Pathological Heterogeneity of Idiopathic Central Nervous System Inflammatory Demyelinating Disorders

  • C. Lucchinetti
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 318)

The last decade has seen a resurgence of interest in MS neuropathology.This resurgence was partly fueled by the development of new molecular and histochemical tools to examine the MS lesion microscopically, as well as technological advances in neuroimaging, which permit a dynamic assessment of lesion formation and disease progression. The heterogeneous pathology of MS in relation to stage of lesion activity, phase of disease, and clinical course is discussed. Pathological studies reveal that the immune factors associated with multiple different effector mechanisms contribute to the inflammation, demyelination, and tissue injury observed in MS lesions. While many agree that pathological heterogeneity exists in white matter demyelinated lesions, it is uncertain whether these observations are patient-dependent and reflect pathogenic heterogeneity or, alternatively, are stage-dependent with multiple mechanisms occurring sequentially within a given patient. Evidence supporting both concepts is presented. Remyelination is present in MS lesions; however, the factors contributing to the extent of repair and oligodendrocyte survival differ depending on the disease phase. A variable and patient-dependent extent of remyelination is observed in chronic MS cases and will likely need to be considered when designing future clinical trials aimed to promote CNS repair. MS is one member of a spectrum of CNS idiopathic inflammatory demyelinating disorders that share the basic pathological hallmark of CNS inflammatory demyelination. Advances based on recent systematic clinicopathologic-serologic correlative approaches have led to novel insights with respect to the classification of these disorders, as well as a better understanding of the underlying pathogenic mechanisms.


Multiple Sclerosis Experimental Autoimmune Encephalomyelitis Multiple Sclerosis Lesion Myelin Oligodendrocyte Glycoprotein Neuromyelitis Optica 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Aboul-Enein F, Lassmann H (2005) Mitochondrial damage and histiotoxic hypoxia: a pathway of tissue injury in inflammatory brain disease. Acta Neuropathol 109:49-55PubMedGoogle Scholar
  2. 2.
    Aboul-Enein F, Rauschka H, Kornek B, Stadelmann C, Stefferl A, Bruck W, Lucchinetti C, Schmidbauer M, Jellinger K et al (2003) Preferential loss of myelin-associated glycoprotein reflects hypoxia-like white matter damage in stroke and inflammatory brain diseases. J Neuropathol Exp Neurol 62:25-33PubMedGoogle Scholar
  3. 3.
    Amiry-Moghaddam M, Otsuka T, Hurn PD, Traystman RJ, Haug FM, Froehner SC, Adams ME, Neely JD, Agre P, Ottersen OP, Bhardwaj A (2003) An alpha-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain. Proc Natl Acad Sci U St A 100:2106-2111Google Scholar
  4. 4.
    Babbe H, Roers A, Waisman A, Lassmann H, Goebels N, Hohlfeld R, Friese M, Schroder R, Deckert M, Schmidt S, Ravid R, Rajewsky K (2000) Clonal expansion 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 192:393-404PubMedGoogle Scholar
  5. 5.
    Baig S, Olsson O, Olsson T, Love A, Jeansson S, Link H (1989) Cells producing antibody to measles and herpes simplex virus in cerebrospinal fluid and blood of patients with multiple sclerosis and controls. Clin Exp Immunol 78:390-395PubMedGoogle Scholar
  6. 6.
    Baker AB (1968) Problems in the classification of multiple sclerosis. In: Alter M, Kurtzke JF (eds) The epidemiology of multiple sclerosis. Charles C. Thomas, Springfield, IL, pp 14-25.Google Scholar
  7. 7.
    Baranzini SE, Jeong MC, Butunoi C et al (1999) B cell repertoire diversity and clonal expansion in multiple sclerosis brain lesions. J Immunol 163:5133-5144PubMedGoogle Scholar
  8. 8.
    Barkhof F, Bruck W, De Groot C, Bergers E, Hulshof S, Geurts J, Polman CH, van der Valk P (2003) Remyelinated lesions in multiple sclerosis: magnetic resonance image appearance. Arch. Neurol. 60:1073-1081PubMedGoogle Scholar
  9. 9.
    Barnett MH, Prineas JW (2004) Pathological heterogeneity in multiple sclerosis: a reflection of lesion stage? Ann Neurol 56:309Google Scholar
  10. 10.
    Barnett MH, Prineas JW (2004) Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Annals of Neurology 55:458-468PubMedGoogle Scholar
  11. 11.
    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 349:139-145PubMedGoogle Scholar
  12. 12.
    Bieber AJ, Ure DR, Rodriguez M (2005) Genetically dominant spinal cord repair in a murine model of chronic progressive multiple sclerosis. J Neuropathol Exp Neurol 64:46-57PubMedGoogle Scholar
  13. 13.
    Bitsch A, Bruhn H, Vougioukas V, Stringaris A, Lassmann H, Frahm J, Bruck W (1999) Inflammatory CNS demyelination: histopathologic correlation with in vivo quantitative proton MR spectroscopy. AJNR Am J Neuroradiol 20:1619-1627PubMedGoogle Scholar
  14. 14.
    Bo L, Dawson T, Wesselingh S et al (1994) Induction of nitric oxide synthase in demyelinating regions of multiple sclerosis brains. Ann Neurol 36:778-786PubMedGoogle Scholar
  15. 15.
    Booss J, Esiri MM, Tourtellotte WW, Mason DY (1983) Immunohistological analysis of T lymphocyte subsets in the central nervous system in chronic progressive multiple sclerosis. J Neurol Sci 62:219-232PubMedGoogle Scholar
  16. 16.
    Boven LA, Van Meurs M, Van Zwam M, Wierenga-Wolf A, Hintzen RQ, Boot RG et al (2006) Myelin-laden macrophages are anti-inflammatory consistent with foam cells in multiple sclerosis. Brain 129:517-526PubMedGoogle Scholar
  17. 17.
    Brown GC, Borutaite V (2002) Nitric oxide inhibition of mitochondrial respiration and its role in cell death. Free Radic Biol Med 33:1440-1450PubMedGoogle Scholar
  18. 18.
    Bruck W, Porada P, Poser S, Rieckmann P, Hanefeld F, Kretchmar HA, et al (1995) Monocyte-macrophage differentiation in early multiple sclerosis lesions. Ann Neurol 38:788-796PubMedGoogle Scholar
  19. 19.
    Charcot JM (1868) Histologie de la sclérose en plaques. Gaz Hop Civils Militaires 140, 141, 143:554-555, 557-558, 566Google Scholar
  20. 20.
    Chen C, Ro L, Chang C, Ho Y, Lu C (1996) Serial MRI studies in pathologically verified Balo’s concentric sclerosis. J Comput Assist Tomogr 20:732-735PubMedGoogle Scholar
  21. 21.
    Christians ES, Yan LJ, Benjamin IJ (202) Heat shock factor 1 and heat shock proteins: critical partners in protection against acute cell injury. Crit Care Med 30:S43-S50Google Scholar
  22. 22.
    Corcione A, Aloisi F, Serafini B, Capello E, Mancardi GL, Pistoia V, Uccelli A (2005) B-cell differentiation in the CNS of patients with multiple sclerosis. Autoimmun Rev 4:594-654Google Scholar
  23. 23.
    Corcione A, Casazza S, Ferretti E, Giunti G, Zappia E, Pistorio A, Gambini C, Mancardi GL, Uccelli A, Pistoia V (2004) Recapitulation of B cell differentiation in the central nervous system of patients with multiple sclerosis. Proc Natl Acad Sci USA 10:11064-11069Google Scholar
  24. 24.
    Courville C (1970) Concentric sclerosis. In: Bruyn PV (ed) Handbook of Clinical Neurology. Elsevier, Amsterdam, pp 437-451.Google Scholar
  25. 25.
    Cross A, Trotter J, Lyons J (2001) B cells and antibodies in CNS demyelinating disease. J Neuroimmunol 112:1-14PubMedGoogle Scholar
  26. 26.
    De Groot C, Ruuls S, Theeuwes J, Dijkstra C, van der Valk P (1997) Immunocytochemical characterization of the expression of inducible and constitutive isoforms of nitric oxide synthase in demyelinating multiple sclerosis lesions. J Neuropathol Exp Neurol 56:10-20PubMedGoogle Scholar
  27. 27.
    Esiri MM (1977) Immunoglobulin-containing cells in multiple sclerosis plaques. Lancet 2:478PubMedGoogle Scholar
  28. 28.
    Forstermann U, Kleinert H (1995) Nitric oxide synthase: expression and expressional control of the three isoforms. Naunyn-Schmiedebergs Arch Pharmacol 352:351-364PubMedGoogle Scholar
  29. 29.
    Franklin RJ (2002) Why does remyelination fail in multiple sclerosis? Nat Rev Neurosci 3:705-714PubMedGoogle Scholar
  30. 30.
    Friese M, Fugger L (2005) Autoreactive CD8+ T cells in multiple sclerosis: a new target for therapy? Brain 128:1747-1763PubMedGoogle Scholar
  31. 31.
    Garbern J, Spence A, Alvord E (1986) Balo’s concentric demyelination diagnosed premortem. Neurology 36:1610-1614PubMedGoogle Scholar
  32. 32.
    Garthwaite G, Goodwin DA, Batchelor AM et al (2002) Nitric oxide toxicity in CNS white matter: an in vitro study using rat optic nerve. Neuroscience 109:145-155PubMedGoogle Scholar
  33. 33.
    Genain CP, Cannella B, Hauser SL, Raine CS (1999) Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nat Med 5:170-175PubMedGoogle Scholar
  34. 34.
    Geurts JJ, Wolswijk G, Bo L, van der Valk P, Polman CH, Troost D, Aronica E (2003) Altered expression patterns of group I and II metabotropic glutamate receptors in multiple sclerosis. Brain 126:1755-1766PubMedGoogle Scholar
  35. 35.
    Gharagozloo A, Poe L, Collins G (1994) Antemortem diagnosis of Balo concentric sclerosis: correlative MR imaging and pathologic features. Radiology 191:817-819PubMedGoogle Scholar
  36. 36.
    Giovannoni G, Heales S, Land J, Thompson E (1998) The potential role of nitric oxide in multiple sclerosis. Multiple Sclerosis 4:212-216PubMedGoogle Scholar
  37. 37.
    Goes vd A, Boorsma W, Hoekstra K, Montagne L, De Groot CJ, Dijkstra CD (2005) Determination of the sequential degradation of myelin proteins by macropahges. J Neuroimm 161:12-20Google Scholar
  38. 38.
    Hafler DA, Slavik JM, Anderson DE, O’Connor KC, De Jager P, Baecher-Allan C (2005) Multiple sclerosis. Immunol Rev 204:208-231PubMedGoogle Scholar
  39. 39.
    Hanemann C, Kleinschmidt A, Reifenberger G, Freud H, Seitz R (1993) Balo concentric sclerosis followed by MRI and positron emission tomography. Neuroradiology 35:578-580PubMedGoogle Scholar
  40. 40.
    Hart M, Earle K (1975) Haemorrhagic and perivenous encephalitis: a clinical-pathological review of 38 cases. J Neurol Neurosurg Psychiatry 38:585-591PubMedGoogle Scholar
  41. 41.
    Hendricks JJ, Teunissen CE, de Vries HE, Dijkstra CD (2005) Macrophages and neurodegeneration. Brain Res Reviews 48:185-195Google Scholar
  42. 42.
    Hill KE, Zollinger LV, Watt HE, Carlson NG, Rose JW (2004) Inducible nitric oxide synthase in chronic active multiple sclerosis plaques: distribution, cellular expression, and association with myelin damage. J Neuroimmunol 151:171-179PubMedGoogle Scholar
  43. 43.
    Hoftberger R, Aboul-Enein F, Brueck W, Lucchinetti CF, Rodriguez M, Schmidbauer M, Jellinger K et al (2004) Expression of major histocompatibility complex class I molecules on the different cell types in multiple sclerosis lesions. Brain Pathol 14:43-50PubMedGoogle Scholar
  44. 44.
    Huseby ES, Liggitt D, Brabb T, Schnabel B, Öhlén C, Goverman J (2001) A pathogenic role for myelin-specific CD8+ T cells in a model for multiple sclerosis. J Exp Med 194:669-676PubMedGoogle Scholar
  45. 45.
    Jung J, Bhat R, Preston G, Guggino W, Baraban J, Agre P (1994) Molecular characterization of an aquaporin cDNA from brain: candidate osmoreceptor and regulator of water balance. Proc Natl Acad Sci USA 91:13052-13056PubMedGoogle Scholar
  46. 46.
    Karaarslan E, Altintas A, Senol U, Yeni N, Dincer A, Bayindir C, KIaraagac N, Siva A (2001) Balo’s concentric sclerosis: clinical and radiologic features of five cases. AJNR Am J Neuroradiol 22:1362-1367PubMedGoogle Scholar
  47. 47.
    Keegan M, Konig F, McClelland R, Bruck W, Morales Y, Bitsch A, Panitch H, Lassmann H, Weinshenker B, Rodriguez M, Parisi J, Lucchinetti CF (2005) Relation between humoral pathological changes in multiple sclerosis and response to therapeutic plasma exchange. Lancet 366:579-582PubMedGoogle Scholar
  48. 48.
    Kerschensteiner M, Gallmeier E, Behrens L, Klinkert WEF, Kolbeck R, Hoppe E, OropezaWekerle RL, Bartke I, Stadelmann C, Lassmann H, Wekerle H, Hohlfeld R (1999) Activated human T cells, B cells and monocytes produce brain-derived neurotrophic factor (BDNF) in vitro and in brain lesions: a neuroprotective role for inflammation? J Exp Med 189:865-870PubMedGoogle Scholar
  49. 49.
    Kerschensteiner M, Stadelmann C, Dechang G, Wekerle H, Hohlfeld R (2003) Neurotrophic cross-talk between the nervous and immune systems: implications for neurological diseases. Ann Neurol 53:292-304PubMedGoogle Scholar
  50. 50.
    Korte J, Born E, Vos L, Breuer T, Wondergem J (1994) Balo concentric sclerosis: MR diagnosis. AJNR Am J Neuroradiol 15:1284-1285PubMedGoogle Scholar
  51. 51.
    Kuhle J, Pohl, Mehling M, Edan G, Freedman M, Hartung HP, Polman C, Miller D, 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 356:371-378PubMedGoogle Scholar
  52. 52.
    Kuroiwa Y (1982) Clinical and epidemiological aspects of multiple sclerosis in Japan. Jpn J Med 21:135-140PubMedGoogle Scholar
  53. 53.
    Lassmann H (1983) Comparative neuropathology of chronic experimental allergic encephalomyelitis and multiple sclerosis. Springer Schriftenr Neurol 25:1-135Google Scholar
  54. 54.
    Lassmann H, Raine C, Antel J, Prineas J (1998) Immunopathology of multiple sclerosis: Report on an international meeting held at the Institute of Neurology of the University of Vienna. J Neuroimmunol 86:213-217PubMedGoogle Scholar
  55. 55.
    Lassmann H, Wisniewski HM (1979) Chronic relapsing experimental allergic encephalomyelitis: morphological sequence of myelin degradation. Brain Res 169:357-368PubMedGoogle Scholar
  56. 56.
    Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR (2005) IgG marker of opticspinal MS binds to the aquaporin-4 water channel. J Exp Med 202:473-477PubMedGoogle Scholar
  57. 57.
    Lennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, Fujihara K, Nakashima I, Weinshenker BG (2004) A serum autoantibody marker of neuromyelitis optica: Distinction from multiple sclerosis. Lancet 364:2106-2112PubMedGoogle Scholar
  58. 58.
    Linington C, Bradl M, Lassmann H, Brunner C, Vass K (1988) Augmentation of demyelination in rat acute allergic encephalomyelitis by circulating mouse monoclonal antibodies directed against a myelin/oligodendrocyte glycoprotein. Am J Pathol 130:443-454PubMedGoogle Scholar
  59. 59.
    Liu J, Zhao M, Brosnan C, Lee S (2001) Expression of inducible nitric oxide synthase and nitrotyrosine in multiple sclerosis lesions. Am J Pathol 158:2057-2066PubMedGoogle Scholar
  60. 60.
    Lock C, Hermans G, Pedotti R et al (2002) Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med 8:500-508PubMedGoogle Scholar
  61. 61.
    Lucchinetti CF, Bruck W, Lassmann H (2004) Evidence for pathogenic heterogeneity in multiple sclerosis. Ann Neurol 56:308PubMedGoogle Scholar
  62. 62.
    Lucchinetti CF, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H (2000) Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 47:707-717PubMedGoogle Scholar
  63. 63.
    Lucchinetti CF, Brueck W, Rodriguez M, Parisi J, Scheithauer B, Lassmann H (1999) A quantitative study on the fate of the oligodendrocyte in multiple sclerosis lesions: a study of 113 cases. Brain 122:2279-2295PubMedGoogle Scholar
  64. 64.
    Lucchinetti CF, Mandler RN, McGavern D, Bruck W, Gleich G, Ransohoff RM, Trebst C, Weinshenker B, Wingerchuk D, Parisi JE, Lassmann H (2002) A role for humoral mechanisms in the pathogenesis of Devic’s neuromyelitis optica. Brain 125:1450-1461PubMedGoogle Scholar
  65. 65.
    Mantovani A, Sica A, Locati M (2005) Macrophage polarization comes of age. Immunity 23:344-346PubMedGoogle Scholar
  66. 66.
    Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677-686PubMedGoogle Scholar
  67. 67.
    Marburg O (1906) Die sogenannte “akute Multiple Sklerose”. J Psychiatr Neurol 27:211-212Google Scholar
  68. 68.
    Martino G, Olsson T, Fredrikson S, Hojeberg B, Kostulas V, Grimaldi LM, Link H (1991) Cells producing antibodies specific for myelin basic protein region 70-89 are predominant in cerebrospinal fluid from patients with multiple sclerosis. Eur J Immunol 21:2971-2976PubMedGoogle Scholar
  69. 69.
    Matute C, Alberdi E, Domercq M, Perez-Cerda F, Perez-Samartin A, Sanchez-Gomez MV (2001) The link between excitotoxic oligodendroglial death and demyelinating diseases. Trends Neurosci 24:224-230PubMedGoogle Scholar
  70. 70.
    Mehta PD, Frisch S, Thormar H et al (1981) Bound antibody in multiple sclerosis brains. J Neurol Sci 49:91-98PubMedGoogle Scholar
  71. 71.
    Neumann H, Medana IM, Bauer J, Lassmann H (2002) Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases. Trends Neurosci 25:313-319PubMedGoogle Scholar
  72. 72.
    O’Connor KC B-OA, Hafler DA (2001) The neuroimmunology of multiple sclerosis: possible roles of T and B lymphocytes in immunopathogenesis. J Clin Immunol 21:81-92PubMedGoogle Scholar
  73. 73.
    Olsson T, Zhi WW, Hojeberg B, Kostulas V, Jiang YP, Anderson G, Ekre HP, Link H (1990) Autoreactive T lymphocytes in multiple sclerosis determined by antigen-induced secretion of interferon-gamma. J Clin Invest 86:981-985PubMedGoogle Scholar
  74. 74.
    Oppenheimer DR (1976) Demyelinating diseases. In: Blackwood W, Corsellis JAN (eds) Greenfield’s neuropathology. Edward Arnold, London pp 470-499Google Scholar
  75. 75.
    Owens GP, Kraus H, Burgoon MP et al (1998) Restricted use of VH4 germline segments in an acute multiple sclerosis brain. Ann Neurol 43:236-243PubMedGoogle Scholar
  76. 76.
    Owens GP, Ritchie AM, Burgoon MP et al (2003) Single-cell repertoire analysis demonstrates that clonal expansion is a prominent feature of the B cell response in multiple sclerosis cerebrospinal flu. J Immunol 171:2725-2733PubMedGoogle Scholar
  77. 77.
    Patrikios P, Stadelmann C, Kutzelnigg A, Rauschka H, Schmidbauer M, Laursen H, Sorensen P, Brück W, Lucchinetti CF, Lassmann H (2006) Remyelination is extensive in a subset of multiple sclerosis patients. Brain 129:3165-3172PubMedGoogle Scholar
  78. 78.
    Pittock SJ, McClelland RL, Achenbach SJ, Konig F, Bitsch A, Bruck W, Lassmann H, Parisi J, Lucchinetti CF (2005) Clinical course, pathologic correlations and outcome of biopsy proven inflammatory demyelinating disease. J Neurol Neurosurg Psychiatry 767:1693-1697Google Scholar
  79. 79.
    Prineas J (1985) The neuropathology of multiple sclerosis. In: Vinken P, Bruyn G, Klawans H (eds) Handbook of clinical neurology. Elsevier Science, New York pp 213-257Google Scholar
  80. 80.
    Prineas J, McDonald WI, Franklin JM (2002) Demyelinating diseases. In: Graham LP (ed) Greenfield’s neuropathology. Edward Arnold, London pp 471-550.Google Scholar
  81. 81.
    Prineas JW, Barnard RO, Revesz T, Kwon EE, Sharer L, Cho ES (1993) Multiple sclerosis. Pathology of recurrent lesions. Brain 116:681-693PubMedGoogle Scholar
  82. 82.
    Prineas JW, Kwon EE, Cho ES, Sharer LR, Barnett MH, Oleszak EL, Hoffman B, Morgan BP (2001) Immunopathology of secondary-progressive multiple sclerosis. Ann Neurol 50:646-657PubMedGoogle Scholar
  83. 83.
    Prineas JW, Wright RG (1978) Macrophages, lymphocytes, and plasma cells in the perivascular compartment in chronic multiple sclerosis. Lab Invest 38:409-421PubMedGoogle Scholar
  84. 84.
    Qin Y, Duquette P, Zhang Y et al (1998) Clonal expansion and somatic hypermutation of V (H) genes of B cells from cerebrospinal fluid in multiple sclerosis. J Clin Invest 102:1045-1050PubMedGoogle Scholar
  85. 85.
    Redford EJ, Kapoor R, Smith KJ (1997) Nitric oxide donors reversibly block axonal conduction: demyelinated axons are especially susceptible. Brain 120:2149-2157PubMedGoogle Scholar
  86. 86.
    Revel M, Valiente E, Gray F, Beges C, Degos J, Brugieres P (1993) Concentric MR patterns in multiple sclerosis. Report of two cases. J Neuroradiol 20:252-257PubMedGoogle Scholar
  87. 87.
    Roemer SF, Parisi JE, Lennon VA, Benarroch EE, Lassmann H, Bruck W, Mandler RN, Weinshenker BG, Pittock SJ, Wingerchuk DM, Lucchinetti CF (2007) Pattern specific loss of aquaporin 4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis. Brain 130:1174-1205Google Scholar
  88. 88.
    Schwartz M, Butovsky O, Bruck W et al (2006) Microglial phenotype: is the commitment reversible? Trends Neurosci 29:68-74PubMedGoogle Scholar
  89. 89.
    Serafini B, Rosicarelli B, Magliozzi R et al (2004) Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol 14:164-174PubMedCrossRefGoogle Scholar
  90. 90.
    Sharp FR, Bernaudin M (2004) HIF1 and oxygen sensing in the brain. Nat Rev Neurosci 5:437-448PubMedGoogle Scholar
  91. 91.
    Smith KJ, Kapoor R, Hall SM, Davies M (2001) Electrically active axons degenerate when exposed to nitric oxide. Ann Neurol 49:470-476PubMedGoogle Scholar
  92. 92.
    Smith KJ, Lassmann H (2002) The role of nitric oxide in multiple sclerosis. Lancet Neurol 1:232-241PubMedGoogle Scholar
  93. 93.
    Smith-Jensen T, Burgoon MP, Anthony J et al (2000) Comparison of immunoglobulin G heavy-chain sequences in MS and SSPE brains reveals an antigen-driven response. Neurology 54:1227-1232PubMedGoogle Scholar
  94. 94.
    Spiegel M, Kruger H, Hofmann E, Kappos L (1989) MRI study of Balo’s concentric sclerosis before and after immunosuppressant therapy. J Neurol 236:487-488PubMedGoogle Scholar
  95. 95.
    Stadelmann C, Kerschensteiner M, Misgeld T et al (2002) BDNF and gp145trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune cells and neuronal cells. Brain 125:75-85PubMedGoogle Scholar
  96. 96.
    Stadelmann C, Ludwin SK, Tabira T, Guseo A, Lucchinetti C, Brück W, Lassmann H (2005) Hypoxic preconditioning explains concentric lesions in Balo’s type of multiple sclerosis. Brain 128:979-987PubMedGoogle Scholar
  97. 97.
    Storch MK, Piddlesden S, Haltia M, Livanainen M, Morgan P, Lassmann H (1998) Multiple sclerosis: in situ evidence for antibody- and complement-mediated demyelination. Ann Neurol 43:465-471PubMedGoogle Scholar
  98. 98.
    Sun D, Whitaker JN, Huang Z, Liu D, Coleclough C, Wekerle H, Raine CS (2001) Myelin antigen-specific CD8+ T cells are encephalitogenic and produce severe disease in C57BL/6 mice. J Immunol 166:7579-7587PubMedGoogle Scholar
  99. 99.
    Sun J, Link H, Olsson T et al (1991) T and B cell responses to myelin-oligodendrocyte glycoprotein in multiple sclerosis. J Immunol 146:1490-1495PubMedGoogle Scholar
  100. 100.
    Traugott U (1983) Multiple sclerosis: relevance of class I and class II MHC-expressing cells to lesion development. J Neuroimmunol 16:283-302Google Scholar
  101. 101.
    Turnbull HM, McIntosh J (1926) Encephalomyelitis following vaccination. Br J Exp Pathol 7:181-222Google Scholar
  102. 102.
    Van Bogaert L (1950) Post-infectious encephalomyelitis and multiple sclerosis; the significance of perivenous encephalomyelitis. J Neuropathol Exp Neurol 9:219-249PubMedGoogle Scholar
  103. 103.
    Vass K, Welch WJ, Nowak TS (1988) Localization of 70-kDa stress protein induction in gerbil brain after ischemia. Acta Neuropathol 77:128-135PubMedGoogle Scholar
  104. 104.
    Werner P Pitt D, Raine CS (2001) Multiple sclerosis: altered glutamate homeostasis in lesions correlates with oligodendrocyte and axonal damage. Ann Neurol 50:169-180Google Scholar
  105. 105.
    Williamson RA, Burgoon MP, Owens GP et al (2001) Anti-DNA antibodies are a major component of the intrathecal B cell response in multiple sclerosis. Proc Natl Acad Sci USA 98:1793-1798PubMedGoogle Scholar
  106. 106.
    Wingerchuk D, Pittock S, Lennon V, Lucchinetti C, Weinshenker B (2005) Neuromyelitis optica diagnostic criteria revisited: validation and incorporation of the NMO-IgG serum autoantibody. Neurology 64:A38Google Scholar
  107. 107.
    Wolswijk G (1998) Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells. J Neurosci 18:601-609PubMedGoogle Scholar
  108. 108.
    Wood DD, Bilbao JM, O’Connors P, Moscarello MA (1996) Acute multiple sclerosis (Marburg type) is associated with developmentally immature myelin basic protein. Ann Neurol 40:18-24PubMedGoogle Scholar
  109. 109.
    Youl BD, Kermode AG, Thompson AJ, Revesz T, Scaravilli F, Barnard RO, Kirkham FJ, Kendall BE, Kingsley D, Moseley IF (1991) Destructive lesions in demyelinating disease. J Neurol Neurosurg Psychiatry 54:288-292PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  • C. Lucchinetti
    • 1
  1. 1.Department of NeurologyMayo Clinic College of MedicineRochesterUSA

Personalised recommendations