Neurofascin as a novel target for autoantibody-mediated axonal injury |
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Authors: | Mathey Emily K Derfuss Tobias Storch Maria K Williams Kieran R Hales Kimberly Woolley David R Al-Hayani Abdulmonem Davies Stephen N Rasband Matthew N Olsson Tomas Moldenhauer Anja Velhin Sviataslau Hohlfeld Reinhard Meinl Edgar Linington Christopher |
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Affiliation: | Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, UK. |
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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. |
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