1621 Human sensory neuron co-cultures to model inflammatory neuropathy

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Disialoysl antibodies target the paired alpha-2–8 linked sialic acid residues found on gangliosides such as GQ1b, GT1b and GD1b. They are associated with specific inflammatory neuropathies – notably Miller Fisher syndrome (MFS) and CANOMAD, which are characterised clinically by sensory and cerebellar ataxia, ophthalmoplegia and areflexia. However, the pathological relevance and topographical targets of disialosyl antibodies in these conditions remain a subject of debate. We used sensory neurons derived from human induced pluripotent stem cells to investigate this area. In co-culture with Schwann cells, myelination occurs and nodes of Ranvier form. In this system, disialosyl antibodies target the nodal axolemma and also bind unmyelinated fibres. When the paranodal junction protein CASPR is disrupted, antibodies penetrate into the internodal region. Incubation with antibody followed by a source of complement results in a neuronal calcium spike followed by acute axonal blebbing and degeneration. In prolonged cultures, the presence of disialosyl antibodies both impairs myelination and induces demyelination. In assays using microfluidic chambers, disialosyl antibodies impair the extent of axonal regeneration at 24 hours. These assays thus reveal the pleiotropic effects of disialosyl antibodies. The utility of this culture system for further investigating MFS, CANOMAD and other inflammatory neuropathies is clearly demonstrated.

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