Neurofascin as a novel target for autoantibody-mediated axonal injury

Emily K. Mathey, Tobias Derfuss, Maria K. Storch, Kieran R. Williams, Kimberly Hales, David Russell Woolley, Abdulmonem Al-Hayani, Stephen N. Davies, Matthew N. Rasband, Tomas Olsson, Anja Moldenhauer, Sviataslau Velhin, Reinhard Hohlfeld, Edgar Meinl, Christopher Linington

Research output: Contribution to journalArticle

274 Citations (Scopus)

Abstract

Axonal injury is considered the major cause of disability in patients with multiple sclerosis ( MS), but the underlying effector mechanisms are poorly understood. Starting with a proteomics- based approach, we identified neurofascin- specific autoantibodies in patients with MS. These autoantibodies recognize the native form of the extracellular domains of both neurofascin 186 ( NF186), a neuronal protein concentrated in myelinated fibers at nodes of Ranvier, and NF155, the oligodendrocyte- specific isoform of neurofascin. Our in vitro studies with hippocampal slice cultures indicate that neurofascin antibodies inhibit axonal conduction in a complement- dependent manner. To evaluate whether circulating antineurofascin antibodies mediate a pathogenic effect in vivo, we cotransferred these antibodies with myelin oligodendrocyte glycoprotein - specific encephalitogenic T cells to mimic the inflammatory pathology of MS and breach the blood - brain barrier. In this animal model, antibodies to neurofascin selectively targeted nodes of Ranvier, resulting in deposition of complement, axonal injury, and disease exacerbation. Collectively, these results identify a novel mechanism of immune- mediated axonal injury that can contribute to axonal pathology in MS.

Original languageEnglish
Pages (from-to)2363-2372
Number of pages10
JournalJournal of Experimental Medicine
Volume204
Issue number10
Early online date10 Sep 2007
DOIs
Publication statusPublished - 1 Oct 2007

Keywords

  • myelin oligodendrocyte glycoprotein
  • progressive multiple-sclerosis
  • membrane attack complex
  • demyelinating disease
  • plasma-exchange
  • nitric-oxide
  • rat-brain
  • antibodies
  • lesions
  • cells

Cite this

Mathey, E. K., Derfuss, T., Storch, M. K., Williams, K. R., Hales, K., Woolley, D. R., ... Linington, C. (2007). Neurofascin as a novel target for autoantibody-mediated axonal injury. Journal of Experimental Medicine, 204(10), 2363-2372. https://doi.org/10.1084/jem.20071053

Neurofascin as a novel target for autoantibody-mediated axonal injury. / Mathey, Emily K.; Derfuss, Tobias; Storch, Maria K.; Williams, Kieran R.; Hales, Kimberly; Woolley, David Russell; Al-Hayani, Abdulmonem; Davies, Stephen N.; Rasband, Matthew N.; Olsson, Tomas; Moldenhauer, Anja; Velhin, Sviataslau; Hohlfeld, Reinhard; Meinl, Edgar; Linington, Christopher.

In: Journal of Experimental Medicine, Vol. 204, No. 10, 01.10.2007, p. 2363-2372.

Research output: Contribution to journalArticle

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', Journal of Experimental Medicine, vol. 204, no. 10, pp. 2363-2372. https://doi.org/10.1084/jem.20071053
Mathey EK, Derfuss T, Storch MK, Williams KR, Hales K, Woolley DR et al. Neurofascin as a novel target for autoantibody-mediated axonal injury. Journal of Experimental Medicine. 2007 Oct 1;204(10):2363-2372. https://doi.org/10.1084/jem.20071053
Mathey, Emily K. ; Derfuss, Tobias ; Storch, Maria K. ; Williams, Kieran R. ; Hales, Kimberly ; Woolley, David Russell ; Al-Hayani, Abdulmonem ; Davies, Stephen N. ; Rasband, Matthew N. ; Olsson, Tomas ; Moldenhauer, Anja ; Velhin, Sviataslau ; Hohlfeld, Reinhard ; Meinl, Edgar ; Linington, Christopher. / Neurofascin as a novel target for autoantibody-mediated axonal injury. In: Journal of Experimental Medicine. 2007 ; Vol. 204, No. 10. pp. 2363-2372.
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