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.

  • Article
  • Published:

The neurite outgrowth inhibitor Nogo A is involved in autoimmune-mediated demyelination

Nature Neuroscience volume 7, pages 736–744 (2004)Cite this article

Abstract

Inhibitors associated with CNS myelin are thought to be important in the failure of axons to regenerate after spinal cord injury and in other neurodegenerative disorders. Here we show that targeting the CNS-specific inhibitor of neurite outgrowth Nogo A by active immunization blunts clinical signs, demyelination and axonal damage associated with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). Mice vaccinated against Nogo A produce Nogo-specific antibodies that block the neurite outgrowth inhibitory activity associated with CNS myelin in vitro. Passive immunization with anti-Nogo IgGs also suppresses EAE. Our results identify Nogo A as an important determinant of the development of EAE and suggest that its blockade may help to maintain and/or to restore the neuronal integrity of the CNS after autoimmune insult in diseases such as MS. Our finding that Nogo A is involved in CNS autoimmune demyelination indicates that this molecule may have a far more complex role than has been previously anticipated.

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: Targeting Nogo A by active vaccination with Nogo(623–640) or by gene deletion reduces the onset and progression of clinical EAE provoked by MOG(35–55) peptide in C57BL/6 mice.
Figure 2: Active vaccination with Nogo(623–640) blunts the formation of CNS inflammation, demyelination and axonal loss in MOG-induced EAE.
Figure 3: Histological scores for the inflammatory (1–5) and demyelinating (1–4) lesions, respectively.
Figure 4: Representative images of CNS histology observed in Nogo-A-deficient and wild-type mice.
Figure 5: Immune responses to MOG in mice vaccinated with Nogo(623–640) and in Nogo-deficient mice.
Figure 6: Immune responses to Nogo after vaccination with Nogo(623–640).
Figure 7: Suppression of EAE after passive vaccination with anti-Nogo(623–640) IgG.

Similar content being viewed by others

References

  1. Keegan, B.M. & Noseworthy, J.H. Multiple sclerosis. Annu. Rev. Med. 53, 285–302 (2002).

    Article  CAS  Google Scholar 

  2. Steinman, L., Martin, R., Bernard, C.C., Conlon, P. & Oksenberg, J.R. Multiple sclerosis: deeper understanding of its pathogenesis reveals new targets for therapy. Annu. Rev. Neurosci. 25, 491–505 (2002).

    Article  CAS  Google Scholar 

  3. Baranzini, S.E. et al. B cell repertoire diversity and clonal expansion in multiple sclerosis brain lesions. J. Immunol. 163, 5133–5144 (1999).

    CAS  PubMed  Google Scholar 

  4. Berger, T. et al. Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event. N. Engl. J. Med. 349, 139–145 (2003).

    Article  CAS  Google Scholar 

  5. Robinson, W.H. et al. Protein microarrays guide tolerizing DNA vaccine treatment of autoimmune encephalomyelitis. Nat. Biotechnol. 21, 1033–1039 (2003).

    Article  CAS  Google Scholar 

  6. Trapp, B.D., Ransohoff, R. & Rudick, R. Axonal pathology in multiple sclerosis: relationship to neurologic disability. Curr. Opin. Neurol. 12, 295–302 (1999).

    Article  CAS  Google Scholar 

  7. Onuki, M., Ayers, M.M., Bernard, C.C. & Orian, J.M. Axonal degeneration is an early pathological feature in autoimmune-mediated demyelination in mice. Microsc. Res. Tech. 52, 731–739 (2001).

    Article  CAS  Google Scholar 

  8. Schwab, M.E. & Caroni, P. Oligodendrocytes and CNS myelin are nonpermissive substrates for neurite growth and fibroblast spreading in vitro. J. Neurosci. 8, 2381–2393 (1988).

    Article  CAS  Google Scholar 

  9. GrandPre, T., Nakamura, F., Vartanian, T. & Strittmatter, S.M. Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature 403, 439–444 (2000).

    Article  CAS  Google Scholar 

  10. Fournier, A.E., GrandPre, T. & Strittmatter, S.M. Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature 409, 341–346 (2001).

    Article  CAS  Google Scholar 

  11. Wang, K.C., Kim, J.A., Sivasankaran, R., Segal, R. & He, Z. p75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature 420, 74–78 (2002).

    Article  CAS  Google Scholar 

  12. Domeniconi, M. et al. Myelin-associated glycoprotein interacts with the Nogo66 receptor to inhibit neurite outgrowth. Neuron 35, 283–290 (2002).

    Article  CAS  Google Scholar 

  13. Wang, K.C. et al. Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417, 941–944 (2002).

    Article  CAS  Google Scholar 

  14. GrandPre, T., Li, S. & Strittmatter, S.M. Nogo-66 receptor antagonist peptide promotes axonal regeneration. Nature 417, 547–551 (2002).

    Article  CAS  Google Scholar 

  15. Hauben, E. et al. Vaccination with a Nogo-A-derived peptide after incomplete spinal-cord injury promotes recovery via a T-cell-mediated neuroprotective response: comparison with other myelin antigens. Proc. Natl. Acad. Sci. USA 98, 15173–15178 (2001).

    Article  CAS  Google Scholar 

  16. Bernard, C.C. et al. Myelin oligodendrocyte glycoprotein: a novel candidate autoantigen in multiple sclerosis. J. Mol. Med. 75, 77–88 (1997).

    Article  CAS  Google Scholar 

  17. Slavin, A. et al. Induction of a multiple sclerosis-like disease in mice with an immunodominant epitope of myelin oligodendrocyte glycoprotein. Autoimmunity 28, 109–120 (1998).

    Article  CAS  Google Scholar 

  18. Zheng, B. et al. Lack of enhanced spinal regeneration in Nogo-deficient mice. Neuron 38, 213–224 (2003).

    Article  CAS  Google Scholar 

  19. Nicholson, L.B. & Kuchroo, V.K. Manipulation of the Th1/Th2 balance in autoimmune disease. Curr. Opin. Immunol. 8, 837–842 (1996).

    Article  CAS  Google Scholar 

  20. Hauben, E. et al. Posttraumatic therapeutic vaccination with modified myelin self-antigen prevents complete paralysis while avoiding autoimmune disease. J. Clin. Invest. 108, 591–599 (2001).

    Article  CAS  Google Scholar 

  21. Acevedo, L. et al. A new role for Nogo as a regulator of vascular remodeling. Nat. Med. 10, 382–388 (2004).

    Article  CAS  Google Scholar 

  22. Merrill, J.L. & Benveniste, E.N. Cytokines in inflammatory brain lesions: helpful and harmful. Trends Neurosci. 19, 331–338 (1996).

    Article  CAS  Google Scholar 

  23. Marusic, S. & Tonegawa, S. Tolerance induction and autoimmune encephalomyelitis amelioration after administration of myelin basic protein–derived peptide. J. Exp. Med. 186, 507–515 (1997).

    Article  CAS  Google Scholar 

  24. Bettelli, E. et al. IL-10 is critical in the regulation of autoimmune encephalomyelitis as demonstrated by studies of IL-10- and IL-4-deficient and transgenic mice. J. Immunol. 161, 3299–3306 (1998).

    CAS  PubMed  Google Scholar 

  25. Merkler, D. et al. Rapid induction of autoantibodies against Nogo-A and MOG in the absence of an encephalitogenic T cell response: implication for immunotherapeutic approaches in neurological diseases. FASEB J. 17, 2275–2277 (2003).

    Article  CAS  Google Scholar 

  26. Weiner, H.L. Oral tolerance: immune mechanisms and the generation of Th3-type TGF-β-secreting regulatory cells. Microbes Infect. 3, 947–954 (2001).

    Article  CAS  Google Scholar 

  27. Bethea, J.R. et al. Systemically administered interleukin-10 reduces tumor necrosis factor-α production and significantly improves functional recovery following traumatic spinal cord injury in rats. J. Neurotrauma 16, 851–863 (1999).

    Article  CAS  Google Scholar 

  28. Fawcett, J.W. & Asher, R.A. The glial scar and central nervous system repair. Brain Res. Bull. 49, 377–391 (1999).

    Article  CAS  Google Scholar 

  29. Huber, A.B., Weinmann, O., Brosamle, C., Oertle, T. & Schwab, M.E. Patterns of Nogo mRNA and protein expression in the developing and adult rat and after CNS lesions. J. Neurosci. 22, 3553–3567 (2002).

    Article  CAS  Google Scholar 

  30. Ahmed, Z. et al. Myelin/axonal pathology in interleukin-12 induced serial relapses of experimental allergic encephalomyelitis in the Lewis rat. Am. J. Pathol. 158, 2127–2138 (2001).

    Article  CAS  Google Scholar 

  31. Kawakami, N. et al. The activation status of neuroantigen-specific T cells in the target organ determines the clinical outcome of autoimmune encephalomyelitis. J. Exp. Med. 199, 185–197 (2004).

    Article  CAS  Google Scholar 

  32. Becher, B., Durell, B.G., Miga, A.V., Hickey, W.F. & Noelle, R.J. The clinical course of experimental autoimmune encephalomyelitis and inflammation is controlled by the expression of CD40 within the central nervous system. J. Exp. Med. 193, 967–974 (2001).

    Article  CAS  Google Scholar 

  33. Brosamle, C., Huber, A.B., Fiedler, M., Skerra, A. & Schwab, M.E. Regeneration of lesioned corticospinal tract fibers in the adult rat induced by a recombinant, humanized IN-1 antibody fragment. J. Neurosci. 20, 8061–8068 (2000).

    Article  CAS  Google Scholar 

  34. Buffo, A. et al. Application of neutralizing antibodies against NI-35/250 myelin-associated neurite growth inhibitory proteins to the adult rat cerebellum induces sprouting of uninjured purkinje cell axons. J. Neurosci. 20, 2275–2286 (2000).

    Article  CAS  Google Scholar 

  35. Linington, C., Engelhardt, B., Kapocs, G. & Lassman, H. Induction of persistently demyelinated lesions in the rat following the repeated adoptive transfer of encephalitogenic T cells and demyelinating antibody. J. Neuroimmunol. 40, 219–224 (1992).

    Article  CAS  Google Scholar 

  36. Achiron, A. et al. Intravenous immunoglobulin treatment of experimental T cell–mediated autoimmune disease. Upregulation of T cell proliferation and downregulation of tumor necrosis factor α secretion. J. Clin. Invest. 93, 600–605 (1994).

    Article  CAS  Google Scholar 

  37. Mistunaga, Y. et al. Direct evidence that a human antibody derived from patient serum can promote myelin repair in a mouse model of chronic-progressive demyelinating disease. FASEB J. 16, 1325–1327 (2002).

    Article  Google Scholar 

  38. Miller, D.J., Bright, J.J., Sriram, S. & Rodriguez, M. Successful treatment of established relapsing experimental autoimmune encephalomyelitis in mice with a monoclonal natural autoantibody. J. Neuroimmunol. 75, 204–209 (1997).

    Article  CAS  Google Scholar 

  39. Bandtlow, C., Zachleder, T. & Schwab, M.E. Oligodendrocytes arrest neurite growth by contact inhibition. J. Neurosci. 10, 3837–3848 (1990).

    Article  CAS  Google Scholar 

  40. Okuda, Y., Okuda, M. & Bernard, C.C. The suppression of T cell apoptosis influences the severity of disease during the chronic phase but not the recovery from the acute phase of experimental autoimmune encephalomyelitis in mice. J. Neuroimmunol. 131, 115–125 (2002).

    Article  CAS  Google Scholar 

  41. McQualter, J.L. et al. Granulocyte macrophage colony-stimulating factor: a new putative therapeutic target in multiple sclerosis. J. Exp. Med. 194, 873–882 (2001).

    Article  CAS  Google Scholar 

  42. Buffo, A., Carulli, D., Rossi, F. & Strata, P. Extrinsic regulation of injury/growth-related gene expression in the inferior olive of the adult rat. Eur. J. Neurosci. 18, 2146–2158 (2003).

    Article  Google Scholar 

  43. 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).

    Article  CAS  Google Scholar 

  44. Karim, F., Volker, D. & Schwab, M.E. Improving axonal growth and functional recovery after experimental spinal cord injury by neutralizing myelin associated inhibitors. Brain Res. Rev. 36, 204–212 (2001).

    Article  Google Scholar 

  45. Huang, D.W., McKerracher, L., Braun, P.E. & David, S. A therapeutic vaccine approach to stimulate axon regeneration in the adult mammalian spinal cord. Neuron 24, 639–647 (1999).

    Article  CAS  Google Scholar 

  46. Sicotte, M. et al. Immunization with myelin or recombinant Nogo-66/MAG in alum promotes axon regeneration and sprouting after corticospinal tract lesions in the spinal cord. Mol. Cell. Neurosci. 23, 251–263 (2003).

    Article  CAS  Google Scholar 

  47. Liu, J. et al. TNF is a potent anti-inflammatory cytokine in autoimmune-mediated demyelination. Nat. Med. 4, 78–83 (1998).

    Article  CAS  Google Scholar 

  48. Barres, B.A., Silverstein, B.E., Corey, D.P. & Chun, L.L. Immunological, morphological, and electrophysiological variation among retinal ganglion cells purified by panning. Neuron 1, 791–803 (1988).

    Article  CAS  Google Scholar 

  49. Meyer-Franke, A., Kaplan, M.R., Pfrieger, F.W. & Barres, B.A. Characterization of the signaling interactions that promote the survival and growth of developing retinal ganglion cells in culture. Neuron 15, 805–819 (1995).

    Article  CAS  Google Scholar 

  50. Norton, W.T. & Poduslo, S.E. Myelination in rat brain: method of myelin isolation. J. Neurochem. 21, 749–757 (1973).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Slavin and S. Baranzini for suggestions and reviewing the manuscript; R. Sobel for help with histology; S. Dunn for the MBP-specific transgenic mice; L. Steinman and P. Fontoura for sharing unpublished results on Nogo A and L. Hazelwood and L. Lee for technical assistance. The work done in C.C.A.B.'s laboratory was supported by grants from the National Health and Medical Research Council of Australia and the US National Multiple Sclerosis Society, as well as a generous donation from Towards a Cure–MS, Australia. W.M. is a recipient of a US National Multiple Sclerosis Society Fellowship. B.Z. is a recipient of a Helen Hay Whitney Fellowship. B.B.'s laboratory is supported by a grant from the National Eye Institute (R01 EY10257) and M.T.-L.'s laboratory by a grant from the International Spinal Research trust. M.T.-L. is an Investigator of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. Department of Biochemistry, Neuroimmunology Laboratory, School of Molecular Sciences, La Trobe University, Bundoora, 3086, Victoria, Australia

    Tara Karnezis, Jonathan L McQualter, Kelly A Jordan, Belinda M Murray & Claude C A Bernard

  2. Department of Neurology and Neurological Sciences, School of Medicine, Stanford University, Stanford, 94305, California, USA

    Tara Karnezis, Peggy P Ho & Marc Tessier-Lavigne

  3. Department of Neurobiology, Developmental Biology, School of Medicine, Stanford University, Stanford, 94305, California, USA

    Wim Mandemakers & Ben Barres

  4. Department of Biological Sciences, Howard Hughes Medical Institute, Stanford University, Stanford, 94305, California, USA

    Binhai Zheng

Authors
  1. Tara Karnezis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wim Mandemakers
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jonathan L McQualter
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Binhai Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peggy P Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kelly A Jordan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Belinda M Murray
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ben Barres
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Marc Tessier-Lavigne
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Claude C A Bernard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Claude C A Bernard.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Karnezis, T., Mandemakers, W., McQualter, J. et al. The neurite outgrowth inhibitor Nogo A is involved in autoimmune-mediated demyelination. Nat Neurosci 7, 736–744 (2004). https://doi.org/10.1038/nn1261

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1261

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