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January 2020; 7 (1) ArticleOpen Access

Antibodies to neurofascin, contactin-1, and contactin-associated protein 1 in CIDP

Clinical relevance of IgG isotype

Andrea Cortese, Raffaella Lombardi, Chiara Briani, Ilaria Callegari, Luana Benedetti, Fiore Manganelli, Marco Luigetti, Sergio Ferrari, Angelo M. Clerici, Girolama Alessandra Marfia, Andrea Rigamonti, Marinella Carpo, Raffaella Fazio, Massimo Corbo, Anna Mazzeo, Fabio Giannini, Giuseppe Cosentino, Elisabetta Zardini, Riccardo Currò, Matteo Gastaldi, Elisa Vegezzi, Enrico Alfonsi, Angela Berardinelli, Ludivine Kouton, Constance Manso, Claudia Giannotta, Pietro Doneddu, View ORCID ProfilePatrizia Dacci, Laura Piccolo, Marta Ruiz, Alessandro Salvalaggio, Chiara De Michelis, Emanuele Spina, Antonietta Topa, Giulia Bisogni, Angela Romano, Sara Mariotto, Giorgia Mataluni, Federica Cerri, Claudia Stancanelli, Mario Sabatelli, Angelo Schenone, Enrico Marchioni, Giuseppe Lauria, Eduardo Nobile-Orazio, View ORCID ProfileJérôme Devaux, Diego Franciotta
First published November 21, 2019, DOI: https://doi.org/10.1212/NXI.0000000000000639
Andrea Cortese
From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico “Carlo Besta,” Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples “Federico II,” Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi “Bonino Pulejo” (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences “Luigi Sacco” (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.
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Raffaella Lombardi
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Chiara Briani
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Citation
Antibodies to neurofascin, contactin-1, and contactin-associated protein 1 in CIDP
Clinical relevance of IgG isotype
Andrea Cortese, Raffaella Lombardi, Chiara Briani, Ilaria Callegari, Luana Benedetti, Fiore Manganelli, Marco Luigetti, Sergio Ferrari, Angelo M. Clerici, Girolama Alessandra Marfia, Andrea Rigamonti, Marinella Carpo, Raffaella Fazio, Massimo Corbo, Anna Mazzeo, Fabio Giannini, Giuseppe Cosentino, Elisabetta Zardini, Riccardo Currò, Matteo Gastaldi, Elisa Vegezzi, Enrico Alfonsi, Angela Berardinelli, Ludivine Kouton, Constance Manso, Claudia Giannotta, Pietro Doneddu, Patrizia Dacci, Laura Piccolo, Marta Ruiz, Alessandro Salvalaggio, Chiara De Michelis, Emanuele Spina, Antonietta Topa, Giulia Bisogni, Angela Romano, Sara Mariotto, Giorgia Mataluni, Federica Cerri, Claudia Stancanelli, Mario Sabatelli, Angelo Schenone, Enrico Marchioni, Giuseppe Lauria, Eduardo Nobile-Orazio, Jérôme Devaux, Diego Franciotta
Neurol Neuroimmunol Neuroinflamm Jan 2020, 7 (1) e639; DOI: 10.1212/NXI.0000000000000639

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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.

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