Neurofascin as a novel target for autoantibody-mediated axonal injury.
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.
Mathey
Emily K
EK
Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, UK.
Derfuss
Tobias
T
Storch
Maria K
MK
Williams
Kieran R
KR
Hales
Kimberly
K
Woolley
David R
DR
Al-Hayani
Abdulmonem
A
Davies
Stephen N
SN
Rasband
Matthew N
MN
Olsson
Tomas
T
Moldenhauer
Anja
A
Velhin
Sviataslau
S
Hohlfeld
Reinhard
R
Meinl
Edgar
E
Linington
Christopher
C
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
D001323:Autoantibodies; D001324:Autoantigens; D015815:Cell Adhesion Molecules; C054305:NFASC protein, human; D009414:Nerve Growth Factors; C504594:Nfasc protein, rat