Anti–neurofascin-155 IgG4 antibodies prevent paranodal complex formation in vivo
Constance Manso, … , Isabel Illa, Jérôme J. Devaux
Constance Manso, … , Isabel Illa, Jérôme J. Devaux
Published March 14, 2019
Citation Information: J Clin Invest. 2019;129(6):2222-2236. https://doi.org/10.1172/JCI124694.
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Research Article Autoimmunity Neuroscience

Anti–neurofascin-155 IgG4 antibodies prevent paranodal complex formation in vivo

Abstract

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 and CASPR1 or induce target internalization. Passive transfer experiments revealed that IgG4 antibodies targeted Nfasc155 on Schwann cell surfaces, 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 antibodies perturb conduction in the absence of demyelination, validating the existence of paranodopathy. These results also shed light on the mechanisms regulating protein insertion at paranodes.

Authors

Constance Manso, Luis Querol, Cinta Lleixà, Mallory Poncelet, Mourad Mekaouche, Jean-Michel Vallat, Isabel Illa, Jérôme J. Devaux

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Figure 9

Schematic representation of the pathogenic mechanisms of anti–paranodal protein autoantibodies.

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Schematic representation of the pathogenic mechanisms of anti–paranodal ...
(A) Representation of a mature node of Ranvier and myelinated axon. Myelin (yellow) covers the axon except at the node of Ranvier (red). At paranodal junctions (green), Nfasc155 interacts with its axonal partners CASPR1/CNTN1. Nfasc155 is also found at Schmidt-Lanterman incisures (dashed green lines). The Schwann cell nucleus is shown in gray. (B) In neonatal animals, the progressive enwrapping of axons by Schwann cells induces the formation of paranodal regions at node borders. The injection of anti-Nfasc155 IgG4 (blue) during the neonatal period does not affect myelination or node/paranode formation, but induces the depletion of Nfasc155, and thereby alters the formation of paranodal septate-like junctions. (C) At adult age, evidence suggests that the Nfasc155/CASPR1/CNTN1 complex is constantly renewed at paranodes possibly through degradation and replenishment mechanisms. The chronic infusion of anti-Nfasc155 IgG4 (blue) may preclude the regeneration of the paranodal axoglial junction by inducing Nfasc155 depletion, and thereby alter paranode structure and conduction.