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¹ Department of Medicine and Therapeutics, Institute of Medical Sciences and ² School of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, UK
³ Department of Neuroimmunology, Max-Planck-Institute of Neurobiology, 82152 Martinsried, Germany
⁴ Institute for Clinical Neuroimmunology, Ludwig-Maximilians-University, 81377 Munich, Germany
⁵ Department of Neurology, Medical University of Graz, 8036 Graz, Austria
⁶ Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06030
⁷ Faculty of Medicine, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
⁸ Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institute, Center for Molecular Medicine, Karolinska University Hospital, 171 76 Stockholm, Sweden
⁹ Institute for Transfusion Medicine, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany

CORRESPONDENCE Edgar Meinl: meinl{at}neuro.mpg.de

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.

E.K. Mathey and T. Derfuss contributed equally to this work.

E. Meinl and C. Linington contributed equally to this work.

S. Velhin's present address is Clinical and Experimental Laboratory for Chronic Neuroinfections, Research Institute for Epidemiology and Microbiology, 220114 Minsk, Belarus.

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