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

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 again...

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Authors: Manso, C, Querol, L, Lleixa, C, Poncelet, M, Mekaouche, M, Vallat, JM, Illa, I, Devaux, JJ
Format: article
Status:Published version
Publication Date:2019
Country:España
Institution:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repository:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p2638
Online Access:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=2638
http://ddd.uab.cat/record/223806
Access Level:Open access
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spelling Anti-neurofascin-155 IgG4 antibodies prevent paranodal complex formation in vivoManso, CQuerol, LLleixa, CPoncelet, MMekaouche, MVallat, JMIlla, IDevaux, JJNeurofascin-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.AMER SOC CLINICAL INVESTIGATION INC2019info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=2638http://ddd.uab.cat/record/223806JOURNAL OF CLINICAL INVESTIGATIONISSN: 00219738ISSNe: 15588238reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pauinstname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)Inglésinfo:eu-repo/semantics/openAccessoai:iibsantpau.fundanetsuite.com:p26382026-06-14T12:41:47Z
dc.title.none.fl_str_mv Anti-neurofascin-155 IgG4 antibodies prevent paranodal complex formation in vivo
title Anti-neurofascin-155 IgG4 antibodies prevent paranodal complex formation in vivo
spellingShingle Anti-neurofascin-155 IgG4 antibodies prevent paranodal complex formation in vivo
Manso, C
title_short Anti-neurofascin-155 IgG4 antibodies prevent paranodal complex formation in vivo
title_full Anti-neurofascin-155 IgG4 antibodies prevent paranodal complex formation in vivo
title_fullStr Anti-neurofascin-155 IgG4 antibodies prevent paranodal complex formation in vivo
title_full_unstemmed Anti-neurofascin-155 IgG4 antibodies prevent paranodal complex formation in vivo
title_sort Anti-neurofascin-155 IgG4 antibodies prevent paranodal complex formation in vivo
dc.creator.none.fl_str_mv Manso, C
Querol, L
Lleixa, C
Poncelet, M
Mekaouche, M
Vallat, JM
Illa, I
Devaux, JJ
author Manso, C
author_facet Manso, C
Querol, L
Lleixa, C
Poncelet, M
Mekaouche, M
Vallat, JM
Illa, I
Devaux, JJ
author_role author
author2 Querol, L
Lleixa, C
Poncelet, M
Mekaouche, M
Vallat, JM
Illa, I
Devaux, JJ
author2_role author
author
author
author
author
author
author
description 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.
publishDate 2019
dc.date.none.fl_str_mv 2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=2638
http://ddd.uab.cat/record/223806
url https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=2638
http://ddd.uab.cat/record/223806
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv AMER SOC CLINICAL INVESTIGATION INC
publisher.none.fl_str_mv AMER SOC CLINICAL INVESTIGATION INC
dc.source.none.fl_str_mv JOURNAL OF CLINICAL INVESTIGATION
ISSN: 00219738
ISSNe: 15588238
reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
instname_str Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
reponame_str r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
collection r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
repository.name.fl_str_mv
repository.mail.fl_str_mv
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