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Axo-glial antigens as targets in multiple sclerosis: implications for axonal and grey matter injury

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Abstract

Multiple sclerosis is thought to be an autoimmune-mediated disease of the central nervous system. For many years, T-cells were regarded as the key players in the pathogenesis, and myelin of white matter was considered as the main victim. However, research during recent years showed a more complex picture. Besides T-cells, also B-cells, antibodies and the innate immunity contribute to the tissue damage. Modern imaging techniques and neuropathological examinations showed that not only myelin but also axons, cortical neurons and nodes of Ranvier are damaged. The autoimmune targets of this widespread injury are so far not known. The identification of the axo-glial proteins contactin-2 and neurofascin provides excellent examples how antibodies can induce axonal injury at the node of Ranvier and how T-cells can destruct cortical integrity. This review will discuss the pathogenic implications of an autoimmune response against these newly discovered antigens.

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References

  1. McFarland HF, Martin R (2007) Multiple sclerosis: a complicated picture of autoimmunity. Nat Immunol 8:913–919. doi:10.1038/ni1507

    Article  CAS  PubMed  Google Scholar 

  2. Sospedra M, Martin R (2005) Immunology of multiple sclerosis. Annu Rev Immunol 23:683–747. doi:10.1146/annurev.immunol.23.021704.115707

    Article  CAS  PubMed  Google Scholar 

  3. Hauser SL, Oksenberg JR (2006) The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron 52:61–76. doi:10.1016/j.neuron.2006.09.011

    Article  CAS  PubMed  Google Scholar 

  4. Krishnamoorthy G, Wekerle H (2009) EAE: an immunologist's magic eye. Eur J Immunol 39:2031–2035. doi:10.1002/eji.200939568

    Article  CAS  PubMed  Google Scholar 

  5. De Jager PL, Jia X, Wang J, de Bakker PI, Ottoboni L, Aggarwal NT, Piccio L, Raychaudhuri S, Tran D, Aubin C, Briskin R, Romano S, Baranzini SE, McCauley JL, Pericak-Vance MA, Haines JL, Gibson RA, Naeglin Y, Uitdehaag B, Matthews PM, Kappos L, Polman C, McArdle WL, Strachan DP, Evans D, Cross AH, Daly MJ, Compston A, Sawcer SJ, Weiner HL, Hauser SL, Hafler DA, Oksenberg JR (2009) Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat Genet 41:776–782. doi:10.1038/ng.401

    Article  PubMed  CAS  Google Scholar 

  6. Kumpfel T, Hoffmann LA, Pellkofer H, Pollmann W, Feneberg W, Hohlfeld R, Lohse P (2008) Multiple sclerosis and the TNFRSF1A R92Q mutation: clinical characteristics of 21 cases. Neurology 71:1812–1820. doi:10.1212/01.wnl.0000335930.18776.47

    Article  CAS  PubMed  Google Scholar 

  7. Dyment DA, Ebers GC, Sadovnick AD (2004) Genetics of multiple sclerosis. Lancet Neurol 3:104–110

    Article  CAS  PubMed  Google Scholar 

  8. Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ, De Jager PL, de Bakker PI, Gabriel SB, Mirel DB, Ivinson AJ, Pericak-Vance MA, Gregory SG, Rioux JD, McCauley JL, Haines JL, Barcellos LF, Cree B, Oksenberg JR, Hauser SL (2007) Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 357:851–862. doi:10.1056/NEJMoa073493

    Article  CAS  PubMed  Google Scholar 

  9. Giovannoni G, Cutter GR, Lunemann J, Martin R, Munz C, Sriram S, Steiner I, Hammerschlag MR, Gaydos CA (2006) Infectious causes of multiple sclerosis. Lancet Neurol 5:887–894. doi:10.1016/S1474-4422(06)70577-4

    Article  PubMed  Google Scholar 

  10. Ascherio A, Munger K (2008) Epidemiology of multiple sclerosis: from risk factors to prevention. Semin Neurol 28:17–28. doi:10.1055/s-2007-1019126

    Article  PubMed  Google Scholar 

  11. Australia and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene) (2009) Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20. Nat Genet 41:824–828. doi:10.1038/ng.396

    Article  CAS  Google Scholar 

  12. Lassmann H, Bruck W, Lucchinetti CF (2007) The immunopathology of multiple sclerosis: an overview. Brain Pathol 17:210–218. doi:10.1111/j.1750-3639.2007.00064.x

    Article  PubMed  Google Scholar 

  13. Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H (2000) Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 47:707–717

    Article  CAS  PubMed  Google Scholar 

  14. Breij EC, Brink BP, Veerhuis R, van den Berg C, Vloet R, Yan R, Dijkstra CD, van der Valk P, Bo L (2008) Homogeneity of active demyelinating lesions in established multiple sclerosis. Ann Neurol 63:16–25. doi:10.1002/ana.21311

    Article  CAS  PubMed  Google Scholar 

  15. Barnett MH, Parratt JD, Cho ES, Prineas JW (2009) Immunoglobulins and complement in postmortem multiple sclerosis tissue. Ann Neurol 65:32–46. doi:10.1002/ana.21524

    Article  PubMed  Google Scholar 

  16. Barnett MH, Prineas JW (2004) Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol 55:458–468. doi:10.1002/ana.20016

    Article  PubMed  Google Scholar 

  17. Metcalf M, Xu D, Okuda DT, Carvajal L, Srinivasan R, Kelley DA, Mukherjee P, Nelson SJ, Vigneron DB, Pelletier D (2009) High-resolution phased-array MRI of the human brain at 7 Tesla: initial experience in multiple sclerosis patients. J Neuroimaging. doi:10.1111/j.1552-6569.2008.00338.x

    PubMed  Google Scholar 

  18. Geurts JJ, Pouwels PJ, Uitdehaag BM, Polman CH, Barkhof F, Castelijns JA (2005) Intracortical lesions in multiple sclerosis: improved detection with 3D double inversion-recovery MR imaging. Radiology 236:254–260. doi:10.1148/radiol.2361040450

    Article  PubMed  Google Scholar 

  19. Davies GR, Ramio-Torrenta L, Hadjiprocopis A, Chard DT, Griffin CM, Rashid W, Barker GJ, Kapoor R, Thompson AJ, Miller DH (2004) Evidence for grey matter MTR abnormality in minimally disabled patients with early relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatry 75:998–1002

    Article  CAS  PubMed  Google Scholar 

  20. Vrenken H, Pouwels PJ, Geurts JJ, Knol DL, Polman CH, Barkhof F, Castelijns JA (2006) Altered diffusion tensor in multiple sclerosis normal-appearing brain tissue: cortical diffusion changes seem related to clinical deterioration. J Magn Reson Imaging 23:628–636. doi:10.1002/jmri.20564

    Article  PubMed  Google Scholar 

  21. De Stefano N, Matthews PM, Filippi M, Agosta F, De Luca M, Bartolozzi ML, Guidi L, Ghezzi A, Montanari E, Cifelli A, Federico A, Smith SM (2003) Evidence of early cortical atrophy in MS: relevance to white matter changes and disability. Neurology 60:1157–1162

    PubMed  Google Scholar 

  22. Ramio-Torrenta L, Sastre-Garriga J, Ingle GT, Davies GR, Ameen V, Miller DH, Thompson AJ (2006) Abnormalities in normal appearing tissues in early primary progressive multiple sclerosis and their relation to disability: a tissue specific magnetisation transfer study. J Neurol Neurosurg Psychiatry 77:40–45. doi:10.1136/jnnp.2004.052316

    Article  CAS  PubMed  Google Scholar 

  23. Bo L, Geurts JJ, van der Valk P, Polman C, Barkhof F (2007) Lack of correlation between cortical demyelination and white matter pathologic changes in multiple sclerosis. Arch Neurol 64:76–80. doi:10.1001/archneur.64.1.76

    Article  PubMed  Google Scholar 

  24. Agosta F, Rovaris M, Pagani E, Sormani MP, Comi G, Filippi M (2006) Magnetization transfer MRI metrics predict the accumulation of disability 8 years later in patients with multiple sclerosis. Brain 129:2620–2627. doi:10.1093/brain/awl208

    Article  PubMed  Google Scholar 

  25. Rovaris M, Judica E, Gallo A, Benedetti B, Sormani MP, Caputo D, Ghezzi A, Montanari E, Bertolotto A, Mancardi G, Bergamaschi R, Martinelli V, Comi G, Filippi M (2006) Grey matter damage predicts the evolution of primary progressive multiple sclerosis at 5 years. Brain 129:2628–2634. doi:10.1093/brain/awl222

    Article  CAS  PubMed  Google Scholar 

  26. Manfredonia F, Ciccarelli O, Khaleeli Z, Tozer DJ, Sastre-Garriga J, Miller DH, Thompson AJ (2007) Normal-appearing brain t1 relaxation time predicts disability in early primary progressive multiple sclerosis. Arch Neurol 64:411–415. doi:10.1001/archneur.64.3.411

    Article  PubMed  Google Scholar 

  27. Fisher E, Lee JC, Nakamura K, Rudick RA (2008) Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol 64:255–265. doi:10.1002/ana.21436

    Article  PubMed  Google Scholar 

  28. Fisniku LK, Chard DT, Jackson JS, Anderson VM, Altmann DR, Miszkiel KA, Thompson AJ, Miller DH (2008) Gray matter atrophy is related to long-term disability in multiple sclerosis. Ann Neurol 64:247–254. doi:10.1002/ana.21423

    Article  PubMed  Google Scholar 

  29. Geurts JJ, Bo L, Pouwels PJ, Castelijns JA, Polman CH, Barkhof F (2005) Cortical lesions in multiple sclerosis: combined postmortem MR imaging and histopathology. AJNR Am J Neuroradiol 26:572–577

    PubMed  Google Scholar 

  30. Kidd D, Barkhof F, McConnell R, Algra PR, Allen IV, Revesz T (1999) Cortical lesions in multiple sclerosis. Brain 122(Pt 1):17–26

    Article  PubMed  Google Scholar 

  31. Peterson JW, Bo L, Mork S, Chang A, Trapp BD (2001) Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 50:389–400

    Article  CAS  PubMed  Google Scholar 

  32. Bo L, Vedeler CA, Nyland H, Trapp BD, Mork SJ (2003) Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration. Mult Scler 9:323–331

    Article  CAS  PubMed  Google Scholar 

  33. Brink BP, Veerhuis R, Breij EC, van der Valk P, Dijkstra CD, Bo L (2005) The pathology of multiple sclerosis is location-dependent: no significant complement activation is detected in purely cortical lesions. J Neuropathol Exp Neurol 64:147–155

    CAS  PubMed  Google Scholar 

  34. Bo L, Vedeler CA, Nyland HI, Trapp BD, Mork SJ (2003) Subpial demyelination in the cerebral cortex of multiple sclerosis patients. J Neuropathol Exp Neurol 62:723–732

    PubMed  Google Scholar 

  35. Vercellino M, Plano F, Votta B, Mutani R, Giordana MT, Cavalla P (2005) Grey matter pathology in multiple sclerosis. J Neuropathol Exp Neurol 64:1101–1107

    Article  PubMed  Google Scholar 

  36. Kutzelnigg A, Lucchinetti CF, Stadelmann C, Bruck W, Rauschka H, Bergmann M, Schmidbauer M, Parisi JE, Lassmann H (2005) Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 128:2705–2712. doi:10.1093/brain/awh641

    Article  PubMed  Google Scholar 

  37. Serafini B, Rosicarelli B, Magliozzi R, Stigliano E, Aloisi F (2004) Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol 14:164–174

    Article  PubMed  Google Scholar 

  38. Magliozzi R, Howell O, Vora A, Serafini B, Nicholas R, Puopolo M, Reynolds R, Aloisi F (2007) Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 130:1089–1104. doi:10.1093/brain/awm038

    Article  PubMed  Google Scholar 

  39. Kooi EJ, Geurts JJ, van Horssen J, Bo L, van der Valk P (2009) Meningeal inflammation is not associated with cortical demyelination in chronic multiple sclerosis. J Neuropathol Exp Neurol 68:1021–1028. doi:10.1097/NEN.0b013e3181b4bf8f

    Article  CAS  PubMed  Google Scholar 

  40. Serafini B, Rosicarelli B, Franciotta D, Magliozzi R, Reynolds R, Cinque P, Andreoni L, Trivedi P, Salvetti M, Faggioni A, Aloisi F (2007) Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J Exp Med 204:2899–2912. doi:10.1084/jem.20071030

    Article  CAS  PubMed  Google Scholar 

  41. Willis SN, Stadelmann C, Rodig SJ, Caron T, Gattenloehner S, Mallozzi SS, Roughan JE, Almendinger SE, Blewett MM, Bruck W, Hafler DA, O'Connor KC (2009) Epstein-Barr virus infection is not a characteristic feature of multiple sclerosis brain. Brain. doi:10.1093/brain/awp200

    Google Scholar 

  42. Bjartmar C, Wujek JR, Trapp BD (2003) Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease. J Neurol Sci 206:165–171

    Article  CAS  PubMed  Google Scholar 

  43. 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

    Article  CAS  PubMed  Google Scholar 

  44. Kuhlmann T, Lingfeld G, Bitsch A, Schuchardt J, Bruck W (2002) Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 125:2202–2212

    Article  PubMed  Google Scholar 

  45. Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, Laursen H, Sorensen PS, Lassmann H (2009) The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 132:1175–1189. doi:10.1093/brain/awp070

    Article  PubMed  Google Scholar 

  46. 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 

  47. Mathey EK, Derfuss T, Storch MK, Williams KR, Hales K, Woolley DR, Al-Hayani A, Davies SN, Rasband MN, Olsson T, Moldenhauer A, Velhin S, Hohlfeld R, Meinl E, Linington C (2007) Neurofascin as a novel target for autoantibody-mediated axonal injury. J Exp Med 204:2363–2372. doi:10.1084/jem.20071053

    Article  CAS  PubMed  Google Scholar 

  48. Sobottka B, Harrer MD, Ziegler U, Fischer K, Wiendl H, Hunig T, Becher B, Goebels N (2009) Collateral bystander damage by myelin-directed CD8+ T cells causes axonal loss. Am J Pathol 175:1160–1166. doi:10.2353/ajpath.2009.090340

    Article  CAS  PubMed  Google Scholar 

  49. Evangelou N, Konz D, Esiri MM, Smith S, Palace J, Matthews PM (2000) Regional axonal loss in the corpus callosum correlates with cerebral white matter lesion volume and distribution in multiple sclerosis. Brain 123(Pt 9):1845–1849

    Article  PubMed  Google Scholar 

  50. Irvine KA, Blakemore WF (2008) Remyelination protects axons from demyelination-associated axon degeneration. Brain 131:1464–1477. doi:10.1093/brain/awn080

    Article  CAS  PubMed  Google Scholar 

  51. Nave KA, Trapp BD (2008) Axon-glial signaling and the glial support of axon function. Annu Rev Neurosci 31:535–561. doi:10.1146/annurev.neuro.30.051606.094309

    Article  CAS  PubMed  Google Scholar 

  52. Einheber S, Bhat MA, Salzer JL (2006) Disrupted axo-glial junctions result in accumulation of abnormal mitochondria at nodes of Ranvier. Neuron Glia Biol 2:165–174. doi:10.1017/S1740925X06000275

    Article  PubMed  Google Scholar 

  53. Kassmann CM, Lappe-Siefke C, Baes M, Brugger B, Mildner A, Werner HB, Natt O, Michaelis T, Prinz M, Frahm J, Nave KA (2007) Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes. Nat Genet 39:969–976. doi:10.1038/ng2070

    Article  CAS  PubMed  Google Scholar 

  54. Meinl E, Krumbholz M, Hohlfeld R (2006) B lineage cells in the inflammatory central nervous system environment: migration, maintenance, local antibody production, and therapeutic modulation. Ann Neurol 59:880–892. doi:10.1002/ana.20890

    Article  CAS  PubMed  Google Scholar 

  55. Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, Bar-Or A, Panzara M, Sarkar N, Agarwal S, Langer-Gould A, Smith CH (2008) B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 358:676–688. doi:10.1056/NEJMoa0706383

    Article  CAS  PubMed  Google Scholar 

  56. 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 366:579–582. doi:10.1016/S0140-6736(05)67102-4

    Article  PubMed  Google Scholar 

  57. Berger T, Weerth S, Kojima K, Linington C, Wekerle H, Lassmann H (1997) Experimental autoimmune encephalomyelitis: the antigen specificity of T lymphocytes determines the topography of lesions in the central and peripheral nervous system. Lab Invest 76:355–364

    CAS  PubMed  Google Scholar 

  58. Geurts JJ, Barkhof F (2008) Grey matter pathology in multiple sclerosis. Lancet Neurol 7:841–851. doi:10.1016/S1474-4422(08)70191-1

    Article  PubMed  Google Scholar 

  59. Derfuss T, Parikh K, Velhin S, Braun M, Mathey E, Krumbholz M, Kumpfel T, Moldenhauer A, Rader C, Sonderegger P, Pollmann W, Tiefenthaller C, Bauer J, Lassmann H, Wekerle H, Karagogeos D, Hohlfeld R, Linington C, Meinl E (2009) Contactin-2/TAG-1-directed autoimmunity is identified in multiple sclerosis patients and mediates gray matter pathology in animals. Proc Natl Acad Sci U S A 106:8302–8307. doi:10.1073/pnas.0901496106

    Article  CAS  PubMed  Google Scholar 

  60. Furley AJ, Morton SB, Manalo D, Karagogeos D, Dodd J, Jessell TM (1990) The axonal glycoprotein TAG-1 is an immunoglobulin superfamily member with neurite outgrowth-promoting activity. Cell 61:157–170

    Article  CAS  PubMed  Google Scholar 

  61. Karagogeos D, Morton SB, Casano F, Dodd J, Jessell TM (1991) Developmental expression of the axonal glycoprotein TAG-1: differential regulation by central and peripheral neurons in vitro. Development 112:51–67

    CAS  PubMed  Google Scholar 

  62. Traka M, Dupree JL, Popko B, Karagogeos D (2002) The neuronal adhesion protein TAG-1 is expressed by Schwann cells and oligodendrocytes and is localized to the juxtaparanodal region of myelinated fibers. J Neurosci 22:3016–3024

    CAS  PubMed  Google Scholar 

  63. Labasque M, Faivre-Sarrailh C (2009) GPI-anchored proteins at the node of Ranvier. FEBS Lett. doi:10.1016/j.febslet.2009.08.025

    PubMed  Google Scholar 

  64. Meinl E, Derfuss T, Linington C (2010) Identifying targets for autoantibodies in CNS inflammation: strategies and achievements. Clin Exp Neuroimmunol. doi:10.1111/j.1759-1961.2009.00006.x

    Google Scholar 

  65. Kozlov SV, Giger RJ, Hasler T, Korvatska E, Schorderet DF, Sonderegger P (1995) The human TAX1 gene encoding the axon-associated cell adhesion molecule TAG-1/axonin-1: genomic structure and basic promoter. Genomics 30:141–148. doi:10.1006/geno.1995.9892

    Article  CAS  PubMed  Google Scholar 

  66. Traka M, Goutebroze L, Denisenko N, Bessa M, Nifli A, Havaki S, Iwakura Y, Fukamauchi F, Watanabe K, Soliven B, Girault JA, Karagogeos D (2003) Association of TAG-1 with Caspr2 is essential for the molecular organization of juxtaparanodal regions of myelinated fibers. J Cell Biol 162:1161–1172

    Article  CAS  PubMed  Google Scholar 

  67. Kunz B, Lierheimer R, Rader C, Spirig M, Ziegler U, Sonderegger P (2002) Axonin-1/TAG-1 mediates cell-cell adhesion by a cis-assisted trans-interaction. J Biol Chem 277:4551–4557

    Article  CAS  PubMed  Google Scholar 

  68. Savvaki M, Panagiotaropoulos T, Stamatakis A, Sargiannidou I, Karatzioula P, Watanabe K, Stylianopoulou F, Karagogeos D, Kleopa KA (2008) Impairment of learning and memory in TAG-1 deficient mice associated with shorter CNS internodes and disrupted juxtaparanodes. Mol Cell Neurosci 39:478–490. doi:10.1016/j.mcn.2008.07.025

    Article  CAS  PubMed  Google Scholar 

  69. Charles P, Tait S, Faivre-Sarrailh C, Barbin G, Gunn-Moore F, Denisenko-Nehrbass N, Guennoc AM, Girault JA, Brophy PJ, Lubetzki C (2002) Neurofascin is a glial receptor for the paranodin/Caspr-contactin axonal complex at the axoglial junction. Curr Biol 12:217–220

    Article  CAS  PubMed  Google Scholar 

  70. Sherman DL, Tait S, Melrose S, Johnson R, Zonta B, Court FA, Macklin WB, Meek S, Smith AJ, Cottrell DF, Brophy PJ (2005) Neurofascins are required to establish axonal domains for saltatory conduction. Neuron 48:737–742. doi:10.1016/j.neuron.2005.10.019

    Article  CAS  PubMed  Google Scholar 

  71. Lambert S, Davis JQ, Bennett V (1997) Morphogenesis of the node of Ranvier: co-clusters of ankyrin and ankyrin-binding integral proteins define early developmental intermediates. J Neurosci 17:7025–7036

    CAS  PubMed  Google Scholar 

  72. Davis JQ, Lambert S, Bennett V (1996) Molecular composition of the node of Ranvier: identification of ankyrin-binding cell adhesion molecules neurofascin (mucin+/third FNIII domain-) and NrCAM at nodal axon segments. J Cell Biol 135:1355–1367

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  74. Eshed Y, Feinberg K, Poliak S, Sabanay H, Sarig-Nadir O, Spiegel I, Bermingham JR Jr, Peles E (2005) Gliomedin mediates Schwann cell-axon interaction and the molecular assembly of the nodes of Ranvier. Neuron 47:215–229. doi:10.1016/j.neuron.2005.06.026

    Article  CAS  PubMed  Google Scholar 

  75. Zonta B, Tait S, Melrose S, Anderson H, Harroch S, Higginson J, Sherman DL, Brophy PJ (2008) Glial and neuronal isoforms of Neurofascin have distinct roles in the assembly of nodes of Ranvier in the central nervous system. J Cell Biol 181:1169–1177. doi:10.1083/jcb.200712154

    Article  CAS  PubMed  Google Scholar 

  76. Backer S, Sakurai T, Grumet M, Sotelo C, Bloch-Gallego E (2002) Nr-CAM and TAG-1 are expressed in distinct populations of developing precerebellar and cerebellar neurons. Neuroscience 113:743–748

    Article  CAS  PubMed  Google Scholar 

  77. Rios JC, Melendez-Vasquez CV, Einheber S, Lustig M, Grumet M, Hemperly J, Peles E, Salzer JL (2000) Contactin-associated protein (Caspr) and contactin form a complex that is targeted to the paranodal junctions during myelination. J Neurosci 20:8354–8364

    CAS  PubMed  Google Scholar 

  78. Melendez-Vasquez C, Carey DJ, Zanazzi G, Reizes O, Maurel P, Salzer JL (2005) Differential expression of proteoglycans at central and peripheral nodes of Ranvier. Glia 52:301–308. doi:10.1002/glia.20245

    Article  PubMed  Google Scholar 

  79. Howell OW, Palser A, Polito A, Melrose S, Zonta B, Scheiermann C, Vora AJ, Brophy PJ, Reynolds R (2006) Disruption of neurofascin localization reveals early changes preceding demyelination and remyelination in multiple sclerosis. Brain 129:3173–3185. doi:10.1093/brain/awl290

    Article  CAS  PubMed  Google Scholar 

  80. 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. doi:10.1093/brain/awl144

    Article  CAS  PubMed  Google Scholar 

  81. 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 U S A 101:8168–8173

    Article  CAS  PubMed  Google Scholar 

  82. Trapp BD, Stys PK (2009) Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol 8:280–291. doi:10.1016/S1474-4422(09)70043-2

    Article  CAS  PubMed  Google Scholar 

  83. Mahad DJ, Ziabreva I, Campbell G, Lax N, White K, Hanson PS, Lassmann H, Turnbull DM (2009) Mitochondrial changes within axons in multiple sclerosis. Brain 132:1161–1174. doi:10.1093/brain/awp046

    Article  PubMed  Google Scholar 

  84. 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. doi:10.1093/brain/awl075

    Article  PubMed  Google Scholar 

  85. Kowal C, Degiorgio LA, Lee JY, Edgar MA, Huerta PT, Volpe BT, Diamond B (2006) Human lupus autoantibodies against NMDA receptors mediate cognitive impairment. Proc Natl Acad Sci U S A 103:19854–19859. doi:10.1073/pnas.0608397104

    Article  CAS  PubMed  Google Scholar 

  86. Yarnitsky D, Gross Y, Lorian A, Shalev A, Lamensdorf I, Bornstein R, Shorer S, Mayevsky A, Patel KP, Abbott NJ, Mayhan WG (2004) Blood-brain barrier opened by stimulation of the parasympathetic sphenopalatine ganglion: a new method for macromolecule delivery to the brain. J Neurosurg 101:303–309

    Article  PubMed  Google Scholar 

  87. Rapoport SI, Hori M, Klatzo I (1972) Testing of a hypothesis for osmotic opening of the blood-brain barrier. Am J Physiol 223:323–331

    CAS  PubMed  Google Scholar 

  88. 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 130:443–454

    CAS  PubMed  Google Scholar 

  89. Rudick RA, Trapp BD (2009) Gray-matter injury in multiple sclerosis. N Engl J Med 361:1505–1506. doi:10.1056/NEJMcibr0905482

    Article  CAS  PubMed  Google Scholar 

  90. Pollinger B, Krishnamoorthy G, Berer K, Lassmann H, Bosl MR, Dunn R, Domingues HS, Holz A, Kurschus FC, Wekerle H (2009) Spontaneous relapsing-remitting EAE in the SJL/J mouse: MOG-reactive transgenic T cells recruit endogenous MOG-specific B cells. J Exp Med 206:1303–1316. doi:10.1084/jem.20090299

    Article  PubMed  CAS  Google Scholar 

  91. Bettelli E, Pagany M, Weiner HL, Linington C, Sobel RA, Kuchroo VK (2003) Myelin oligodendrocyte glycoprotein-specific T cell receptor transgenic mice develop spontaneous autoimmune optic neuritis. J Exp Med 197:1073–1081

    Article  CAS  PubMed  Google Scholar 

  92. Krishnamoorthy G, Saxena A, Mars LT, Domingues HS, Mentele R, Ben-Nun A, Lassmann H, Dornmair K, Kurschus FC, Liblau RS, Wekerle H (2009) Myelin-specific T cells also recognize neuronal autoantigen in a transgenic mouse model of multiple sclerosis. Nat Med 15:626–632. doi:10.1038/nm.1975

    Article  CAS  PubMed  Google Scholar 

  93. Voltz R (2002) Paraneoplastic neurological syndromes: an update on diagnosis, pathogenesis, and therapy. Lancet Neurol 1:294–305

    Article  PubMed  Google Scholar 

  94. DeGiorgio LA, Konstantinov KN, Lee SC, Hardin JA, Volpe BT, Diamond B (2001) A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat Med 7:1189–1193

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  96. Mahad D, Lassmann H, Turnbull D (2008) Review: mitochondria and disease progression in multiple sclerosis. Neuropathol Appl Neurobiol 34:577–589. doi:10.1111/j.1365-2990.2008.00987.x

    Article  CAS  PubMed  Google Scholar 

  97. Trapp BD, Nave KA (2008) Multiple sclerosis: an immune or neurodegenerative disorder? Annu Rev Neurosci 31:247–269. doi:10.1146/annurev.neuro.30.051606.094313

    Article  CAS  PubMed  Google Scholar 

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Acknowledgement

Work of the authors is supported by the Deutsche Forschungsgemeinschaft (SFB 571), Verein zur Therapieforschung für Multiple Sklerose-Kranke, BMBF (krankheitsbezogenes Kompetenznetz Multiple Sklerose, Förderkennzeichen 01GI0905), Excellency Initiative of the Ludwig-Maximilian-University Munich.

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Correspondence to Edgar Meinl.

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Derfuss, T., Linington, C., Hohlfeld, R. et al. Axo-glial antigens as targets in multiple sclerosis: implications for axonal and grey matter injury. J Mol Med 88, 753–761 (2010). https://doi.org/10.1007/s00109-010-0632-3

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  • DOI: https://doi.org/10.1007/s00109-010-0632-3

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