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 7

Autoantibodies preferentially affect motor axons.

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Autoantibodies preferentially affect motor axons. (A–D) The distribution...
(A–D) The distribution of the axonal population according to the nodal diameters of axons was examined in L6 ventral roots (A and B) and dorsal roots (C and D) of animals treated with control IgG4 (n = 1297 nodes for ventral roots and 1061 nodes for dorsal roots from 11 animals) or anti-Nfasc155 IgG4 from patient CIDP1 (n = 1376 nodes for ventral roots and 875 nodes for dorsal roots from 11 animals). The respective proportion of normal nodes (open boxes) or nodes lacking paranodes (hatched boxes) is represented on the left, and the distribution of the total axonal population is represented on the right. The percentage of nodes showing paranodal alterations was calculated in ventral (B) and dorsal roots (D). Scatter plots represent the percentage of normal nodes in each animal. Paranodes were more significantly affected in ventral root axons than in dorsal roots (**P < 0.005 by unpaired 2-tailed Student’s t tests for 2 samples of equal variance). (E and F) The mean length of nodes lacking paranodes (hatched boxes) or appearing normal (open boxes) was measured in 11 animals for each group, as well as the mean paranodal length. No significant alterations in node or paranode length were observed between control and anti-Nfasc155 IgG4–treated animals (unpaired 2-tailed Student’s t tests and 1-way ANOVA followed by Bonferroni’s post hoc tests). In B and D–F, bars represents mean and SEM. In A and C, box bounds represent the first and third quartiles, lines within the box represent the median, and whiskers show the minimal and maximal values.