title: Neurofascin as a novel target for autoantibody-mediated axonal injury.
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.
authors.affiliation: Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, UK.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Mathey
authors.forename: Tobias
authors.initials: T
authors.lastname: Derfuss
authors.forename: Maria K
authors.initials: MK
authors.lastname: Storch
authors.forename: Kieran R
authors.initials: KR
authors.lastname: Williams
authors.forename: Kimberly
authors.initials: K
authors.lastname: Hales
authors.forename: David R
authors.initials: DR
authors.lastname: Woolley
authors.forename: Abdulmonem
authors.initials: A
authors.lastname: Al-Hayani
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Davies
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Rasband
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.forename: Anja
authors.initials: A
authors.lastname: Moldenhauer
authors.forename: Sviataslau
authors.initials: S
authors.lastname: Velhin
authors.forename: Reinhard
authors.initials: R
authors.lastname: Hohlfeld
authors.forename: Edgar
authors.initials: E
authors.lastname: Meinl
authors.forename: Christopher
authors.initials: C
authors.lastname: Linington
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D001369:Axons / Q000276:immunology* / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000276:immunology*; D002490:Central Nervous System / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004594:Electrophysiology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D009103:Multiple Sclerosis / Q000276:immunology / Q000473:pathology; D009186:Myelin Sheath / Q000378:metabolism; D009414:Nerve Growth Factors / Q000276:immunology*; D051381:Rats
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D015815:Cell Adhesion Molecules; C054305:NFASC protein, human; D009414:Nerve Growth Factors; C504594:Nfasc protein, rat