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Advances in multiple Sclerosis and Experimental Demyelinating Diseases pp 93–131Cite as

Immunological Aspects of Axon Injury in Multiple Sclerosis

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Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 318))

The role of immune-mediated axonal injury in the induction of nonremitting functional deficits associated with multiple sclerosis is an area of active research that promises to substantially alter our understanding of the pathogenesis of this disease and modify or change our therapeutic focus. This review summarizes the current state of research regarding changes in axonal function during demyelination, provides evidence of axonal dysmorphia and degeneration associated with demyelination, and identifies the cellular and molecular effectors of immune-mediated axonal injury. Finally, a unifying hypothesis that links neuronal stress associated with demyelination-induced axonal dysfunction to immune recognition and immunopathology is provided in an effort to shape future experimentation.

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References

  1. Aguayo AJ, Attiwell M, Trecarten J, Perkins S, Bray GM (1977) Abnormal myelination in transplanted Trembler mouse Schwann cells. Nature 265:73-75

    CAS  PubMed  Google Scholar 

  2. Ahern GP, Hsu SF, Klyachko VA, Jackson MB (2000) Induction of persistent sodium current by exogenous and endogenous nitric oxide. J Biol Chem 275:28810-18815

    CAS  PubMed  Google Scholar 

  3. Ahmed Z, Doward AI, Pryce G, Taylor DL, Pocock JM, Leonard JP, Baker D, Cuzner ML (2002) A role for caspase-1 and -3 in the pathology of experimental allergic encephalomyelitis: inflammation versus degeneration. Am J Pathol 161:1577-1586

    CAS  PubMed  Google Scholar 

  4. Akenami FO, Siren V, Koskiniemi M, Siimes MA, Teravainen H, Vaheri A (1996) Cerebrospinal fluid activity of tissue plasminogen activator in patients with neurological diseases. J Clin Pathol 49:577-580

    CAS  PubMed  Google Scholar 

  5. Akenami FO, Siren V, Wessman M, Koskiniemi M, Vaheri A (1999) Tissue plasminogen activator gene expression in multiple sclerosis brain tissue. J Neurol Sci 165:71-76

    CAS  PubMed  Google Scholar 

  6. Allan SM, Rothwell NJ (2001) Cytokines and acute neurodegeneration. Nat Rev Neurosci 2:734-744

    CAS  PubMed  Google Scholar 

  7. Ames A 3rd (2000) CNS energy metabolism as related to function. Brain Res Brain Res Rev 34:42-68

    CAS  PubMed  Google Scholar 

  8. Andrews H, White K, Thomson C, Edgar J, Bates D, Griffiths I, Turnbull D, Nichols P (2006) Increased axonal mitochondrial activity as an adaptation to myelin deficiency in the Shiverer mouse. J Neurosci Res 83:1533-1539

    CAS  PubMed  Google Scholar 

  9. Andrews HE, Nichols PP, Bates D, Turnbull DM (2005) Mitochondrial dysfunction plays a key role in progressive axonal loss in multiple sclerosis. Med Hypotheses 64:669-677

    CAS  PubMed  Google Scholar 

  10. Andrews PI, McNamara JO (1996) Rasmussen’s encephalitis: an autoimmune disorder? Curr Opin Neurobiol 6:673-678

    CAS  PubMed  Google Scholar 

  11. Augusto O, Bonini MG, Amanso AM, Linares E, Santos CC, De Menezes SL (2002) Nitrogen dioxide and carbonate radical anion: two emerging radicals in biology. Free Radic Biol Med 32:841-859

    CAS  PubMed  Google Scholar 

  12. Ayers MM, Anderson RM (1976) Development of onion bulb neuropathy in the Tremebler mouse. Morphometric study. Acta Neuropathol (Berl) 36:137-152

    CAS  Google Scholar 

  13. Baba T, Ishizu A, Iwasaki S, Suzuki A, Tomaru U, Ikeda H, Yoshiki T, Kasahara M (2006) CD4+/CD8+ macrophages infiltrating at inflammatory sites: a population of monocytes/macrophages with a cytotoxic phenotype. Blood 107:2004-2012

    CAS  PubMed  Google Scholar 

  14. 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 expansions of CD8(+) T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction. J Exp Med 192:393-404

    CAS  PubMed  Google Scholar 

  15. Babinski J (1885) Recherche sur l’anatomie pathologique de la sclérose en plaque et étude comparative des diverses variétés de sclérose de la moelle. Archives de Physiologie Normale et Pathologique 2:186-207

    Google Scholar 

  16. Backstrom E, Chambers BJ, Kristensson K, Ljunggren HG (2000) Direct NK cell-mediated lysis of syngenic dorsal root ganglia neurons in vitro. J Immunol 165:4895-4900

    CAS  PubMed  Google Scholar 

  17. Backstrom E, Chambers BJ, Ho EL, Naidenko OV, Mariotti R, Fremont DH, Yokoyama WM, Kristensson K, Ljunggren HG (2003) Natural killer cell-mediated lysis of dorsal root ganglia neurons via RAE1/NKG2D interactions. Eur J Immunol 33:92-100

    CAS  PubMed  Google Scholar 

  18. Bagasra O, Michaels FH, Zheng YM, Bobroski LE, Spitsin SV, Fu ZF, Tawadros R, Koprowski H (1995) Activation of the inducible form of nitric oxide synthase in the brains of patients with multiple sclerosis. Proc Natl Acad Sci USA 92:12041-12045

    CAS  PubMed  Google Scholar 

  19. Bailey SL, Carpentier PA, McMahon EJ, Begolka WS, Miller SD (2006) Innate and adaptive immune responses of the central nervous system. Crit Rev Immunol 26:149-188

    CAS  PubMed  Google Scholar 

  20. Bains JS, Ferguson AV (1997) Nitric oxide depolarizes type II paraventricular nucleus neurons in vitro. Neuroscience 79:149-159

    CAS  PubMed  Google Scholar 

  21. Barry M, Bleackley RC (2002) Cytotoxic T lymphocytes: all roads lead to death. Nat Rev Immunol 2:401-409

    CAS  PubMed  Google Scholar 

  22. Baslow MH (2002) Evidence supporting a role for N-acetyl-L-aspartate as a molecular water pump in myelinated neurons in the central nervous system. An analytical review. Neurochem Int 40:295-300

    CAS  PubMed  Google Scholar 

  23. Baslow MH (2003) N-acetylaspartate in the vertebrate brain: metabolism and function. Neurochem Res 28:941-953

    CAS  PubMed  Google Scholar 

  24. Baslow MH (2003) Brain N-acetylaspartate as a molecular water pump and its role in the etiology of Canavan disease: a mechanistic explanation. J Mol Neurosci 21:185-190

    CAS  PubMed  Google Scholar 

  25. Bauer J, Bien CG, Lassmann H (2002) Rasmussen’s encephalitis: a role for autoimmune cytotoxic T lymphocytes. Curr Opin Neurol 15:197-200

    PubMed  Google Scholar 

  26. Beattie EC, Zhou J, Grimes ML, Bunnett NW, Howe CL, Mobley WC (1996) A signaling endosome hypothesis to explain NGF actions: potential implications for neurodegeneration. Cold Spring Harb Symp Quant Biol 61:389-406

    CAS  PubMed  Google Scholar 

  27. 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 64:46-57

    CAS  PubMed  Google Scholar 

  28. Bien CG, Bauer J, Deckwerth TL, Wiendl H, Deckert M, Wiestler OD, Schramm J, Elger CE, Lassmann H (2002) Destruction of neurons by cytotoxic T cells: a new pathogenic mechanism in Rasmussen’s encephalitis. Ann Neurol 51:311-318

    CAS  PubMed  Google Scholar 

  29. Bitsch A, Schuchardt J, Bunkowski S, Kuhlmann T, Bruck W (2000) Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain 123:1174-1183

    PubMed  Google Scholar 

  30. Bjartmar C, Yin X, Trapp BD (1999) Axonal pathology in myelin disorders. J Neurocytol 28:383-395

    CAS  PubMed  Google Scholar 

  31. Bjartmar C, Kidd G, Mork S, Rudick R, Trapp BD (2000) Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients. Ann Neurol 48:893-901

    CAS  PubMed  Google Scholar 

  32. Black JA, Liu S, Hains BC, Saab CY, Waxman SG (2006) Long-term protection of central axons with phenytoin in monophasic and chronic-relapsing EAE. Brain 129:3196-3208

    PubMed  Google Scholar 

  33. Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8:57-69

    CAS  PubMed  Google Scholar 

  34. Boiko T, Rasband MN, Levinson SR, Caldwell JH, Mandel G, Trimmer JS, Matthews G (2001) Compact myelin dictates the differential targeting of two sodium channel isoforms in the same axon. Neuron 30:91-104

    CAS  PubMed  Google Scholar 

  35. 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 62:219-232

    CAS  PubMed  Google Scholar 

  36. Bostock H, Grafe P (1985) Activity-dependent excitability changes in normal and demyelinated rat spinal root axons. J Physiol 365:239-257

    CAS  PubMed  Google Scholar 

  37. Brady ST, Witt AS, Kirkpatrick LL, de Waegh SM, Readhead C, Tu PH, Lee VM (1999) Formation of compact myelin is required for maturation of the axonal cytoskeleton. J Neurosci 19:7278-7288

    CAS  PubMed  Google Scholar 

  38. Brenner RE, Munro PM, Williams SC, Bell JD, Barker GJ, Hawkins CP, Landon DN, McDonald WI (1993) The proton NMR spectrum in acute EAE: the significance of the change in the Cho:Cr ratio. Magn Reson Med 29:737-745

    CAS  PubMed  Google Scholar 

  39. Brookes PS, Bolanos JP, Heales SJ (1999) The assumption that nitric oxide inhibits mitochondrial ATP synthesis is correct. FEBS Lett 446:261-263

    CAS  PubMed  Google Scholar 

  40. Brorson JR, Schumacker PT, Zhang H (1999) Nitric oxide acutely inhibits neuronal energy production. The Committees on Neurobiology and Cell Physiology. J Neurosci 19:147-158

    CAS  PubMed  Google Scholar 

  41. Brown GC, Cooper CE (1994) Nanomolar concentrations of nitric oxide reversibly inhibit synaptosomal respiration by competing with oxygen at cytochrome oxidase. FEBS Lett 356:295-298

    CAS  PubMed  Google Scholar 

  42. Browne KA, Blink E, Sutton VR, Froelich CJ, Jans DA, Trapani JA (1999) Cytosolic delivery of granzyme B by bacterial toxins: evidence that endosomal disruption, in addition to transmembrane pore formation, is an important function of perforin. Mol Cell Biol 19:8604-8615

    CAS  PubMed  Google Scholar 

  43. Cabarrocas J, Bauer J, Piaggio E, Liblau R, Lassmann H (2003) Effective and selective immune surveillance of the brain by MHC class I-restricted cytotoxic T lymphocytes. Eur J Immunol 33:1174-1182

    CAS  PubMed  Google Scholar 

  44. Calderon B, Suri A, Unanue ER (2006) In CD4+ T-cell-induced diabetes, macrophages are the final effector cells that mediate islet beta-cell killing: studies from an acute model. Am J Pathol 169:2137-2147

    CAS  PubMed  Google Scholar 

  45. Caldwell JH, Schaller KL, Lasher RS, Peles E, Levinson SR (2000) Sodium channel Na(v)1.6 is localized at nodes of ranvier, dendrites, and synapses. Proc Natl Acad Sci USA 97:5616-5620

    CAS  PubMed  Google Scholar 

  46. Campagnoni AT (1988) Molecular biology of myelin proteins from the central nervous system. J Neurochem 51:1-14

    CAS  PubMed  Google Scholar 

  47. Carson MJ, Reilly CR, Sutcliffe JG, Lo D (1999) Disproportionate recruitment of CD8+ T cells into the central nervous system by professional antigen-presenting cells. Am J Pathol 154:481-494

    CAS  PubMed  Google Scholar 

  48. Catalfamo M, Henkart PA (2003) Perforin and the granule exocytosis cytotoxicity pathway. Curr Opin Immunol 15:522-527

    CAS  PubMed  Google Scholar 

  49. Chiu SY, Schwarz W (1987) Sodium and potassium currents in acutely demyelinated internodes of rabbit sciatic nerves. J Physiol 391:631-649

    CAS  PubMed  Google Scholar 

  50. Cho SG, Yi SY, Yoo YS (2005) IFNgamma and TNFalpha synergistically induce neurite outgrowth on PC12 cells. Neurosci Lett 378:49-54

    CAS  PubMed  Google Scholar 

  51. Christopherson KS, Bredt DS (1997) Nitric oxide in excitable tissues: physiological roles and disease. J Clin Invest 100:2424-2429

    CAS  PubMed  Google Scholar 

  52. Ciccarelli O, Werring DJ, Barker GJ, Griffin CM, Wheeler-Kingshott CA, Miller DH, Thompson AJ (2003) A study of the mechanisms of normal-appearing white matter damage in multiple sclerosis using diffusion tensor imaging - evidence of Wallerian degeneration. J Neurol 250:287-292

    PubMed  Google Scholar 

  53. Clark JF, Doepke A, Filosa JA, Wardle RL, Lu A, Meeker TJ, Pyne-Geithman GJ (2006) N-acetylaspartate as a reservoir for glutamate. Med Hypotheses 67:506-512

    CAS  PubMed  Google Scholar 

  54. Cleeter MW, Cooper JM, Darley-Usmar VM, Moncada S, Schapira AH (1994) Reversible inhibition of cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, by nitric oxide. Implications for neurodegenerative diseases. FEBS Lett 345:50-54

    CAS  PubMed  Google Scholar 

  55. Coleman M (2005) Axon degeneration mechanisms: commonality amid diversity. Nat Rev Neurosci 6:889-898

    CAS  PubMed  Google Scholar 

  56. Coleman MP, Perry VH (2002) Axon pathology in neurological disease: a neglected therapeutic target. Trends Neurosci 25:532-537

    CAS  PubMed  Google Scholar 

  57. Coman I, Aigrot MS, Seilhean D, Reynolds R, Girault JA, Zalc B, Lubetzki C (2006) Nodal, paranodal and juxtaparanodal axonal proteins during demyelination and remyelination in multiple sclerosis. Brain 129:3186-3195

    CAS  PubMed  Google Scholar 

  58. Compston A, Lassmann H, McDonald I (2006) The story of multiple sclerosis. In: Confavreux C, Lassmann H, McDonald I, Miller D, Noseworthy J, Smith K, Wekerle H (eds) McAlpine’s Multiple Sclerosis. Elsevier, Philadelphia, pp. 3-68

    Google Scholar 

  59. Condie RM, Good RA (1959) Experimental allergic encephalomyelitis: its production, prevention, and pathology as studied by light and electron microscopy. Prog Neurobiol 4:321-392

    CAS  PubMed  Google Scholar 

  60. Craner MJ, Lo AC, Black JA, Waxman SG (2003) Abnormal sodium channel distribution in optic nerve axons in a model of inflammatory demyelination. Brain 126:1552-1561

    PubMed  Google Scholar 

  61. Craner MJ, Hains BC, Lo AC, Black JA, Waxman SG (2004) Co-localization of sodium channel Nav1.6 and the sodium-calcium exchanger at sites of axonal injury in the spinal cord in EAE. Brain 127:294-303

    PubMed  Google Scholar 

  62. Craner MJ, Newcombe J, Black JA, Hartle C, Cuzner ML, Waxman SG (2004) Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger. Proc Natl Acad Sci USA 101:8168-8173

    CAS  PubMed  Google Scholar 

  63. Criste GA, Trapp BD (2006) N-acetyl-L-aspartate in multiple sclerosis. Adv Exp Med Biol 576:199-214; discussion 361-363

    CAS  PubMed  Google Scholar 

  64. Cross AH, Manning PT, Stern MK, Misko TP (1997) Evidence for the production of peroxynitrite in inflammatory CNS demyelination. J Neuroimmunol 80:121-130

    CAS  PubMed  Google Scholar 

  65. Davie CA, Barker GJ, Webb S, Tofts PS, Thompson AJ, Harding AE, McDonald WI, Miller DH (1995) Persistent functional deficit in multiple sclerosis and autosomal dominant cerebellar ataxia is associated with axon loss. Brain 118:1583-1592

    PubMed  Google Scholar 

  66. Davis FA, Bergen D, Schauf C, McDonald I, Deutsch W (1976) Movement phosphenes in optic neuritis: a new clinical sign. Neurology 26:1100-1104

    CAS  PubMed  Google Scholar 

  67. De Stefano N, Narayanan S, Francis GS, Arnaoutelis R, Tartaglia MC, Antel JP, Matthews PM, Arnold DL (2001) Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability. Arch Neurol 58:65-70

    CAS  PubMed  Google Scholar 

  68. De Stefano N, Narayanan S, Francis SJ, Smith S, Mortilla M, Tartaglia MC, Bartolozzi ML, Guidi L, Federico A, Arnold DL (2002) Diffuse axonal and tissue injury in patients with multiple sclerosis with low cerebral lesion load and no disability. Arch Neurol 59:1565-1571

    PubMed  Google Scholar 

  69. de Waegh S, Brady ST (1990) Altered slow axonal transport and regeneration in a myelindeficient mutant mouse: the trembler as an in vivo model for Schwann cell-axon interactions. J Neurosci 10:1855-1865

    CAS  PubMed  Google Scholar 

  70. de Waegh SM, Brady ST (1991) Local control of axonal properties by Schwann cells: neurofilaments and axonal transport in homologous and heterologous nerve grafts. J Neurosci Res 30:201-212

    CAS  PubMed  Google Scholar 

  71. de Waegh SM, Lee VM, Brady ST (1992) Local modulation of neurofilament phosphorylation, axonal caliber, and slow axonal transport by myelinating Schwann cells. Cell 68:451-463

    CAS  PubMed  Google Scholar 

  72. Delcroix JD, Valletta J, Wu C, Howe CL, Lai CF, Cooper JD, Belichenko PV, Salehi A, Mobley WC (2004) Trafficking the NGF signal: implications for normal and degenerating neurons. Prog Brain Res 146:3-23

    CAS  PubMed  Google Scholar 

  73. DeLuca GC, Ebers GC, Esiri MM (2004) Axonal loss in multiple sclerosis: a pathological survey of the corticospinal and sensory tracts. Brain 127:1009-1018

    CAS  PubMed  Google Scholar 

  74. Demjen D, Klussmann S, Kleber S, Zuliani C, Stieltjes B, Metzger C, Hirt UA, Walczak H, Falk W, Essig M, Edler L, Krammer PH, Martin-Villalba A (2004) Neutralization of CD95 ligand promotes regeneration and functional recovery after spinal cord injury. Nat Med 10:389-395

    CAS  PubMed  Google Scholar 

  75. Diefenbach A, Hsia JK, Hsiung MY, Raulet DH (2003) A novel ligand for the NKG2D receptor activates NK cells and macrophages and induces tumor immunity. Eur J Immunol 33:381-391

    CAS  PubMed  Google Scholar 

  76. Dittel BN, Merchant RM, Janeway CA Jr (1999) Evidence for Fas-dependent and Fasindependent mechanisms in the pathogenesis of experimental autoimmune encephalomyelitis. J Immunol 162:6392-400

    CAS  PubMed  Google Scholar 

  77. Drew PD, Lonergan M, Goldstein ME, Lampson LA, Ozato K, McFarlin DE (1993) Regulation of MHC class I and beta 2-microglobulin gene expression in human neuronal cells. Factor binding to conserved cis-acting regulatory sequences correlates with expression of the genes. J Immunol 150:3300-3310

    CAS  PubMed  Google Scholar 

  78. Dutta R, McDonough J, Yin X, Peterson J, Chang A, Torres T, Gudz T, Macklin WB, Lewis DA, Fox RJ, Rudick R, Mirnics K, Trapp BD (2006) Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol 59:478-489

    CAS  PubMed  Google Scholar 

  79. Edgar JM, McLaughlin M, Yool D, Zhang SC, Fowler JH, Montague P, Barrie JA, McCulloch MC, Duncan ID, Garbern J, Nave KA, Griffiths IR (2004) Oligodendroglial modulation of fast axonal transport in a mouse model of hereditary spastic paraplegia. J Cell Biol 166:121-131

    CAS  PubMed  Google Scholar 

  80. Espey MG, Miranda KM, Thomas DD, Xavier S, Citrin D, Vitek MP, Wink DA (2002) A chemical perspective on the interplay between NO, reactive oxygen species, and reactive nitrogen oxide species. Ann N Y Acad Sci 962:195-206

    CAS  PubMed  Google Scholar 

  81. Everding B, Wilhelm S, Averesch S, Scherdin U, Holzel F, Steffen M (2000) IFN-gammainduced change in microtubule organization and alpha-tubulin expression during growth inhibition of lung squamous carcinoma cells. J Interferon Cytokine Res 20:983-990

    CAS  PubMed  Google Scholar 

  82. Ferguson B, Matyszak MK, Esiri MM, Perry VH (1997) Axonal damage in acute multiple sclerosis lesions. Brain 120:393-399

    PubMed  Google Scholar 

  83. Fiette L, Aubert C, Brahic M, Rossi CP (1993) Theiler’s virus infection of beta 2-microglobulin-deficient mice. J Virol 67:589-592

    CAS  PubMed  Google Scholar 

  84. Fischer U, Janicke RU, Schulze-Osthoff K (2003) Many cuts to ruin: a comprehensive update of caspase substrates. Cell Death Differ 10:76-100

    CAS  PubMed  Google Scholar 

  85. Fisher E, Rudick RA, Simon JH, Cutter G, Baier M, Lee JC, Miller D, Weinstock-Guttman B, Mass MK, Dougherty DS, Simonian NA (2002) Eight-year follow-up study of brain atrophy in patients with MS. Neurology 59:1412-1420

    CAS  PubMed  Google Scholar 

  86. Fitch MT, Doller C, Combs CK, Landreth GE, Silver J (1999) Cellular and molecular mechanisms of glial scarring and progressive cavitation: in vivo and in vitro analysis of inflammation-induced secondary injury after CNS trauma. J Neurosci 19:8182-8198

    CAS  PubMed  Google Scholar 

  87. Flugel A, Berkowicz T, Ritter T, Labeur M, Jenne DE, Li Z, Ellwart JW, Willem M, Lassmann H, Wekerle H (2001) Migratory activity and functional changes of green fluorescent effector cells before and during experimental autoimmune encephalomyelitis. Immunity 14:547-560

    CAS  PubMed  Google Scholar 

  88. Froelich CJ, Orth K, Turbov J, Seth P, Gottlieb R, Babior B, Shah GM, Bleackley RC, Dixit VM, Hanna W (1996) New paradigm for lymphocyte granule-mediated cytotoxicity. Target cells bind and internalize granzyme B, but an endosomolytic agent is necessary for cytosolic delivery and subsequent apoptosis. J Biol Chem 271:29073-29079

    CAS  PubMed  Google Scholar 

  89. Galea I, Bechmann I, Perry VH (2007) What is immune privilege (not)? Trends Immunol 28:12-18

    CAS  PubMed  Google Scholar 

  90. Garbern JY, Yool DA, Moore GJ, Wilds IB, Faulk MW, Klugmann M, Nave KA, Sistermans EA, van der Knaap MS, Bird TD, Shy ME, Kamholz JA, Griffiths IR (2002) Patients lacking the major CNS myelin protein, proteolipid protein 1, develop length-dependent axonal degeneration in the absence of demyelination and inflammation. Brain 125:551-561

    PubMed  Google Scholar 

  91. Gay FW, Drye TJ, Dick GW, Esiri MM (1997) The application of multifactorial cluster analysis in the staging of plaques in early multiple sclerosis. Identification and characterization of the primary demyelinating lesion. Brain 120:1461-1483

    PubMed  Google Scholar 

  92. Gentleman SM, Nash MJ, Sweeting CJ, Graham DI, Roberts GW (1993) Beta-amyloid precursor protein (beta APP) as a marker for axonal injury after head injury. Neurosci Lett 160:139-144

    CAS  PubMed  Google Scholar 

  93. 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 126:1755-1766

    CAS  PubMed  Google Scholar 

  94. Gilgun-Sherki Y, Panet H, Holdengreber V, Mosberg-Galili R, Offen D (2003) Axonal damage is reduced following glatiramer acetate treatment in C57/bl mice with chronic-induced experimental autoimmune encephalomyelitis. Neurosci Res 47:201-207

    CAS  PubMed  Google Scholar 

  95. Giulian D, Vaca K, Corpuz M (1993) Brain glia release factors with opposing actions upon neuronal survival. J Neurosci 13:29-37

    CAS  PubMed  Google Scholar 

  96. Giuliani F, Goodyer CG, Antel JP, Yong VW (2003) Vulnerability of human neurons to T cell-mediated cytotoxicity. J Immunol 171:368-379

    CAS  PubMed  Google Scholar 

  97. Gold R, Linington C, Lassmann H (2006) Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 129:1953-1971

    PubMed  Google Scholar 

  98. Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953-964

    CAS  PubMed  Google Scholar 

  99. Griffiths I, Klugmann M, Anderson T, Yool D, Thomson C, Schwab MH, Schneider A, Zimmermann F, McCulloch M, Nadon N, Nave KA (1998) Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 280:1610-1633

    CAS  PubMed  Google Scholar 

  100. Guyton MK, Wingrave JM, Yallapragada AV, Wilford GG, Sribnick EA, Matzelle DD, Tyor WR, Ray SK, Banik NL(2005) Upregulation of calpain correlates with increased neurodegeneration in acute experimental auto-immune encephalomyelitis. J Neurosci Res 81:53-61

    CAS  PubMed  Google Scholar 

  101. Guzman NJ, Fang MZ, Tang SS, Ingelfinger JR, Garg LC (1995) Autocrine inhibition of Na+/K(+)-ATPase by nitric oxide in mouse proximal tubule epithelial cells. J Clin Invest 95:2083-2088

    CAS  PubMed  Google Scholar 

  102. Gveric D, Hanemaaijer R, Newcombe J, van Lent NA, Sier CF, Cuzner ML (2001) Plasminogen activators in multiple sclerosis lesions: implications for the inflammatory response and axonal damage. Brain 124:1978-1988

    CAS  PubMed  Google Scholar 

  103. Herzog RI, Cummins TR, Ghassemi F, Dib-Hajj SD, Waxman SG (2003) Distinct repriming and closed-state inactivation kinetics of Nav1.6 and Nav1.7 sodium channels in mouse spinal sensory neurons. J Physiol 551:741-750

    CAS  PubMed  Google Scholar 

  104. Hickey WF (1999) Leukocyte traffic in the central nervous system: the participants and their roles. Semin Immunol 11:125-137

    CAS  PubMed  Google Scholar 

  105. Hingorani R, Choi IH, Akolkar P, Gulwani-Akolkar B, Pergolizzi R, Silver J, Gregersen PK (1993) Clonal predominance of T cell receptors within the CD8+ CD45RO+ subset in normal human subjects. J Immunol 151:5762-5769

    CAS  PubMed  Google Scholar 

  106. Hoftberger R, Aboul-Enein F, Brueck W, Lucchinetti C, Rodriguez M, Schmidbauer M, Jellinger K, Lassmann H (2004) Expression of major histocompatibility complex class I molecules on the different cell types in multiple sclerosis lesions. Brain Pathol 14:43-50

    CAS  PubMed  Google Scholar 

  107. Horn TF, Wolf G, Duffy S, Weiss S, Keilhoff G, MacVicar BA (2002) Nitric oxide promotes intracellular calcium release from mitochondria in striatal neurons. Faseb J 16:1611-1622

    CAS  PubMed  Google Scholar 

  108. Horwitz MS, Evans CF, Klier FG, Oldstone MB (1999) Detailed in vivo analysis of interferon-gamma induced major histocompatibility complex expression in the central nervous system: astrocytes fail to express major histocompatibility complex class I and II molecules. Lab Invest 79:235-242

    CAS  PubMed  Google Scholar 

  109. Howe CL, Mobley WC (2004) Signaling endosome hypothesis: A cellular mechanism for long distance communication. J Neurobiol 58:207-216

    PubMed  Google Scholar 

  110. Howe CL, Mobley WC (2005) Long-distance retrograde neurotrophic signaling. Curr Opin Neurobiol 15:40-48

    CAS  PubMed  Google Scholar 

  111. Howe CL, Rodriguez M (2005) Remyelination as neuroprotection. In: Waxman SG (ed) Multiple Sclerosis as a Neuronal Disease. Elsevier, Burlington, MA, pp. 389-419

    Google Scholar 

  112. Howe CL, Adelson JD, Rodriguez M (2007) Absence of perforin expression confers axonal protection despite demyelination. Neurobiol Dis 25:354-359

    CAS  PubMed  Google Scholar 

  113. Hsieh ST, Kidd GJ, Crawford TO, Xu Z, Lin WM, Trapp BD, Cleveland DW, Griffin JW (1994) Regional modulation of neurofilament organization by myelination in normal axons. J Neurosci 14:6392-6401

    CAS  PubMed  Google Scholar 

  114. Huh GS, Boulanger LM, Du H, Riquelme PA, Brotz TM, Shatz CJ (2000) Functional requirement for class I MHC in CNS development and plasticity. Science 290:2155-2159

    CAS  PubMed  Google Scholar 

  115. Iwahashi T, Inoue A, Koh CS, Shin TK, Kim BS (1999) Expression and potential role of inducible nitric oxide synthase in the central nervous system of Theiler’s murine encephalomyelitis virus-induced demyelinating disease. Cell Immunol 194:186-193

    CAS  PubMed  Google Scholar 

  116. Jack C, Ruffini F, Bar-Or A, Antel JP (2005) Microglia and multiple sclerosis. J Neurosci Res 81:363-373

    CAS  PubMed  Google Scholar 

  117. Johnson AJ, Upshaw J, Pavelko KD, Rodriguez M, Pease LR (2001) Preservation of motor function by inhibition of CD8+ virus peptide-specific T cells in Theiler’s virus infection. FASEB J 15:2760-2762

    CAS  PubMed  Google Scholar 

  118. Joly E, Mucke L, Oldstone MB (1991) Viral persistence in neurons explained by lack of major histocompatibility class I expression. Science 253:1283-5

    CAS  PubMed  Google Scholar 

  119. Joly E, Oldstone MB (1992) Neuronal cells are deficient in loading peptides onto MHC class I molecules. Neuron 8:1185-1190

    CAS  PubMed  Google Scholar 

  120. Kaplan MR, Cho MH, Ullian EM, Isom LL, Levinson SR, Barres BA (2001) Differential control of clustering of the sodium channels Na(v)1.2 and Na(v)1.6 at developing CNS nodes of Ranvier. Neuron 30:105-119

    CAS  PubMed  Google Scholar 

  121. Kapoor R, Li YG, Smith KJ (1997) Slow sodium-dependent potential oscillations contribute to ectopic firing in mammalian demyelinated axons. Brain 120:647-652

    PubMed  Google Scholar 

  122. Kapoor R, Davies M, Blaker PA, Hall SM, Smith KJ (2003) Blockers of sodium and calcium entry protect axons from nitric oxide-mediated degeneration. Ann Neurol 53:174-180

    CAS  PubMed  Google Scholar 

  123. Kim BS, Lyman MA, Kang BS, Kang HK, Lee HG, Mohindru M, Palma JP (2001) Pathogenesis of virus-induced immune-mediated demyelination. Immunol Res 24:121-130

    CAS  PubMed  Google Scholar 

  124. Kim IJ, Beck HN, Lein PJ, Higgins D (2002) Interferon gamma induces retrograde dendritic retraction and inhibits synapse formation. J Neurosci 22:4530-4539

    CAS  PubMed  Google Scholar 

  125. Kim JH, Budde MD, Liang HF, Klein RS, Russell JH, Cross AH, Song SK (2006) Detecting axon damage in spinal cord from a mouse model of multiple sclerosis. Neurobiol Dis 21:626-632

    CAS  PubMed  Google Scholar 

  126. Kirkpatrick LL, Brady ST (1994) Modulation of the axonal microtubule cytoskeleton by myelinating Schwann cells. J Neurosci 14:7440-7450

    CAS  PubMed  Google Scholar 

  127. Kirkpatrick LL, Witt AS, Payne HR, Shine HD, Brady ST (2001) Changes in microtubule stability and density in myelin-deficient shiverer mouse CNS axons. J Neurosci 21:2288-2297

    CAS  PubMed  Google Scholar 

  128. Klugmann M, Schwab MH, Puhlhofer A, Schneider A, Zimmermann F, Griffiths IR, Nave KA (1997) Assembly of CNS myelin in the absence of proteolipid protein. Neuron 18:59-70

    CAS  PubMed  Google Scholar 

  129. Koprowski H, Zheng YM, Heber-Katz E, Fraser N, Rorke L, Fu ZF, Hanlon C, Dietzschold B (1993) In vivo expression of inducible nitric oxide synthase in experimentally induced neurologic diseases. Proc Natl Acad Sci USA 90:3024-3027

    CAS  PubMed  Google Scholar 

  130. Kornek B, Lassmann H (1999) Axonal pathology in multiple sclerosis. Brain Pathol 9:651-656

    CAS  PubMed  Google Scholar 

  131. Kornek B, Storch MK, Weissert R, Wallstroem E, Stefferl A, Olsson T, Linington C, Schmidbauer M, Lassmann H (2000) Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol 157:267-276

    CAS  PubMed  Google Scholar 

  132. Kornek B, Storch MK, Bauer J, Djamshidian A, Weissert R, Wallstroem E, Stefferl A, Zimprich F, Olsson T, Linington C, Schmidbauer M, Lassmann H (2001) Distribution of a calcium channel subunit in dystrophic axons in multiple sclerosis and experimental autoimmune encephalomyelitis. Brain 124:1114-1124

    CAS  PubMed  Google Scholar 

  133. Kumar S, Mattan NS, de Vellis J (2006) Canavan disease: a white matter disorder. Ment Retard Dev Disabil Res Rev 12:157-165

    PubMed  Google Scholar 

  134. Kurenny DE, Moroz LL, Turner RW, Sharkey KA, Barnes S (1994) Modulation of ion channels in rod photoreceptors by nitric oxide. Neuron 13:315-324

    CAS  PubMed  Google Scholar 

  135. Lampert P, Carpenter S (1965) Electron microscopic studies on the vascular permeability and the mechanism of demyelination in experimental allergic encephalomyelitis. J Neuropathol Exp Neurol 24:11-24

    CAS  PubMed  Google Scholar 

  136. Lampson LA, Fisher CA, Whelan JP (1983) Striking paucity of HLA-A, B, C and beta 2-microglobulin on human neuroblastoma cell lines. J Immunol 130:2471-2478

    CAS  PubMed  Google Scholar 

  137. Lampson LA, Whelan JP (1983) Paucity of HLA-A,B,C molecules on human cells of neuronal origin: microscopic analysis of neuroblastoma cell lines and tumor. Ann NY Acad Sci 420:107-114

    CAS  PubMed  Google Scholar 

  138. Lampson LA (1995) Interpreting MHC class I expression and class I/class II reciprocity in the CNS: reconciling divergent findings. Microsc Res Tech 32:267-285

    CAS  PubMed  Google Scholar 

  139. Lana-Peixoto MA, Teixeira AL (2002) Simple phonic tic in multiple sclerosis. Mult Scler 8:510-511

    CAS  PubMed  Google Scholar 

  140. Lanier LL (2005) NKG2D in innate and adaptive immunity. Adv Exp Med Biol 560:51-56

    CAS  PubMed  Google Scholar 

  141. Lassmann H (2003) Axonal injury in multiple sclerosis. J Neurol Neurosurg Psychiatry 74:695-697

    CAS  PubMed  Google Scholar 

  142. Lassmann H, Wekerle H (2005) The pathology of multiple sclerosis. In: Waxman SG (ed) Multiple Sclerosis as a Neuronal Disease. Elsevier, Burlington, MA, pp. 557-599

    Google Scholar 

  143. Lawrence JM, Morris RJ, Wilson DJ, Raisman G (1990) Mechanisms of allograft rejection in the rat brain. Neuroscience 37:431-462

    CAS  PubMed  Google Scholar 

  144. Leinders-Zufall T, Brennan P, Widmayer P, S PC, Maul-Pavicic A, Jager M, Li XH, Breer H, Zufall F, Boehm T (2004) MHC class I peptides as chemosensory signals in the vomeronasal organ. Science 306:1033-1037

    CAS  PubMed  Google Scholar 

  145. Lieberman J (2003) The ABCs of granule-mediated cytotoxicity: new weapons in the arsenal. Nat Rev Immunol 3:361-370

    CAS  PubMed  Google Scholar 

  146. Linker RA, Rott E, Hofstetter HH, Hanke T, Toyka KV, Gold R (2005) EAE in beta-2 microglobulin-deficient mice: axonal damage is not dependent on MHC-I restricted immune responses. Neurobiol Dis 19:218-228

    CAS  PubMed  Google Scholar 

  147. Love S, Coakham HB (2001) Trigeminal neuralgia: pathology and pathogenesis. Brain 124:2347-2360

    CAS  PubMed  Google Scholar 

  148. Low PA (1976) Hereditary hypertrophic neuropathy in the trembler mouse. Part 2. Histopathological studies: electron microscopy. J Neurol Sci 30:343-368

    CAS  PubMed  Google Scholar 

  149. Lu F, Selak M, O’Connor J, Croul S, Lorenzana C, Butunoi C, Kalman B (2000) Oxidative damage to mitochondrial DNA and activity of mitochondrial enzymes in chronic active lesions of multiple sclerosis. J Neurol Sci 177:95-103

    CAS  PubMed  Google Scholar 

  150. Mancardi G, Hart B, Roccatagliata L, Brok H, Giunti D, Bontrop R, Massacesi L, Capello E, Uccelli A (2001) Demyelination and axonal damage in a non-human primate model of multiple sclerosis. J Neurol Sci 184:41-49

    CAS  PubMed  Google Scholar 

  151. Marburg O (1906) Die sogenannte “akute multiple Sklerose” (Encephalomyelitis peraxialis scleroticans). Jahrb Neurol Psych 27:211-312

    Google Scholar 

  152. Massa PT, Ozato K, McFarlin DE (1993) Cell type-specific regulation of major histocompatibility complex (MHC) class I gene expression in astrocytes, oligodendrocytes, and neurons. Glia 8:201-207

    CAS  PubMed  Google Scholar 

  153. Mata M, Kupina N, Fink DJ (1992) Phosphorylation-dependent neurofilament epitopes are reduced at the node of Ranvier. J Neurocytol 21:199-210

    CAS  PubMed  Google Scholar 

  154. McDonald I, Compston A (2006) The symptoms and signs of multiple sclerosis. In: Confavreux C, Lassmann H, Mcdonald I, Miller, D, Noseworthy J, Smith K, Wekerle H (eds) McAlpine’s Multiple Sclerosis. Elsevier, Philadelphia, pp. 287-346

    Google Scholar 

  155. McDonald WI (1963) The effects of experimental demyelination on conduction in peripheral nerve: a histological and electrophysiological study. II. Electrophysiological observations. Brain 86:501-524

    CAS  Google Scholar 

  156. McDonald WI, Sears TA (1970) The effects of experimental demyelination on conduction in the central nervous system. Brain 93:583-598

    CAS  PubMed  Google Scholar 

  157. McGavern DB, Murray PD, Rivera-Quinones C, Schmelzer JD, Low PA, Rodriguez M (2000) Axonal loss results in spinal cord atrophy, electrophysiological abnormalities and neurological deficits following demyelination in a chronic inflammatory model of multiple sclerosis. Brain 123:519-531

    PubMed  Google Scholar 

  158. Medana I, Martinic MA, Wekerle H, Neumann H (2001) Transection of major histocompatibility complex class I-induced neurites by cytotoxic T lymphocytes. Am J Pathol 159:809-815

    CAS  PubMed  Google Scholar 

  159. Medana IM, Gallimore A, Oxenius A, Martinic MM, Wekerle H, Neumann H (2000) MHC class I-restricted killing of neurons by virus-specific CD8+ T lymphocytes is effected through the Fas/FasL, but not the perforin pathway. Eur J Immunol 30:3623-3633

    CAS  PubMed  Google Scholar 

  160. Merkler D, Ernsting T, Kerschensteiner M, Bruck W, Stadelmann C (2006) A new focal EAE model of cortical demyelination: multiple sclerosis-like lesions with rapid resolution of inflammation and extensive remyelination. Brain 129:1972-1983

    PubMed  Google Scholar 

  161. Metkar SS, Wang B, Aguilar-Santelises M, Raja SM, Uhlin-Hansen L, Podack E, Trapani JA, Froelich CJ (2002) Cytotoxic cell granule-mediated apoptosis: perforin delivers granzyme B-serglycin complexes into target cells without plasma membrane pore formation. Immunity 16:417-428

    CAS  PubMed  Google Scholar 

  162. Miller DH, Barkhof F, Frank JA, Parker GJ, Thompson AJ (2002) Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain 125:1676-1695

    PubMed  Google Scholar 

  163. Miller SD, Olson JK, Croxford JL (2001) Multiple pathways to induction of virus-induced autoimmune demyelination: lessons from Theiler’s virus infection. J Autoimmun 16:219-227

    CAS  PubMed  Google Scholar 

  164. Moffett JR, Namboodiri MA, Cangro CB, Neale JH (1991) Immunohistochemical localization of N-acetylaspartate in rat brain. Neuroreport 2:131-134

    CAS  PubMed  Google Scholar 

  165. Mogyoros I, Bostock H, Burke D (2000) Mechanisms of paresthesias arising from healthy axons. Muscle Nerve 23:310-320

    CAS  PubMed  Google Scholar 

  166. Moncada S, Erusalimsky JD (2002) Does nitric oxide modulate mitochondrial energy generation and apoptosis? Nat Rev Mol Cell Biol 3:214-220

    CAS  PubMed  Google Scholar 

  167. Monteyne P, Bureau JF, Brahic M (1997) The infection of mouse by Theiler’s virus: from genetics to immunology. Immunol Rev 159:163-176

    CAS  PubMed  Google Scholar 

  168. Mori S, Zhang J (2006) Principles of diffusion tensor imaging and its applications to basic neuroscience research. Neuron 51:527-539

    CAS  PubMed  Google Scholar 

  169. Munoz-Fernandez MA, Fresno M (1998) The role of tumour necrosis factor, interleukin 6, interferon-gamma and inducible nitric oxide synthase in the development and pathology of the nervous system. Prog Neurobiol 56:307-340

    CAS  PubMed  Google Scholar 

  170. Murad F (2006) Shattuck Lecture. Nitric oxide and cyclic GMP in cell signaling and drug development. N Engl J Med 355:2003-2011

    CAS  PubMed  Google Scholar 

  171. Murphy S, Simmons ML, Agullo L, Garcia A, Feinstein DL, Galea E, Reis DJ, MincGolomb D, Schwartz JP (1993) Synthesis of nitric oxide in CNS glial cells. Trends Neurosci 16:323-328

    CAS  PubMed  Google Scholar 

  172. Murray PD, McGavern DB, Lin X, Njenga MK, Leibowitz J, Pease LR, Rodriguez M (1998) Perforin-dependent neurologic injury in a viral model of multiple sclerosis. J Neurosci 18:7306-7314

    CAS  PubMed  Google Scholar 

  173. Murray PD, Pavelko KD, Leibowitz J, Lin X, Rodriguez M (1998) CD4(+) and CD8(+) T cells make discrete contributions to demyelination and neurologic disease in a viral model of multiple sclerosis. J Virol 72:7320-7329

    CAS  PubMed  Google Scholar 

  174. Mutsaers SE, Carroll WM (1998) Focal accumulation of intra-axonal mitochondria in demyelination of the cat optic nerve. Acta Neuropathol (Berl) 96:139-143

    CAS  Google Scholar 

  175. Neumann H, Cavalie A, Jenne DE, Wekerle H (1995) Induction of MHC class I genes in neurons. Science 269:549-552

    CAS  PubMed  Google Scholar 

  176. Neumann H, Schmidt H, Cavalie A, Jenne D, Wekerle H (1997) Major histocompatibility complex (MHC) class I gene expression in single neurons of the central nervous system: differential regulation by interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha. J Exp Med 185:305-316

    CAS  PubMed  Google Scholar 

  177. Neumann H (2001) Control of glial immune function by neurons. Glia 36:191-199

    CAS  PubMed  Google Scholar 

  178. Neumann H, Medana IM, Bauer J, Lassmann H (2002) Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases. Trends Neurosci 25:313-319

    CAS  PubMed  Google Scholar 

  179. Neumann H, Schweigreiter R, Yamashita T, Rosenkranz K, Wekerle H, Barde YA (2002) Tumor necrosis factor inhibits neurite outgrowth and branching of hippocampal neurons by a rho-dependent mechanism. J Neurosci 22:854-862

    CAS  PubMed  Google Scholar 

  180. Nitsch R, Pohl EE, Smorodchenko A, Infante-Duarte C, Aktas O, Zipp F (2004) Direct impact of T cells on neurons revealed by two-photon microscopy in living brain tissue. J Neurosci 24:2458-2464

    CAS  PubMed  Google Scholar 

  181. Njenga MK, Pavelko KD, Baisch J, Lin X, David C, Leibowitz J, Rodriguez M (1996) Theiler’s virus persistence and demyelination in major histocompatibility complex class IIdeficient mice. J Virol 70:1729-1737

    CAS  PubMed  Google Scholar 

  182. Nordin M, Nystrom B, Wallin U, Hagbarth KE (1984) Ectopic sensory discharges and paresthesiae in patients with disorders of peripheral nerves, dorsal roots and dorsal columns. Pain 20:231-245

    CAS  PubMed  Google Scholar 

  183. Ogasawara K, Lanier LL (2005) NKG2D in NK and T cell-mediated immunity. J Clin Immunol 25:534-540

    CAS  PubMed  Google Scholar 

  184. Okuda Y, Nakatsuji Y, Fujimura H, Esumi H, Ogura T, Yanagihara T, Sakoda S (1995) Expression of the inducible isoform of nitric oxide synthase in the central nervous system of mice correlates with the severity of actively induced experimental allergic encephalomyelitis. J Neuroimmunol 62:103-112

    CAS  PubMed  Google Scholar 

  185. Oleszak EL, Zaczynska E, Bhattacharjee M, Butunoi C, Legido A, Katsetos CD (1998) Inducible nitric oxide synthase and nitrotyrosine are found in monocytes/macrophages and/or astrocytes in acute, but not in chronic, multiple sclerosis. Clin Diagn Lab Immunol 5:438-445

    CAS  PubMed  Google Scholar 

  186. Oleszak EL, Chang JR, Friedman H, Katsetos CD, Platsoucas CD (2004) Theiler’s virus infection: a model for multiple sclerosis. Clin Microbiol Rev 17:174-207

    CAS  PubMed  Google Scholar 

  187. Ostermann PO, Westerberg CE (1975) Paroxysmal attacks in multiple sclerosis. Brain 98:189-202

    CAS  PubMed  Google Scholar 

  188. Papadopoulos D, Pham-Dinh D, Reynolds R (2006) Axon loss is responsible for chronic neurological deficit following inflammatory demyelination in the rat. Exp Neurol 197:373-385

    CAS  PubMed  Google Scholar 

  189. Peles E, Salzer JL (2000) Molecular domains of myelinated axons. Curr Opin Neurobiol 10:558-565

    CAS  PubMed  Google Scholar 

  190. Peterson JW, Kidd GJ, Trapp BD (2005) Axonal degeneration in multiple sclerosis: the histopathological evidence. In Waxman SG (ed) Multiple Sclerosis as a Neuronal Disease. Elsevier, Burlington, MA, pp. 165-184

    Google Scholar 

  191. Petrache I, Birukova A, Ramirez SI, Garcia JG, Verin AD (2003) The role of the microtubules in tumor necrosis factor-alpha-induced endothelial cell permeability. Am J Respir Cell Mol Biol 28:574-581

    CAS  PubMed  Google Scholar 

  192. Pinkoski MJ, Hobman M, Heibein JA, Tomaselli K, Li F, Seth P, Froelich CJ, Bleackley RC (1998) Entry and trafficking of granzyme B in target cells during granzyme B-perforin-mediated apoptosis. Blood 92:1044-1054

    CAS  PubMed  Google Scholar 

  193. Pioro EP, Wang Y, Moore JK, Ng TC, Trapp BD, Klinkosz B, Mitsumoto H (1998) Neuronal pathology in the wobbler mouse brain revealed by in vivo proton magnetic resonance spectroscopy and immunocytochemistry. Neuroreport 9:3041-3046

    CAS  PubMed  Google Scholar 

  194. Poderoso JJ, Carreras MC, Lisdero C, Riobo N, Schopfer F, Boveris A (1996) Nitric oxide inhibits electron transfer and increases superoxide radical production in rat heart mitochondria and submitochondrial particles. Arch Biochem Biophys 328:85-92

    CAS  PubMed  Google Scholar 

  195. Poliak S, Peles E (2003) The local differentiation of myelinated axons at nodes of Ranvier. Nat Rev Neurosci 4:968-980

    CAS  PubMed  Google Scholar 

  196. Popovich PG, Guan Z, McGaughy V, Fisher L, Hickey WF, Basso DM (2002) The neuropathological and behavioral consequences of intraspinal microglial/macrophage activation. J Neuropathol Exp Neurol 61:623-633

    CAS  PubMed  Google Scholar 

  197. Posnett DN, Sinha R, Kabak S, Russo C (1994) Clonal populations of T cells in normal elderly humans: the T cell equivalent to “benign monoclonal gammapathy”. J Exp Med 179:609-618

    CAS  PubMed  Google Scholar 

  198. Pullen LC, Miller SD, Dal Canto MC, Kim BS (1993) Class I-deficient resistant mice intracerebrally inoculated with Theiler’s virus show an increased T cell response to viral antigens and susceptibility to demyelination. Eur J Immunol 23:2287-2293

    CAS  PubMed  Google Scholar 

  199. Radi R (2004) Nitric oxide, oxidants, and protein tyrosine nitration. Proc Natl Acad Sci USA 101:4003-4008

    CAS  PubMed  Google Scholar 

  200. Raja SM, Metkar SS, Froelich CJ (2003) Cytotoxic granule-mediated apoptosis: unraveling the complex mechanism. Curr Opin Immunol 15:528-532

    CAS  PubMed  Google Scholar 

  201. Rall GF, Mucke L, Oldstone MB (1995) Consequences of cytotoxic T lymphocyte interaction with major histocompatibility complex class I-expressing neurons in vivo. J Exp Med 182:1201-1212

    CAS  PubMed  Google Scholar 

  202. Ransohoff RM, Tani M (1998) Do chemokines mediate leukocyte recruitment in post-traumatic CNS inflammation? Trends Neurosci 21:154-159

    CAS  PubMed  Google Scholar 

  203. Rasminsky M (1978) Ectopic generation of impulses and cross-talk in spinal nerve roots of “dystrophic” mice. Ann Neurol 3:351-357

    CAS  PubMed  Google Scholar 

  204. Rasminsky M (1980) Ephaptic transmission between single nerve fibres in the spinal nerve roots of dystrophic mice. J Physiol 305:151-169

    CAS  PubMed  Google Scholar 

  205. Raulet DH (2006) Missing self recognition and self tolerance of natural killer (NK) cells. Semin Immunol 18:145-150

    CAS  PubMed  Google Scholar 

  206. Ray SK, Banik NL (2003) Calpain and its involvement in the pathophysiology of CNS injuries and diseases: therapeutic potential of calpain inhibitors for prevention of neurodegeneration. Curr Drug Targets CNS Neurol Disord 2:173-189

    CAS  PubMed  Google Scholar 

  207. Redford EJ, Kapoor R, Smith KJ (1997) Nitric oxide donors reversibly block axonal conduction: demyelinated axons are especially susceptible. Brain 120:2149-2157

    PubMed  Google Scholar 

  208. Renganathan M, Cummins TR, Waxman SG (2002) Nitric oxide blocks fast, slow, and persistent Na+ channels in C-type DRG neurons by S-nitrosylation. J Neurophysiol 87:761-775

    CAS  PubMed  Google Scholar 

  209. Richards TL, Alvord EC Jr, Peterson J, Cosgrove S, Petersen R, Petersen K, Heide AC, Cluff J, Rose LM (1995) Experimental allergic encephalomyelitis in non-human primates: MRI and MRS may predict the type of brain damage. NMR Biomed 8:49-58

    CAS  PubMed  Google Scholar 

  210. Rieckmann P, Maurer M (2002) Anti-inflammatory strategies to prevent axonal injury in multiple sclerosis. Curr Opin Neurol 15:361-370

    PubMed  Google Scholar 

  211. Ritchie JM, Rogart RB (1977) Density of sodium channels in mammalian myelinated nerve fibers and nature of the axonal membrane under the myelin sheath. Proc Natl Acad Sci USA 74:211-215

    CAS  PubMed  Google Scholar 

  212. Rivera-Quinones C, McGavern D, Schmelzer JD, Hunter SF, Low PA, Rodriguez M (1998) Absence of neurological deficits following extensive demyelination in a class I-deficient murine model of multiple sclerosis. Nat Med 4:187-193

    CAS  PubMed  Google Scholar 

  213. Roach A, Takahashi N, Pravtcheva D, Ruddle F, Hood L (1985) Chromosomal mapping of mouse myelin basic protein gene and structure and transcription of the partially deleted gene in Shiverer mutant mice. Cell 42:149-155

    CAS  PubMed  Google Scholar 

  214. Rodriguez M, Dunkel AJ, Thiemann RL, Leibowitz J, Zijlstra M, Jaenisch R (1993) Abrogation of resistance to Theiler’s virus-induced demyelination in H-2b mice deficient in beta 2-microglobulin. J Immunol 151:266-276

    CAS  PubMed  Google Scholar 

  215. Rodriguez M, Zoecklein LJ, Howe CL, Pavelko KD, Gamez JD, Nakane S, Papke LM (2003) Gamma interferon is critical for neuronal viral clearance and protection in a susceptible mouse strain following early intracranial Theiler’s murine encephalomyelitis virus in fection. J Virol 77:12252-12265

    CAS  PubMed  Google Scholar 

  216. Rodriguez M, Zoecklein L, Gamez JD, Pavelko KD, Papke LM, Nakane S, Howe C, Radhakrishnan S, Hansen MJ, David CS, Warrington AE, Pease LR (2006) STAT4- and STAT6-signaling molecules in a murine model of multiple sclerosis. FASEB J 20:343-345

    CAS  PubMed  Google Scholar 

  217. Rudick RA, Fisher E, Lee JC, Simon J, Jacobs L (1999) Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Multiple Sclerosis Collaborative Research Group. Neurology 53:1698-1704

    CAS  PubMed  Google Scholar 

  218. Rudick RA, Fisher E (2005) Brain atrophy as a measure of neurodegeneration and neuroprotection. In: Waxman SG (ed) Multiple Sclerosis as a Neuronal Disease. Elsevier, Burlington, MA, pp. 201-214

    Google Scholar 

  219. Sahenk Z, Whitaker JN, Mendell JR (1990) Immunocytochemical evidence for the retrograde transport of intraaxonal cathepsin D: possible relevance to the dying-back process. Brain Res 510:1-6

    CAS  PubMed  Google Scholar 

  220. Sakurai M, Kanazawa I (1999) Positive symptoms in multiple sclerosis: their treatment with sodium channel blockers, lidocaine and mexiletine. J Neurol Sci 162:162-168

    CAS  PubMed  Google Scholar 

  221. Salvesen GS, Dixit VM (1999) Caspase activation: the induced-proximity model. Proc Natl Acad Sci USA 96:10964-10967

    CAS  PubMed  Google Scholar 

  222. Sathornsumetee S, McGavern DB, Ure DR, Rodriguez M (2000) Quantitative ultrastructural analysis of a single spinal cord demyelinated lesion predicts total lesion load, axonal loss, and neurological dysfunction in a murine model of multiple sclerosis. Am J Pathol 157:1365-1376

    CAS  PubMed  Google Scholar 

  223. Scarisbrick IA, Rodriguez M (2003) Hit-hit and hit-run: viruses in the playing field of multiple sclerosis. Curr Neurol Neurosci Rep 3:265-271

    CAS  PubMed  Google Scholar 

  224. Schiffer R, Pope LE (2005) Review of pseudobulbar affect including a novel and potential therapy. J Neuropsychiatry Clin Neurosci 17:447-454

    CAS  PubMed  Google Scholar 

  225. Schwab R, Szabo P, Manavalan JS, Weksler ME, Posnett DN, Pannetier C, Kourilsky P, Even J (1997) Expanded CD4+ and CD8+ T cell clones in elderly humans. J Immunol 158:4493-4499

    CAS  PubMed  Google Scholar 

  226. Sherriff FE, Bridges LR, Sivaloganathan S (1994) Early detection of axonal injury after human head trauma using immunocytochemistry for beta-amyloid precursor protein. Acta Neuropathol (Berl) 87:55-62

    CAS  Google Scholar 

  227. Shi L, Mai S, Israels S, Browne K, Trapani JA, Greenberg AH (1997) Granzyme B (GraB) autonomously crosses the cell membrane and perforin initiates apoptosis and GraB nuclear localization. J Exp Med 185:855-866

    CAS  PubMed  Google Scholar 

  228. Shields DC, Schaecher KE, Saido TC, Banik NL (1999) A putative mechanism of demyelination in multiple sclerosis by a proteolytic enzyme, calpain. Proc Natl Acad Sci USA 96:11486-11491

    CAS  PubMed  Google Scholar 

  229. Shrager P (1987) The distribution of sodium and potassium channels in single demyelinated axons of the frog. J Physiol 392:587-602

    CAS  PubMed  Google Scholar 

  230. Shriver LP, Dittel BN (2006) T-cell-mediated disruption of the neuronal microtubule network: correlation with early reversible axonal dysfunction in acute experimental autoimmune encephalomyelitis. Am J Pathol 169:999-1011

    CAS  PubMed  Google Scholar 

  231. Siebert H, Bruck W (2003) The role of cytokines and adhesion molecules in axon degeneration after peripheral nerve axotomy: a study in different knockout mice. Brain Res 960:152-156

    CAS  PubMed  Google Scholar 

  232. Signoretti S, Marmarou A, Tavazzi B, Lazzarino G, Beaumont A, Vagnozzi R (2001) N-acetylaspartate reduction as a measure of injury severity and mitochondrial dysfunction following diffuse traumatic brain injury. J Neurotrauma 18:977-991

    CAS  PubMed  Google Scholar 

  233. Simmons ML, Frondoza CG, Coyle JT (1991) Immunocytochemical localization of N-acetyl-aspartate with monoclonal antibodies. Neuroscience 45:37-45

    CAS  PubMed  Google Scholar 

  234. Smith DH, Uryu K, Saatman KE, Trojanowski JQ, McIntosh TK (2003) Protein accumulation in traumatic brain injury. Neuromolecular Med 4:59-72

    CAS  PubMed  Google Scholar 

  235. Smith EJ, Blakemore WF, McDonald WI (1979) Central remyelination restores secure conduction. Nature 280:395-396

    CAS  PubMed  Google Scholar 

  236. Smith KJ, McDonald WI (1980) Spontaneous and mechanically evoked activity due to central demyelinating lesion. Nature 286:154-155

    CAS  PubMed  Google Scholar 

  237. Smith KJ (1994) Conduction properties of central demyelinated and remyelinated axons, and their relation to symptom production in demyelinating disorders. Eye 8:224-237

    PubMed  Google Scholar 

  238. Smith KJ, Lassmann H (2002) The role of nitric oxide in multiple sclerosis. Lancet Neurol 1:232-241

    CAS  PubMed  Google Scholar 

  239. Smith KJ (2006) Axonal protection in multiple sclerosis - a particular need during remyelination? Brain 129:3147-3149

    PubMed  Google Scholar 

  240. Song SK, Sun SW, Ramsbottom MJ, Chang C, Russell J, Cross AH (2002) Dysmyelination revealed through MRI as increased radial (but unchanged axial) diffusion of water. Neuroimage 17:1429-1436

    PubMed  Google Scholar 

  241. Song SK, Sun SW, Ju WK, Lin SJ, Cross AH, Neufeld AH (2003) Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia. Neuroimage 20:1714-1722

    PubMed  Google Scholar 

  242. Song SK, Kim JH, Lin SJ, Brendza RP, Holtzman DM (2004) Diffusion tensor imaging detects age-dependent white matter changes in a transgenic mouse model with amyloid deposition. Neurobiol Dis 15:640-647

    CAS  PubMed  Google Scholar 

  243. Song SK, Yoshino J, Le TQ, Lin SJ, Sun SW, Cross AH, Armstrong RC (2005) Demyelination increases radial diffusivity in corpus callosum of mouse brain. Neuroimage 26:132-140

    PubMed  Google Scholar 

  244. Spissu A, Cannas A, Ferrigno P, Pelaghi AE, Spissu M (1999) Anatomic correlates of painful tonic spasms in multiple sclerosis. Mov Disord 14:331-335

    CAS  PubMed  Google Scholar 

  245. Stephanova DI, Daskalova M (2005) Differences in potentials and excitability properties in simulated cases of demyelinating neuropathies. Part II. Paranodal demyelination. Clin Neurophysiol 116:1159-166

    CAS  PubMed  Google Scholar 

  246. Stohlman SA, Hinton DR (2001) Viral induced demyelination. Brain Pathol 11:92-106

    CAS  PubMed  Google Scholar 

  247. Stys PK, Waxman SG, Ransom BR (1992) Ionic mechanisms of anoxic injury in mammalian CNS white matter: role of Na+ channels and Na(+)-Ca2+ exchanger. J Neurosci 12:430-439

    CAS  PubMed  Google Scholar 

  248. Suidan HS, Bouvier J, Schaerer E, Stone SR, Monard D, Tschopp J (1994) Granzyme A released upon stimulation of cytotoxic T lymphocytes activates the thrombin receptor on neuronal cells and astrocytes. Proc Natl Acad Sci USA 91:8112-8116

    CAS  PubMed  Google Scholar 

  249. Suter U, Welcher AA, Ozcelik T, Snipes GJ, Kosaras B, Francke U, Billings-Gagliardi S, Sidman RL, Shooter EM (1992) Trembler mouse carries a point mutation in a myelin gene. Nature 356:241-244

    CAS  PubMed  Google Scholar 

  250. Thorburn A (2004) Death receptor-induced cell killing. Cell Signal 16:139-144

    CAS  PubMed  Google Scholar 

  251. Trapani JA, Smyth MJ (2002) Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol 2:735-747

    CAS  PubMed  Google Scholar 

  252. Trapani JA, Sutton VR (2003) Granzyme B: pro-apoptotic, antiviral and antitumor functions. Curr Opin Immunol 15:533-543

    CAS  PubMed  Google Scholar 

  253. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338:278-285

    CAS  PubMed  Google Scholar 

  254. Turrin NP, Rivest S (2006) Tumor necrosis factor alpha but not interleukin 1 beta mediates neuroprotection in response to acute nitric oxide excitotoxicity. J Neurosci 26:143-151

    CAS  PubMed  Google Scholar 

  255. Ure D, Rodriguez M (2000) Extensive injury of descending neurons demonstrated by retrograde labeling in a virus-induced murine model of chronic inflammatory demyelination. J Neuropathol Exp Neurol 59:664-678

    CAS  PubMed  Google Scholar 

  256. Ure DR, Rodriguez M (2002) Preservation of neurologic function during inflammatory demyelination correlates with axon sparing in a mouse model of multiple sclerosis. Neuroscience 111:399-411

    CAS  PubMed  Google Scholar 

  257. Vladimirova O, O’Connor J, Cahill A, Alder H, Butunoi C, Kalman B (1998) Oxidative damage to DNA in plaques of MS brains. Mult Scler 4:413-418

    CAS  PubMed  Google Scholar 

  258. Voskoboinik I, Smyth MJ, Trapani JA (2006) Perforin-mediated target-cell death and immune homeostasis. Nat Rev Immunol 6:940-952

    CAS  PubMed  Google Scholar 

  259. Wang T, Allie R, Conant K, Haughey N, Turchan-Chelowo J, Hahn K, Rosen A, Steiner J, Keswani S, Jones M, Calabresi PA, Nath A (2006) Granzyme B mediates neurotoxicity through a G-protein-coupled receptor. FASEB J 20:1209-1211

    CAS  PubMed  Google Scholar 

  260. Waxman SG (1977) Conduction in myelinated, unmyelinated, and demyelinated fibers. Arch Neurol 34:585-589

    CAS  PubMed  Google Scholar 

  261. Waxman SG (1981) Clinicopathological correlations in multiple sclerosis and related diseases. Adv Neurol 31:169-182

    CAS  PubMed  Google Scholar 

  262. Waxman SG, Ritchie JM (1993) Molecular dissection of the myelinated axon. Ann Neurol 33:121-136

    CAS  PubMed  Google Scholar 

  263. Waxman SG (2005). Multiple Sclerosis as a Neuronal Disease. Elsevier, Burlington, MA.

    Google Scholar 

  264. Westenbroek RE, Noebels JL, Catterall WA (1992) Elevated expression of type II Na+ channels in hypomyelinated axons of Shiverer mouse brain. J Neurosci 12:2259-2267

    CAS  PubMed  Google Scholar 

  265. Wujek JR, Bjartmar C, Richer E, Ransohoff RM, Yu M, Tuohy VK, Trapp BD (2002) Axon loss in the spinal cord determines permanent neurological disability in an animal model of multiple sclerosis. J Neuropathol Exp Neurol 61:23-32

    PubMed  Google Scholar 

  266. Yeager MP, DeLeo JA, Hoopes PJ, Hartov A, Hildebrandt L, Hickey WF (2000) Trauma and inflammation modulate lymphocyte localization in vivo: quantitation of tissue entry and retention using indium-111-labeled lymphocytes. Crit Care Med 28:1477-1482

    CAS  PubMed  Google Scholar 

  267. Zabaleta M, Marino R, Borges J, Camargo B, Ordaz P, De Sanctis JB, Bianco NE (2002) Activity profile in multiple sclerosis: an integrative approach. A preliminary report. Mult Scler 8:343-349

    CAS  PubMed  Google Scholar 

  268. Zenzola A, De Mari M, De Blasi R, Carella A, Lamberti P (2001) Paroxysmal dystonia with thalamic lesion in multiple sclerosis. Neurol Sci 22:391-394

    CAS  PubMed  Google Scholar 

  269. Zielasek J, Reichmann H, Kunzig H, Jung S, Hartung HP, Toyka KV (1995) Inhibition of brain macrophage/microglial respiratory chain enzyme activity in experimental autoimmune encephalomyelitis of the Lewis rat. Neurosci Lett 184:129-132

    CAS  PubMed  Google Scholar 

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  1. Departments of Neuroscience and Neurology, Translational Immunovirology and Biodefense Program, Molecular Neuroscience Program, Mayo Clinic College of Medicine, Guggenheim 442-C, 200 First Street SW, Rochester, MN 55905, USA

    C. L. Howe

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  1. Department of Neurology and Immunology, Mayo Clinic, College of Medicine, 200 First Street SW, Rochester, MN 55905, USA

    Moses Rodriguez

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Howe, C.L. (2008). Immunological Aspects of Axon Injury in Multiple Sclerosis. In: Rodriguez, M. (eds) Advances in multiple Sclerosis and Experimental Demyelinating Diseases. Current Topics in Microbiology and Immunology, vol 318. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-73677-6_5

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