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 5

The chronic intrathecal infusion of autoantibodies induces gait abnormalities and motor nerve conduction slowing.

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The chronic intrathecal infusion of autoantibodies induces gait abnormal...
(A–C) Adult Lewis rats received daily intrathecal infusions (100 μg/d) of control IgG4 (black circles; n = 15 animals) or anti-Nfasc155 IgG4 from patient CIDP1 (gray circles; n = 15 animals) during 3 weeks. The clinical score was monitored daily and averaged. The passive infusion of anti-Nfasc155 IgG4 induced progressive clinical symptoms. (B and C) Footprint analysis revealed abnormal spreading of hind limbs in animals treated with anti-Nfasc155 IgG4 compared with control animals. The footprint angle (gray lines) was significantly increased in animals treated with anti-Nfasc155 IgG4 compared with controls. (D–G) L6 ventral and dorsal roots from animals injected with control IgG4 or anti-Nfasc155 IgG4 were recorded on day 21 after the beginning of the injections (n = 12–14 nerves from 12–14 animals). Representative CAPs from control IgG4–treated (black traces) and anti-Nfasc155 IgG4–treated (gray traces) animals are shown in D and F. The peak amplitude, CAP duration, and conduction velocities at peak amplitude are represented in E and G for ventral and dorsal roots, respectively. The ventral spinal nerves of animals treated with anti-Nfasc155 IgG4 showed a significant decrease in CAP amplitude and conduction velocity compared with controls. This was associated with a significant increase in CAP duration. By contrast, nerve activity was not significantly affected in dorsal root. *P < 0.05, **P < 0.005 by unpaired 2-tailed Student’s t tests for 2 samples of equal variance. Bars represent mean and SD.