Antibodies to neurofascin, contactin-1, and contactin-associated protein 1 in CIDP
Clinical relevance of IgG isotype
Citation Manager Formats
Make Comment
See Comments

Abstract
Objective To assess the prevalence and isotypes of anti-nodal/paranodal antibodies to nodal/paranodal proteins in a large chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) cohort, compare clinical features in seronegative vs seropositive patients, and gather evidence of their isotype-specific pathogenic role.
Methods Antibodies to neurofascin-155 (Nfasc155), neurofascin-140/186 (Nfasc140/186), contactin-1 (CNTN1), and contactin-associated protein 1 (Caspr1) were detected with ELISA and/or cell-based assay. Antibody pathogenicity was tested by immunohistochemistry on skin biopsy, intraneural injection, and cell aggregation assay.
Results Of 342 patients with CIDP, 19 (5.5%) had antibodies against Nfasc155 (n = 9), Nfasc140/186 and Nfasc155 (n = 1), CNTN1 (n = 3), and Caspr1 (n = 6). Antibodies were absent from healthy and disease controls, including neuropathies of different causes, and were mostly detected in patients with European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) definite CIDP (n = 18). Predominant antibody isotypes were immunoglobulin G (IgG)4 (n = 13), IgG3 (n = 2), IgG1 (n = 2), or undetectable (n = 2). IgG4 antibody-associated phenotypes included onset before 30 years, severe neuropathy, subacute onset, tremor, sensory ataxia, and poor response to intravenous immunoglobulin (IVIG). Immunosuppressive treatments, including rituximab, cyclophosphamide, and methotrexate, proved effective if started early in IVIG-resistant IgG4-seropositive cases. Five patients with an IgG1, IgG3, or undetectable isotype showed clinical features indistinguishable from seronegative patients, including good response to IVIG. IgG4 autoantibodies were associated with morphological changes at paranodes in patients' skin biopsies. We also provided preliminary evidence from a single patient about the pathogenicity of anti-Caspr1 IgG4, showing their ability to penetrate paranodal regions and disrupt the integrity of the Nfasc155/CNTN1/Caspr1 complex.
Conclusions Our findings confirm previous data on the tight clinico-serological correlation between antibodies to nodal/paranodal proteins and CIDP. Despite the low prevalence, testing for their presence and isotype could ultimately be part of the diagnostic workup in suspected inflammatory demyelinating neuropathy to improve diagnostic accuracy and guide treatment.
Classification of evidence This study provides Class III evidence that antibodies to nodal/paranodal proteins identify patients with CIDP (sensitivity 6%, specificity 100%).
Glossary
- Caspr1=
- contactin-associated protein 1;
- CBA=
- cell-based assay;
- CIDP=
- chronic inflammatory demyelinating polyradiculoneuropathy;
- CNTN1=
- contactin-1;
- EFNS/PNS=
- European Federation of Neurological Societies/Peripheral Nerve Society;
- GBS=
- Guillain-Barré syndrome;
- GFP=
- green fluorescent protein;
- HC=
- healthy control;
- IVIG=
- intravenous immunoglobulin;
- MMN=
- multifocal motor neuropathy;
- MRC=
- medical research council;
- Nfasc155=
- neurofascin-155;
- ONLS=
- Overall Neuropathy Limitation Scale;
- PN=
- peripheral neuropathy
Footnotes
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.
↵* These authors contributed equally to this work.
The Article Processing Charge was funded by the MRC and Wellcome Trust.
Class of Evidence: NPub.org/coe
- Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Letters: Rapid online correspondence
REQUIREMENTS
You must ensure that your Disclosures have been updated within the previous six months. Please go to our Submission Site to add or update your Disclosure information.
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.
You May Also be Interested in
Dr. Babak Hooshmand and Dr. David Smith
► Watch
Related Articles
- No related articles found.
Topics Discussed
Alert Me
Recommended articles
-
Article
Antiparanodal antibodies and IgG subclasses in acute autoimmune neuropathyLuise Appeltshauser, Anna-Michelle Brunder, Annika Heinius et al.Neurology: Neuroimmunology & Neuroinflammation, July 24, 2020 -
Article
Anti-neurofascin antibody in patients with combined central and peripheral demyelinationNobutoshi Kawamura, Ryo Yamasaki, Tomomi Yonekawa et al.Neurology, July 24, 2013 -
Article
Neurofascin IgG4 antibodies in CIDP associate with disabling tremor and poor response to IVIgLuis Querol, Gisela Nogales-Gadea, Ricardo Rojas-Garcia et al.Neurology, February 12, 2014 -
Clinical/Scientific Notes
Neurofascin-155 as a putative antigen in combined central and peripheral demyelinationAndrea Cortese, Jérôme J. Devaux, Elisabetta Zardini et al.Neurology: Neuroimmunology & Neuroinflammation, June 07, 2016