Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Autoimmune antigenic targets at the node of Ranvier in demyelinating disorders

Nature Reviews Neurology volume 11, pages 143–156 (2015)Cite this article

Subjects

Key Points

  • Fast reversal of electrophysiological blockade after plasmapheresis or intravenous immunoglobulin treatment for acute and chronic inflammatory demyelinating polyneuropathy might reflect removal or neutralization of an autoantibody

  • Many proteins at the node of Ranvier, particularly those with extracellular domains, could act as autoantigens

  • Autoantibodies against antigens at the node of Ranvier might cause demyelination or axonal degeneration at the node and exacerbate symptoms in demyelinating syndromes

  • Potential autoantibody targets at the node of Ranvier that have been identified to date include Caspr1, CNPase, contactin-1, contactin-2, gliomedin, moesin, neurofascin 155 and neurofascin 186

  • Specific autoantibodies have been detected in only a few patients; however, the plethora of potential antigens in the node of Ranvier suggests that other autoantibodies remain to be discovered

Abstract

Mounting evidence suggests that autoantibodies contribute to the pathogenesis of demyelination in the PNS and CNS. Rapid reversal of electrophysiological blockade after plasmapheresis or intravenous immunoglobulin treatment for acute or chronic inflammatory demyelinating polyneuropathy is more likely to result from removal or neutralization of an antibody that impairs saltatory conduction than from remyelination. Although up to 30% of patients with acute or chronic inflammatory demyelinating polyneuropathy harbour autoantibodies, specific antigens have been identified in no more than 13% of cases. To date, autoantigens identified at the node of Ranvier include neurofascin 186, gliomedin and possibly moesin in the nodal domain, and contactin-1, Caspr1 and neurofascin 155 in the paranodal domain. In some patients with multiple sclerosis, paranodal CNPase and juxtaparanodal contactin-2 trigger a humoral response. This Review explores the molecular anatomy of the node of Ranvier, focusing on proteins with extracellular domains that could serve as antigens. The clinical implications of node-specific antibody responses are addressed, and the best approaches to identify antibodies that target nodal proteins are highlighted. Also discussed are the roles of these antibodies as either secondary, disease-exacerbating responses, or as a primary effector mechanism that defines demyelination or axonal degeneration at the node, identifies disease subtypes or determines response to treatments.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Molecular anatomy of the node of Ranvier.
Figure 2: Mouse sciatic nerve teased fibres immunostained with serum from patients with chronic inflammatory demyelinating polyneuropathy.

Similar content being viewed by others

References

  1. Nylander, A. & Hafler, D. A. Multiple sclerosis. J. Clin. Invest. 122, 1180–1188 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Lennon, V. A., Kryzer, T. J., Pittock, S. J., Verkman, A. S. & Hinson, S. R. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J. Exp. Med. 202, 473–477 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Srivastava, R. et al. Potassium channel KIR4.1 as an immune target in multiple sclerosis. N. Engl. J. Med. 367, 115–123 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Brickshawana, A. et al. Investigation of the KIR4.1 potassium channel as a putative antigen in patients with multiple sclerosis: a comparative study. Lancet Neurol. 13, 795–806 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Reindl, M., Di Pauli, F., Rostasy, K. & Berger, T. The spectrum of MOG autoantibody-associated demyelinating diseases. Nat. Rev. Neurol. 9, 455–461 (2013).

    CAS  PubMed  Google Scholar 

  6. Dalakas, M. C. Pathogenesis and treatment of anti-MAG neuropathy. Curr. Treat. Options Neurol. 12, 71–83 (2010).

    PubMed  Google Scholar 

  7. Kaida, K. & Kusunoki, S. Antibodies to gangliosides and ganglioside complexes in Guillain–Barré syndrome and Fisher syndrome: mini-review. J. Neuroimmunol. 223, 5–12 (2010).

    CAS  PubMed  Google Scholar 

  8. Hughes, R. A., Allen, D., Makowska, A. & Gregson, N. A. Pathogenesis of chronic inflammatory demyelinating polyradiculoneuropathy. J. Peripher. Nerv. Syst. 11, 30–46 (2006).

    PubMed  Google Scholar 

  9. Köller, H., Kieseier, B. C., Jander, S. & Hartung, H. P. Chronic inflammatory demyelinating polyneuropathy. N. Engl. J. Med. 352, 1343–1356 (2005).

    PubMed  Google Scholar 

  10. Patwa, H. S., Chaudhry, V., Katzberg, H., Rae-Grant, A. D. & So, Y. T. Evidence-based guideline: intravenous immunoglobulin in the treatment of neuromuscular disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 78, 1009–1015 (2012).

    CAS  PubMed  Google Scholar 

  11. Cortese, I. et al. Evidence-based guideline update: Plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 76, 294–300 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Schirmer, L., Srivastava, R. & Hemmer, B. To look for a needle in a haystack: the search for autoantibodies in multiple sclerosis. Mult. Scler. 20, 271–279 (2014).

    PubMed  Google Scholar 

  13. Krumbholz, M., Derfuss, T., Hohlfeld, R. & Meinl, E. B cells and antibodies in multiple sclerosis pathogenesis and therapy. Nat. Rev. Neurol. 8, 613–623 (2012).

    CAS  PubMed  Google Scholar 

  14. Einheber, S. et al. The axonal membrane protein Caspr, a homologue of neurexin IV, is a component of the septate-like paranodal junctions that assemble during myelination. J. Cell Biol. 139, 1495–1506 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Rasband, M. N. Composition, assembly, and maintenance of excitable membrane domains in myelinated axons. Semin. Cell Dev. Biol. 22, 178–184 (2011).

    CAS  PubMed  Google Scholar 

  16. Pan, Z. et al. A common ankyrin-G-based mechanism retains KCNQ and NaV channels at electrically active domains of the axon. J. Neurosci. 26, 2599–2613 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Poliak, S. et al. Juxtaparanodal clustering of Shaker-like K+ channels in myelinated axons depends on Caspr2 and TAG-1. J. Cell Biol. 162, 1149–1160 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Kearney, J. A. et al. Molecular and pathological effects of a modifier gene on deficiency of the sodium channel Scn8a (Nav1.6). Hum. Mol. Genet. 11, 2765–2775 (2002).

    CAS  PubMed  Google Scholar 

  19. Zhou, L., Messing, A. & Chiu, S. Y. Determinants of excitability at transition zones in Kv1.1-deficient myelinated nerves. J. Neurosci. 19, 5768–5781 (1999).

    CAS  PubMed  Google Scholar 

  20. Susuki, K. et al. Three mechanisms assemble central nervous system nodes of Ranvier. Neuron 78, 469–482 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Thaxton, C., Pillai, A. M., Pribisko, A. L., Dupree, J. L. & Bhat, M. A. Nodes of Ranvier act as barriers to restrict invasion of flanking paranodal domains in myelinated axons. Neuron 69, 244–257 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Feinberg, K. et al. A glial signal consisting of gliomedin and NrCAM clusters axonal Na+ channels during the formation of nodes of Ranvier. Neuron 65, 490–502 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Sherman, D. L. et al. Neurofascins are required to establish axonal domains for saltatory conduction. Neuron 48, 737–742 (2005).

    CAS  PubMed  Google Scholar 

  24. Weber, P. et al. Mice deficient for tenascin-R display alterations of the extracellular matrix and decreased axonal conduction velocities in the CNS. J. Neurosci. 19, 4245–4262 (1999).

    CAS  PubMed  Google Scholar 

  25. Bekku, Y. et al. Bral1: its role in diffusion barrier formation and conduction velocity in the CNS. J. Neurosci. 30, 3113–3123 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Peles, E. et al. Identification of a novel contactin-associated transmembrane receptor with multiple domains implicated in protein–protein interactions. EMBO J. 16, 978–988 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Brakebusch, C. et al. Brevican-deficient mice display impaired hippocampal CA1 long-term potentiation but show no obvious deficits in learning and memory. Mol. Cell Biol. 22, 7417–7427 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Dours-Zimmermann, M. T. et al. Versican V2 assembles the extracellular matrix surrounding the nodes of Ranvier in the CNS. J. Neurosci. 29, 7731–7742 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Melendez-Vasquez, C. et al. Differential expression of proteoglycans at central and peripheral nodes of Ranvier. Glia 52, 301–308 (2005).

    PubMed  Google Scholar 

  30. Miró, X. et al. Studies in humans and mice implicate neurocan in the etiology of mania. Am. J. Psychiatry 169, 982–990 (2012).

    PubMed  Google Scholar 

  31. Boyle, M. E. et al. Contactin orchestrates assembly of the septate-like junctions at the paranode in myelinated peripheral nerve. Neuron 30, 385–397 (2001).

    CAS  PubMed  Google Scholar 

  32. Pillai, A. M. et al. Spatiotemporal ablation of myelinating glia-specific neurofascin (Nfasc NF155) in mice reveals gradual loss of paranodal axoglial junctions and concomitant disorganization of axonal domains. J. Neurosci. Res. 87, 1773–1793 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Rios, J. C. et al. Contactin-associated protein (Caspr) and contactin form a complex that is targeted to the paranodal junctions during myelination. J. Neurosci. 20, 8354–8364 (2000).

    CAS  PubMed  Google Scholar 

  34. Feltri, M. L. et al. Conditional disruption of β1 integrin in Schwann cells impedes interactions with axons. J. Cell Biol. 156, 199–209 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Nodari, A. et al. α6β4 integrin and dystroglycan cooperate to stabilize the myelin sheath. J. Neurosci. 28, 6714–6719 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Obremski, V. J., Hall, A. M. & Fernandez-Valle, C. Merlin, the neurofibromatosis type 2 gene product, and β1 integrin associate in isolated and differentiating Schwann cells. J. Neurobiol. 37, 487–501 (1998).

    CAS  PubMed  Google Scholar 

  37. Saito, F. et al. Unique role of dystroglycan in peripheral nerve myelination, nodal structure, and sodium channel stabilization. Neuron 38, 747–758 (2003).

    CAS  PubMed  Google Scholar 

  38. Einheber, S., Milner, T. A., Giancotti, F. & Salzer, J. L. Axonal regulation of Schwann cell integrin expression suggests a role for α6β4 in myelination. J. Cell Biol. 123, 1223–1236 (1993).

    CAS  PubMed  Google Scholar 

  39. Montag, D. et al. Mice deficient for the myelin-associated glycoprotein show subtle abnormalities in myelin. Neuron 13, 229–246 (1994).

    CAS  PubMed  Google Scholar 

  40. Traka, M. et al. Association of TAG-1 with Caspr2 is essential for the molecular organization of juxtaparanodal regions of myelinated fibers. J. Cell Biol. 162, 1161–1172 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Goutebroze, L., Carnaud, M., Denisenko, N., Boutterin, M. C. & Girault, J. A. Syndecan-3 and syndecan-4 are enriched in Schwann cell perinodal processes. BMC Neurosci. 4, 29 (2003).

    PubMed  PubMed Central  Google Scholar 

  42. Martin, S., Levine, A. K., Chen, Z. J., Ughrin, Y. & Levine, J. M. Deposition of the NG2 proteoglycan at nodes of Ranvier in the peripheral nervous system. J. Neurosci. 21, 8119–8128 (2001).

    CAS  PubMed  Google Scholar 

  43. Rambukkana, A. et al. Role of α-dystroglycan as a Schwann cell receptor for Mycobacterium leprae. Science 282, 2076–2079 (1998).

    CAS  PubMed  Google Scholar 

  44. Occhi, S. et al. Both laminin and Schwann cell dystroglycan are necessary for proper clustering of sodium channels at nodes of Ranvier. J. Neurosci. 25, 9418–9427 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Guilbot, A. et al. A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot–Marie–Tooth disease. Hum. Mol. Genet. 10, 415–421 (2001).

    CAS  PubMed  Google Scholar 

  46. Jarjour, A. A. et al. Maintenance of axo-oligodendroglial paranodal junctions requires DCC and netrin-1. J. Neurosci. 28, 11003–11014 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Nie, D. Y. et al. Nogo-A at CNS paranodes is a ligand of Caspr: possible regulation of K+ channel localization. EMBO J. 22, 5666–5678 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Kim, J. E., Li, S., GrandPré, T., Qiu, D. & Strittmatter, S. M. Axon regeneration in young adult mice lacking Nogo-A/B. Neuron 38, 187–199 (2003).

    CAS  PubMed  Google Scholar 

  49. Chernousov, M. A., Stahl, R. C. & Carey, D. J. Tetraspanins are involved in Schwann cell–axon interaction. J. Neurosci. Res. 91, 1419–1428 (2013).

    CAS  PubMed  Google Scholar 

  50. Ishibashi, T. et al. Tetraspanin protein CD9 is a novel paranodal component regulating paranodal junctional formation. J. Neurosci. 24, 96–102 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Sagane, K. et al. Ataxia and peripheral nerve hypomyelination in ADAM22-deficient mice. BMC Neurosci. 6, 33 (2005).

    PubMed  PubMed Central  Google Scholar 

  52. Salzer, J. L. Polarized domains of myelinated axons. Neuron 40, 297–318 (2003).

    CAS  PubMed  Google Scholar 

  53. Abrams, C. K. & Scherer, S. S. Gap junctions in inherited human disorders of the central nervous system. Biochim. Biophys. Acta 1818, 2030–2047 (2012).

    CAS  PubMed  Google Scholar 

  54. Kamasawa, N. et al. Connexin-47 and connexin-32 in gap junctions of oligodendrocyte somata, myelin sheaths, paranodal loops and Schmidt–Lanterman incisures: implications for ionic homeostasis and potassium siphoning. Neuroscience 136, 65–86 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Altevogt, B. M., Kleopa, K. A., Postma, F. R., Scherer, S. S. & Paul, D. L. Connexin29 is uniquely distributed within myelinating glial cells of the central and peripheral nervous systems. J. Neurosci. 22, 6458–6470 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Li, X. et al. Connexin29 expression, immunocytochemistry and freeze-fracture replica immunogold labelling (FRIL) in sciatic nerve. Eur. J. Neurosci. 16, 795–806 (2002).

    PubMed  PubMed Central  Google Scholar 

  57. Scherer, S. S. et al. Connexin32 is a myelin-related protein in the PNS and CNS. J. Neurosci. 15, 8281–8294 (1995).

    CAS  PubMed  Google Scholar 

  58. Gow, A. et al. CNS myelin and Sertoli cell tight junction strands are absent in Osp/claudin-11 null mice. Cell 99, 649–659 (1999).

    CAS  PubMed  Google Scholar 

  59. Alanne, M. H. et al. Tight junction proteins in human Schwann cell autotypic junctions. J. Histochem. Cytochem. 57, 523–529 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Miyamoto, T. et al. Tight junctions in Schwann cells of peripheral myelinated axons: a lesson from claudin-19-deficient mice. J. Cell Biol. 169, 527–538 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Fannon, A. M. et al. Novel E-cadherin-mediated adhesion in peripheral nerve: Schwann cell architecture is stabilized by autotypic adherens junctions. J. Cell Biol. 129, 189–202 (1995).

    CAS  PubMed  Google Scholar 

  62. Zhou, D. et al. AnkyrinG is required for clustering of voltage-gated Na channels at axon initial segments and for normal action potential firing. J. Cell Biol. 143, 1295–1304 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Yang, Y., Lacas-Gervais, S., Morest, D. K., Solimena, M. & Rasband, M. N. βIV spectrins are essential for membrane stability and the molecular organization of nodes of Ranvier. J. Neurosci. 24, 7230–7240 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Ogawa, Y. et al. Spectrins and ankyrinB constitute a specialized paranodal cytoskeleton. J. Neurosci. 26, 5230–5239 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Zhang, C., Susuki, K., Zollinger, D. R., Dupree, J. L. & Rasband, M. N. Membrane domain organization of myelinated axons requires βII spectrin. J. Cell Biol. 203, 437–443 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Horresh, I. et al. Multiple molecular interactions determine the clustering of Caspr2 and Kv1 channels in myelinated axons. J. Neurosci. 28, 14213–14222 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Melendez-Vasquez, C. V. et al. Nodes of Ranvier form in association with ezrin–radixin–moesin (ERM)-positive Schwann cell processes. Proc. Natl Acad. Sci. USA 98, 1235–1240 (2001).

    CAS  PubMed  Google Scholar 

  68. Melendez-Vasquez, C. V., Einheber, S. & Salzer, J. L. Rho kinase regulates Schwann cell myelination and formation of associated axonal domains. J. Neurosci. 24, 3953–3963 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Devaux, J. J., Odaka, M. & Yuki, N. Nodal proteins are target antigens in Guillain–Barré syndrome. J. Peripher. Nerv. Syst. 17, 62–71 (2012).

    CAS  PubMed  Google Scholar 

  70. Kawamura, N. et al. Anti-neurofascin antibody in patients with combined central and peripheral demyelination. Neurology 81, 714–722 (2013).

    CAS  PubMed  Google Scholar 

  71. Kwa, M. S. et al. Autoimmunoreactivity to Schwann cells in patients with inflammatory neuropathies. Brain 126, 361–375 (2003).

    PubMed  Google Scholar 

  72. Kusunoki, S. Antiganglioside antibodies in Guillain–Barré syndrome. Intern. Med. 36, 599–600 (1997).

    CAS  PubMed  Google Scholar 

  73. Griffin, J. W. et al. Guillain–Barré syndrome in northern China. The spectrum of neuropathological changes in clinically defined cases. Brain 118, 577–595 (1995).

    PubMed  Google Scholar 

  74. Willison, H. J. Gangliosides as targets for autoimmune injury to the nervous system. J. Neurochem. 103 (Suppl. 1), 143–149 (2007).

    CAS  PubMed  Google Scholar 

  75. Kanda, T., Numata, Y. & Mizusawa, H. Chronic inflammatory demyelinating polyneuropathy: decreased claudin-5 and relocated ZO-1. J. Neurol. Neurosurg. Psychiatry 75, 765–769 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Cifuentes-Diaz, C. et al. Nodes of Ranvier and paranodes in chronic acquired neuropathies. PLoS ONE 6, e14533 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Doppler, K., Werner, C. & Sommer, C. Disruption of nodal architecture in skin biopsies of patients with demyelinating neuropathies. J. Peripher. Nerv. Syst. 18, 168–176 (2013).

    CAS  PubMed  Google Scholar 

  78. Markoullis, K. et al. Gap junction pathology in multiple sclerosis lesions and normal-appearing white matter. Acta Neuropathol. 123, 873–886 (2012).

    CAS  PubMed  Google Scholar 

  79. Lonigro, A. & Devaux, J. J. Disruption of neurofascin and gliomedin at nodes of Ranvier precedes demyelination in experimental allergic neuritis. Brain 132, 260–273 (2009).

    PubMed  Google Scholar 

  80. Coman, I. et al. Nodal, paranodal and juxtaparanodal axonal proteins during demyelination and remyelination in multiple sclerosis. Brain 129, 3186–3195 (2006).

    CAS  PubMed  Google Scholar 

  81. Howell, O. W. et al. Disruption of neurofascin localization reveals early changes preceding demyelination and remyelination in multiple sclerosis. Brain 129, 3173–3185 (2006).

    CAS  PubMed  Google Scholar 

  82. Ng, J. K. et al. Neurofascin as a target for autoantibodies in peripheral neuropathies. Neurology 79, 2241–2248 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Querol, L. et al. Neurofascin IgG4 antibodies in CIDP associate with disabling tremor and poor response to IVIg. Neurology 82, 879–886 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Sawai, S. et al. Moesin is a possible target molecule for cytomegalovirus-related Guillain–Barré syndrome. Neurology 83, 113–117 (2014).

    CAS  PubMed  Google Scholar 

  85. Devaux, J. J. Antibodies to gliomedin cause peripheral demyelinating neuropathy and the dismantling of the nodes of Ranvier. Am. J. Pathol. 181, 1402–1413 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Yan, W. et al. Antibodies to neurofascin exacerbate adoptive transfer experimental autoimmune neuritis. J. Neuroimmunol. 15, 13–17 (2014).

    Google Scholar 

  87. Mathey, E. K. et al. Neurofascin as a novel target for autoantibody-mediated axonal injury. J. Exp. Med. 204, 2363–2372 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Leite, M. I. et al. IgG1 antibodies to acetylcholine receptors in 'seronegative' myasthenia gravis. Brain 131, 1940–1952 (2008).

    PubMed  PubMed Central  Google Scholar 

  89. Lovato, L. et al. Transketolase and 2′,3′-cyclic-nucleotide 3'-phosphodiesterase type I isoforms are specifically recognized by IgG autoantibodies in multiple sclerosis patients. Mol. Cell Proteomics 7, 2337–2349 (2008).

    CAS  PubMed  Google Scholar 

  90. Niehaus, A. et al. Patients with active relapsing–remitting multiple sclerosis synthesize antibodies recognizing oligodendrocyte progenitor cell surface protein: implications for remyelination. Ann. Neurol. 48, 362–371 (2000).

    CAS  PubMed  Google Scholar 

  91. Masaki, K. et al. Connexin 43 astrocytopathy linked to rapidly progressive multiple sclerosis and neuromyelitis optica. PLoS ONE 8, e72919 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Masaki, K. et al. Extensive loss of connexins in Balo's disease: evidence for an auto-antibody-independent astrocytopathy via impaired astrocyte-oligodendrocyte/myelin interaction. Acta Neuropathol. 123, 887–900 (2012).

    PubMed  Google Scholar 

  93. Querol, L. et al. Antibodies to contactin-1 in chronic inflammatory demyelinating polyneuropathy. Ann. Neurol. 73, 370–380 (2013).

    CAS  PubMed  Google Scholar 

  94. Labasque, M. et al. Specific contactin N-glycans are implicated in neurofascin binding and autoimmune targeting in peripheral neuropathies. J. Biol. Chem. 289, 7907–7918 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Pruss, H., Schwab, J. M., Derst, C., Görtzen, A. & Veh, R. W. Neurofascin as target of autoantibodies in Guillain–Barré syndrome. Brain 134, e173 (2011).

    PubMed  Google Scholar 

  96. Kwa, M. S., van Schaik, I. N., Brand, A., Baas, F. & Vermeulen, M. Investigation of serum response to PMP22, connexin 32 and P0 in inflammatory neuropathies. J. Neuroimmunol. 116, 220–225 (2001).

    CAS  PubMed  Google Scholar 

  97. Stathopoulos, P. A., Biba, A., Karagogeos, D., Dalakas, M. Search for autoantibodies targeting the nodes of Ranvier in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Neurology 82 (10 Suppl.), P1.028 (2014).

    Google Scholar 

  98. Dalakas, M. C. Pathophysiology of autoimmune polyneuropathies. Presse Med. 42, e181–e192 (2013).

    PubMed  Google Scholar 

  99. Zhu, J. et al. The B cell repertoire in experimental allergic neuritis involves multiple myelin proteins and GM1. J. Neurol. Sci. 125, 132–137 (1994).

    CAS  PubMed  Google Scholar 

  100. Ilyas, A. A., Gu, Y., Dalakas, M. C., Quarles, R. H. & Bhatt, S. Induction of experimental ataxic sensory neuronopathy in cats by immunization with purified SGPG. J. Neuroimmunol. 193, 87–93 (2008).

    CAS  PubMed  Google Scholar 

  101. Yuki, N., Tagawa, Y. & Handa, S. Autoantibodies to peripheral nerve glycosphingolipids SPG, SLPG, and SGPG in Guillain–Barré syndrome and chronic inflammatory demyelinating polyneuropathy. J. Neuroimmunol. 70, 1–6 (1996).

    CAS  PubMed  Google Scholar 

  102. Ilyas, A. A., Mithen, F. A., Dalakas, M. C., Chen, Z. W. & Cook, S. D. Antibodies to acidic glycolipids in Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy. J. Neurol. Sci. 107, 111–121 (1992).

    CAS  PubMed  Google Scholar 

  103. Ilyas, A. A. et al. Antibodies to sulfated glycolipids in Guillain–Barré syndrome. J. Neurol. Sci. 105, 108–117 (1991).

    CAS  PubMed  Google Scholar 

  104. Wajgt, A. & Górny, M. CSF antibodies to myelin basic protein and to myelin-associated glycoprotein in multiple sclerosis. Evidence of the intrathecal production of antibodies. Acta Neurol. Scand. 68, 337–343 (1983).

    CAS  PubMed  Google Scholar 

  105. Nobile-Orazio, E., Spagnol, G. & Scarlato, G. Failure to detect anti-MAG antibodies by RIA in CSF of patients with multiple sclerosis. J. Neuroimmunol. 11, 165–169 (1986).

    CAS  PubMed  Google Scholar 

  106. Möller, J. R., Johnson, D., Brady, R. O., Tourtellotte, W. W. & Quarles, R. H. Antibodies to myelin-associated glycoprotein (MAG) in the cerebrospinal fluid of multiple sclerosis patients. J. Neuroimmunol. 22, 55–61 (1989).

    PubMed  Google Scholar 

  107. Baig, S. et al. Multiple sclerosis: cells secreting antibodies against myelin-associated glycoprotein are present in cerebrospinal fluid. Scand. J. Immunol. 33, 73–79 (1991).

    CAS  PubMed  Google Scholar 

  108. Quintana, F. J. et al. Antigen microarrays identify CNS-produced autoantibodies in RRMS. Neurology 78, 532–539 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Quintana, F. J. et al. Antigen microarrays identify unique serum autoantibody signatures in clinical and pathologic subtypes of multiple sclerosis. Proc. Natl Acad. Sci. USA 105, 18889–18894 (2008).

    CAS  PubMed  Google Scholar 

  110. Reindl, M. et al. Serum and cerebrospinal fluid antibodies to Nogo-A in patients with multiple sclerosis and acute neurological disorders. J. Neuroimmunol. 145, 139–147 (2003).

    CAS  PubMed  Google Scholar 

  111. Walsh, M. J. & Murray, J. M. Dual implication of 2′,3′-cyclic nucleotide 3' phosphodiesterase as major autoantigen and C3 complement-binding protein in the pathogenesis of multiple sclerosis. J. Clin. Invest. 101, 1923–1931 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Irani, S. R. et al. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia. Brain 133, 2734–2748 (2010).

    PubMed  PubMed Central  Google Scholar 

  113. Lai, M. et al. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol. 9, 776–785 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Lancaster, E. et al. Investigations of Caspr2, an autoantigen of encephalitis and neuromyotonia. Ann. Neurol. 69, 303–311 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Iijima, M. et al. Single nucleotide polymorphism of TAG-1 influences IVIg responsiveness of Japanese patients with CIDP. Neurology 73, 1348–1352 (2009).

    CAS  PubMed  Google Scholar 

  116. Pang, S. Y. et al. Single-nucleotide polymorphism of transient axonal glycoprotein-1 and its correlation with clinical features and prognosis in chronic inflammatory demyelinating polyneuropathy. J. Peripher. Nerv. Syst. 17, 72–75 (2012).

    CAS  PubMed  Google Scholar 

  117. Dalakas, M. C. Potential biomarkers for monitoring therapeutic response in patients with CIDP. J. Peripher. Nerv. Syst. 16 (Suppl. 1), 63–67 (2011).

    PubMed  Google Scholar 

  118. Alexopoulos, H. P., Karagogeos, D., Karageorgiou, C., Dalakas, M. Are anti-TAG-1 autoantibodies markers in autoimmune demyelinating disorders of the PNS and CNS? Ann. Neurol. 70 (Suppl. S15), S73 (2011).

    Google Scholar 

  119. Derfuss, T. et al. Contactin-2/TAG-1-directed autoimmunity is identified in multiple sclerosis patients and mediates gray matter pathology in animals. Proc. Natl Acad. Sci. USA 106, 8302–8307 (2009).

    CAS  PubMed  Google Scholar 

  120. Boronat, A. et al. Analysis of antibodies to surface epitopes of contactin-2 in multiple sclerosis. J. Neuroimmunol. 244, 103–106 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Alexopoulos, H. C. et al. Search for nodal and paranodal autoantibodies in patients with multiple sclerosis. Neurology 78 (Meeting Abstracts 1) P07.088 (2012).

    Google Scholar 

  122. Pavlakis, P. A., Karagogeos, D., Dalakas, M. Search for nodal and paranodal autoantibodies in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Neurology 78 (Meeting Abstracts 1), P05.159 (2012).

    Google Scholar 

  123. Irani, S. R., Gelfand, J. M., Al-Diwani, A. & Vincent, A. Cell-surface central nervous system autoantibodies: clinical relevance and emerging paradigms. Ann. Neurol. 76, 168–184 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Lancaster, E. et al. Antibodies to the GABAB receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol. 9, 67–76 (2010).

    CAS  PubMed  Google Scholar 

  125. Larman, H. B. et al. PhIP-Seq characterization of autoantibodies from patients with multiple sclerosis, type 1 diabetes and rheumatoid arthritis. J. Autoimmun. 43, 1–9 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Querol, L. et al. Protein array-based profiling of CSF identifies RBPJ as an autoantigen in multiple sclerosis. Neurology 81, 956–963 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Bar-Or, A. et al. Induction of antigen-specific tolerance in multiple sclerosis after immunization with DNA encoding myelin basic protein in a randomized, placebo-controlled phase 1/2 trial. Arch. Neurol. 64, 1407–1415 (2007).

    PubMed  Google Scholar 

  128. Ousman, S. S. et al. Protective and therapeutic role for αB-crystallin in autoimmune demyelination. Nature 448, 474–479 (2007).

    CAS  PubMed  Google Scholar 

  129. Cepok, S. et al. Identification of Epstein–Barr virus proteins as putative targets of the immune response in multiple sclerosis. J. Clin. Invest. 115, 1352–1360 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Archelos, J. J. et al. Isolation and characterization of an oligodendrocyte precursor-derived B-cell epitope in multiple sclerosis. Ann. Neurol. 43, 15–24 (1998).

    CAS  PubMed  Google Scholar 

  131. Cortese, I. et al. Identification of peptides specific for cerebrospinal fluid antibodies in multiple sclerosis by using phage libraries. Proc. Natl Acad. Sci. USA 93, 11063–11067 (1996).

    CAS  PubMed  Google Scholar 

  132. Somers, V. et al. Autoantibody profiling in multiple sclerosis reveals novel antigenic candidates. J. Immunol. 180, 3957–3963 (2008).

    CAS  PubMed  Google Scholar 

  133. Govarts, C., Somers, K., Hupperts, R., Stinissen, P. & Somers, V. Analysis of antibody reactivity in paired cerebrospinal fluid and serum of a relapsing remitting multiple sclerosis patient. Autoimmunity 42, 699–704 (2009).

    CAS  PubMed  Google Scholar 

  134. Desmazieres, A. et al. Differential stability of PNS and CNS nodal complexes when neuronal neurofascin is lost. J. Neurosci. 34, 5083–5088 (2014).

    PubMed  PubMed Central  Google Scholar 

  135. Huang, J. K. et al. Glial membranes at the node of Ranvier prevent neurite outgrowth. Science 310, 1813–1817 (2005).

    CAS  PubMed  Google Scholar 

  136. Lee, X. et al. Oligodendrocyte differentiation and myelination defects in OMgp null mice. Mol. Cell Neurosci. 46, 752–761 (2011).

    CAS  PubMed  Google Scholar 

  137. Averill, S., Robson, L. G., Jeromin, A. & Priestley, J. V. Neuronal calcium sensor-1 is expressed by dorsal root ganglion cells, is axonally transported to central and peripheral terminals, and is concentrated at nodes. Neuroscience 123, 419–427 (2004).

    CAS  PubMed  Google Scholar 

  138. de Rezende, V. B. et al. NCS-1 deficiency causes anxiety and depressive-like behavior with impaired non-aversive memory in mice. Physiol. Behav. 130, 91–98 (2014).

    PubMed  Google Scholar 

  139. Piton, A. et al. Mutations in the calcium-related gene IL1RAPL1 are associated with autism. Hum. Mol. Genet. 17, 3965–3974 (2008).

    CAS  PubMed  Google Scholar 

  140. Cooper, E. C. Made for “anchorin”: Kv7.2/7.3 (KCNQ2/KCNQ3) channels and the modulation of neuronal excitability in vertebrate axons. Semin. Cell Dev. Biol. 22, 185–192 (2011).

    CAS  PubMed  Google Scholar 

  141. Singh, N. A. et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat. Genet. 18, 25–29 (1998).

    CAS  PubMed  Google Scholar 

  142. Charlier, C. et al. A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nat. Genet. 18, 53–55 (1998).

    CAS  PubMed  Google Scholar 

  143. Tamura, A. et al. Achlorhydria by ezrin knockdown: defects in the formation/expansion of apical canaliculi in gastric parietal cells. J. Cell Biol. 169, 21–28 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Kikuchi, S. et al. Radixin deficiency causes conjugated hyperbilirubinemia with loss of Mrp2 from bile canalicular membranes. Nat. Genet. 31, 320–325 (2002).

    CAS  PubMed  Google Scholar 

  145. Doi, Y. et al. Normal development of mice and unimpaired cell adhesion/cell motility/actin-based cytoskeleton without compensatory up-regulation of ezrin or radixin in moesin gene knockout. J. Biol. Chem. 274, 2315–2321 (1999).

    CAS  PubMed  Google Scholar 

  146. Shenolikar, S., Voltz, J. W., Minkoff, C. M., Wade, J. B. & Weinman, E. J. Targeted disruption of the mouse NHERF-1 gene promotes internalization of proximal tubule sodium-phosphate cotransporter type IIa and renal phosphate wasting. Proc. Natl Acad. Sci. USA 99, 11470–11475 (2002).

    CAS  PubMed  Google Scholar 

  147. Shimizu, Y. et al. ROCK-I regulates closure of the eyelids and ventral body wall by inducing assembly of actomyosin bundles. J. Cell Biol. 168, 941–953 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Bartsch, U. The extracellular matrix molecule tenascin-C: expression in vivo and functional characterization in vitro. Prog. Neurobiol. 49, 145–168 (1996).

    CAS  PubMed  Google Scholar 

  149. Cifuentes-Diaz, C. et al. The peripheral nerve and the neuromuscular junction are affected in the tenascin-C-deficient mouse. Cell. Mol. Biol. (Noisy-le-grand) 44, 357–379 (1998).

    CAS  Google Scholar 

  150. Harroch, S. et al. No obvious abnormality in mice deficient in receptor protein tyrosine phosphatase β. Mol. Cell Biol. 20, 7706–7715 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Kucharova, K. & Stallcup, W. B. The NG2 proteoglycan promotes oligodendrocyte progenitor proliferation and developmental myelination. Neuroscience 166, 185–194 (2010).

    CAS  PubMed  Google Scholar 

  152. Strader, A. D., Reizes, O., Woods, S. C., Benoit, S. C. & Seeley, R. J. Mice lacking the syndecan-3 gene are resistant to diet-induced obesity. J. Clin. Invest. 114, 1354–1360 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Kaksonen, M. et al. Syndecan-3-deficient mice exhibit enhanced LTP and impaired hippocampus-dependent memory. Mol. Cell. Neurosci. 21, 158–172 (2002).

    CAS  PubMed  Google Scholar 

  154. Ishiguro, K. et al. Syndecan-4 deficiency leads to high mortality of lipopolysaccharide-injected mice. J. Biol. Chem. 276, 47483–47488 (2001).

    CAS  PubMed  Google Scholar 

  155. Echtermeyer, F. et al. Delayed wound repair and impaired angiogenesis in mice lacking syndecan-4. J. Clin. Invest. 107, R9–R14 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Buttermore, E. D. et al. The cytoskeletal adaptor protein band 4.1B is required for the maintenance of paranodal axoglial septate junctions in myelinated axons. J. Neurosci. 31, 8013–8024 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Chauhan, V. S., Tuvia, S., Buhusi, M., Bennett, V. & Grant, A. O. Abnormal cardiac Na+ channel properties and QT heart rate adaptation in neonatal ankyrinB knockout mice. Circ. Res. 86, 441–447 (2000).

    CAS  PubMed  Google Scholar 

  158. Serafini, T. et al. Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system. Cell 87, 1001–1014 (1996).

    CAS  PubMed  Google Scholar 

  159. Fazeli, A. et al. Phenotype of mice lacking functional Deleted in colorectal cancer (Dcc) gene. Nature 386, 796–804 (1997).

    CAS  PubMed  Google Scholar 

  160. Furuse, M. et al. Claudin-based tight junctions are crucial for the mammalian epidermal barrier: a lesson from claudin-1-deficient mice. J. Cell Biol. 156, 1099–1111 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Muto, S. et al. Claudin-2-deficient mice are defective in the leaky and cation-selective paracellular permeability properties of renal proximal tubules. Proc. Natl Acad. Sci. USA 107, 8011–8016 (2010).

    CAS  PubMed  Google Scholar 

  162. Katsuno, T. et al. Deficiency of zonula occludens-1 causes embryonic lethal phenotype associated with defected yolk sac angiogenesis and apoptosis of embryonic cells. Mol. Biol. Cell 19, 2465–2475 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Berx, G., Becker, K. F., Höfler, H. & van Roy, F. Mutations of the human E-cadherin (CDH1) gene. Hum. Mutat. 12, 226–237 (1998).

    CAS  PubMed  Google Scholar 

  164. Young, P. et al. E-cadherin is required for the correct formation of autotypic adherens junctions of the outer mesaxon but not for the integrity of myelinated fibers of peripheral nerves. Mol. Cell. Neurosci. 21, 341–351 (2002).

    CAS  PubMed  Google Scholar 

  165. Haegel, H. et al. Lack of β-catenin affects mouse development at gastrulation. Development 121, 3529–3537 (1995).

    CAS  PubMed  Google Scholar 

  166. Tang, W. et al. Connexin29 is highly expressed in cochlear Schwann cells, and it is required for the normal development and function of the auditory nerve of mice. J. Neurosci. 26, 1991–1999 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Edgar, J. M. et al. Early ultrastructural defects of axons and axon–glia junctions in mice lacking expression of Cnp1. Glia 57, 1815–1824 (2009).

    PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Dr Kleopa from the Cyprus Institute of Neurology and Genetics for helping them with the establishment of single teased nerve fibre preparations.

Author information

Authors and Affiliations

  1. Department of Pathophysiology, Neuroimmunology Unit, Faculty of Medicine, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Goudi, 11527, Athens, Greece

    Panos Stathopoulos, Harry Alexopoulos & Marinos C. Dalakas

Authors
  1. Panos Stathopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Harry Alexopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marinos C. Dalakas
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched data for the article and made substantial contributions to discussion of the content, writing of the article and review and/or editing of the manuscript before submission.

Corresponding author

Correspondence to Marinos C. Dalakas.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Stathopoulos, P., Alexopoulos, H. & Dalakas, M. Autoimmune antigenic targets at the node of Ranvier in demyelinating disorders. Nat Rev Neurol 11, 143–156 (2015). https://doi.org/10.1038/nrneurol.2014.260

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2014.260

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing