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.
- myelin oligodendrocyte glycoprotein
- progressive multiple-sclerosis
- membrane attack complex
- demyelinating disease