Anti–neurofascin-155 IgG4 antibodies prevent paranodal complex formation in vivo
Journal of Clinical Investigation. 2019-04-29; 129(6): 2222-2236
DOI: 10.1172/jci124694
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Neurofascin-155 (Nfasc155) is an essential glial cell adhesion molecule expressed
in paranodal septate-like junctions of peripheral and central myelinated axons.
The genetic deletion of Nfasc155 results in the loss of septate-like junctions
and in conduction slowing. In humans, IgG4 antibodies against Nfasc155 are
implicated in the pathogenesis of chronic inflammatory demyelinating
polyneuropathy (CIDP). These antibodies are associated with an aggressive onset,
a refractoriness to intravenous immunoglobulin, and tremor of possible cerebellar
origin. Here, we examined the pathogenic effects of patient-derived anti-Nfasc155
IgG4. These antibodies did not inhibit the ability of Nfasc155 to complex with
its axonal partners contactin-1/CASPR1 or induce target internalization. Passive
transfer experiments revealed that IgG4 antibodies target Nfasc155 on Schwann
cell surface, and diminished Nfasc155 protein levels and prevented paranodal
complex formation in neonatal animals. In adult animals, chronic intrathecal
infusions of antibodies also induced the loss of Nfasc155 and of paranodal
specialization and resulted in conduction alterations in motor nerves. These
results indicate that anti-Nfasc155 IgG4 perturb conduction in absence of
demyelination, validating the existence of paranodopathy. These results also shed
light on the mechanisms regulating protein insertion at paranodes.