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

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286 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., Al-Hayani, A., Davies, S. N., Rasband, M. N., 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, 204(10), 2363-2372. https://doi.org/10.1084/jem.20071053