1994) Macrophage-inactivation IL-13 suppresses experimental autoimmune encephalomyelitis in rats. J Immunol 153:4258–4267PubMedGoogle Scholar
  28. 28.
    Racke MK, Burnett D, Pak SH et al (1995) Retinoid treatment of experimental allergic encephalomyelitis. IL-4 production correlates with improved disease course. J Immunol 154:450–458PubMedGoogle Scholar
  29. 29.
    Racke MK, Sriram S, Carlino J et al (1993) Long-term treatment of chronic relapsing experimental allergic encephalomyelitis by transforming growth factor-beta2. J Neuroimmunol 46:175–183PubMedCrossRefGoogle Scholar
  30. 30.
    Racke MK, Dhib-Jalbut S, Cannella B et al (1991) Prevention and treatment of chronic relapsing experimental allergic encephalomyelitis by transforming growth factor-betal. J Immunol 146:3012–3017PubMedGoogle Scholar
  31. 31.
    Rott O, Fleischer B, Cash E (1994) Interleukin-10 prevents experimental allergic encephalomyelitis in rats. Eur J Immunol 24:1434–1440PubMedCrossRefGoogle Scholar
  32. 32.
    Rovaris M, Barnes D, Woodrofe N et al (1996) Patterns of disease activity in MS patients: a study with quantitative gadolinium-enhanced brain MRI and cytokine measurement in different clinical subgroups. J Neurol 247:536–542CrossRefGoogle Scholar
  33. 33.
    Springer TA (1994) Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76:301–314PubMedCrossRefGoogle Scholar
  34. 34.
    Kuchroo VK, Martin CA, Greer JM et al (1993) Cytokines and adhesion molecules contribute to the ability of myelin proteolipid protein-specific T cell clones to mediate experimental allergic encephalomyelitis. J Immunol 151:4371–4382PubMedGoogle Scholar
  35. 35.
    Anderson JA, Lentsch AB, Hadjiminas DJ et al (1996) The role of cytokines, adhesion molecules, and chemokines in interleukin-2-induced lymphocytic infiltration in C57BL/6 Mice. J Clin Invest 97:1952–1959PubMedCrossRefGoogle Scholar
  36. 36.
    Previtali SC, Archelos JJ, Hartung HP (1997) Modulation of the expression of integrins on glial cells during experimental autoimmune encephalomyelitis. A central role for TNF-alpha. Am J Pathol 151:1425–1435PubMedGoogle Scholar
  37. 37.
    Yednock TA, Cannon C, Fritz LC et al (1992) Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature 356:63–66PubMedCrossRefGoogle Scholar
  38. 38.
    Dopp JM, Breneman SM, Olschowka JA (1994) Expression of ICAM-1, VCAM-1, L-selectin, and leukosialin in the mouse central nervous system during the induction and remission stages of experimental allergic encephalomyelitis. J Neuroimmunol 54:129–144PubMedCrossRefGoogle Scholar
  39. 39.
    Steffen BJ, Butcher EC, Engelhardt B (1994) Evidence for involvement of ICAM-1 andGoogle Scholar
  40. VCAM-1 in lymphocyte interaction with endothelium in experimental autoimmune encephalomyelitis in the central nervous system in the SJL/J mouse. Am J Pathol 145:189–201Google Scholar
  41. 40.
    Gordon EJ, Myers KJ, Dougherty JP et al (1995) Both anti-CD11a (LFA-1) and anti-CD11b (MAC-1) therapy delay the onset and diminish the severity of experimental autoimmune encephalomyelitis. J Neuroimmunol 62:153–160PubMedCrossRefGoogle Scholar
  42. 41.
    Kobayashi Y, Kawai K, Honda H et al (1995) Antibodies against leukocyte function-associated antigen-1 and against intercellular adhesion molecule-1 together suppress the progression of experimental allergic encephalomyelitis. Cell Immunol 164:295–305PubMedCrossRefGoogle Scholar
  43. 42.
    Soilu-Hanninen M, Roytta M, Salmi A, Salonen R (1997) Therapy with antibody against leukocyte integrin VLA-4 (CD49d) is effective and safe in virus-facilitated experimental allergic encephalomyelitis. J Neuroimmunol 72:95–105PubMedCrossRefGoogle Scholar
  44. 43.
    Hohlfeld R (1997) Biotechnological agents for the immunotherapy of multiple sclerosis. Principle, problems and perspectives. Brain 120:865–916PubMedCrossRefGoogle Scholar
  45. 44.
    Porrini AM, Gambi D, Malatesta G (1992) Memory and naive CD4+ lymphocytes in multiple sclerosis. J Neurol 239:437–440PubMedCrossRefGoogle Scholar
  46. 45.
    Svenningsson A, Hansson GK, Andersen O et al (1993) Adhesion molecule expression on cerebrospinal fluid T lymphocytes: evidence for common recruitment mechanisms in multiple sclerosis, aseptic meningitis, and normal controls. Ann Neurol 34:155–161PubMedCrossRefGoogle Scholar
  47. 46.
    Salmaggi A, Dufour A, Eoli M et al (1996) Low serum interleukin-10 levels in multiple sclerosis: further evidence for decreased systemic immunosupression? J Neurol 243:13–17PubMedCrossRefGoogle Scholar
  48. 47.
    Stüber A, Martin R, Stone LA et al (1996) Expression pattern of activation and adhesion molecules on peripheral blood CD4+ T-lymphocytes in relapsing-remitting multiple sclerosis patients: a serial analysis. J Neuroimmunol 66:147–151PubMedCrossRefGoogle Scholar
  49. 48.
    Lou J, Chofflon M, Juillard C et al (1997) Brain microvascular endothelial cells and leukocytes derived from patients with multiple sclerosis exhibit increased adhesion capacity. NeuroReport 8:629–633PubMedCrossRefGoogle Scholar
  50. 49.
    Dore-Duffy P, Newman W, Balabanov R et al (1995) Circulating, soluble adhesion proteins in cerebrospinal fluid and serum of patients with multiple sclerosis: correlation with clinical activity. Ann Neurol 37:55–62PubMedCrossRefGoogle Scholar
  51. 50.
    Hartung HP, Reiners K, Archelos JJ et al (1995) Circulating adhesion molecules and tumor necrosis factor receptor in multiple sclerosis: correlation with magnetic resonance imaging. Ann Neurol 38:186–193PubMedCrossRefGoogle Scholar
  52. 51.
    Martin S, Rieckmann P, Melchers I et al (1995) Circulating forms of ICAM-3 (cICAM-3). Elevated levels in autoimmune diseases and lack of association with cICAM-1. J Immunol 154:1951–1955PubMedGoogle Scholar
  53. 52.
    Matsuda M, Tsukada N, Miyagi K, Yanagisawa N (1995) Increased levels of soluble vascular cell adhesion molecule-1 (VCAM-1) in the cerebrospinal fluid and sera of patients with multiple sclerosis and human T lymphotropic virus type-1 associated myelopathy. J Neuroimmunol 59:35–40PubMedCrossRefGoogle Scholar
  54. 53.
    Franciotta D, Piccolo G, Zardini E et al (1997) Soluble CD8 and ICAM-1 in serum and CSF of MS patients treated with 6-methylprednisolone. Acta Neurol Scand 95:275–279PubMedCrossRefGoogle Scholar
  55. 54.
    McDonnell GV, McMillan SA, Douglas JP et al (1998) Raised CSF levels of soluble adhesion molecules across the clinical spectrum of multiple sclerosis. J Neuroimmunol 85:186–192PubMedCrossRefGoogle Scholar
  56. 55.
    Baggiolini M (1998) Chemokines and leukocyte traffic. Nature 392:565–568PubMedCrossRefGoogle Scholar
  57. 56.
    McManus C, Berman JW, Brett FM et al (1998) MCP-1, MCP-2 and MCP-3 expression in multiple sclerosis lesions: an immunohistochemical and in situ hybridization study. J Neuroimmunol 86:20–29PubMedCrossRefGoogle Scholar
  58. 57.
    Simpson JE, Newcombe J, Cuzner ML, Woodroofe MN (1998) Expression of monocyte chemoattractant protein-1 and other b-chemokines by resident glia and inflammatory cells in multiple sclerosis lesions. J Neuroimmunol 84:238–244PubMedCrossRefGoogle Scholar
  59. 58.
    Simpson JE, Newcombe J, Cuzner ML, Woodroofe MN (2000) Expression of the inter-Google Scholar
  60. feron-gamma-inducible chemokines IP-10 and Mig and their receptor, CXCR3, in multiple sclerosis lesions. Neuropathol Appl Neurobiol 26:133–142Google Scholar
  61. 59.
    Sorensen TL, Tani M, Jensen J et al (1999) Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. J Clin Invest 103:807–815PubMedCrossRefGoogle Scholar
  62. 60.
    Miyagishi R, Kikuchi S, Fukazawa T, Tashiro K (1995) Macrophage inflammatory protein-1 alpha in the cerebrospinal fluid of patients with multiple sclerosis and other inflammatory neurological diseases. J Neurol Sci 129:223–227PubMedCrossRefGoogle Scholar
  63. 61.
    Strunk T, Bubel S, Mascher B et al (2000) Increased numbers of CCR5+ interferon-gamma and tumor-necrosis factor-alpha secreting T lymphocytes in multiple sclerosis patients. Ann Neurol 47:269–273PubMedCrossRefGoogle Scholar
  64. 62.
    Balashov KE, Rottman JB, Weiner HL, Hancock WW (1999) CCR5(+) and CXCR3(+) T cells are increased in multiple sclerosis and their ligands MIP-1 alpha and IP-10 are expressed in demyelinating brain lesions. Proc Natl Acad Sci USA 96:6873–6878PubMedCrossRefGoogle Scholar

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© Springer-Verlag Italia, Milano 2002

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  • X. Montalban

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