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 GastaldiElisa 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

Research output: Contribution to journalArticle

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%).

Original languageEnglish
JournalNeurology: Neuroimmunology and NeuroInflammation
Volume7
Issue number1
DOIs
Publication statusPublished - Jan 2020

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    Cortese, A., Lombardi, R., Briani, C., Callegari, I., Benedetti, L., Manganelli, F., Luigetti, M., Ferrari, S., Clerici, A. M., Marfia, G. A., Rigamonti, A., Carpo, M., Fazio, R., Corbo, M., Mazzeo, A., Giannini, F., Cosentino, G., Zardini, E., Currò, R., ... Franciotta, D. (2020). Antibodies to neurofascin, contactin-1, and contactin-associated protein 1 in CIDP: Clinical relevance of IgG isotype. Neurology: Neuroimmunology and NeuroInflammation, 7(1). https://doi.org/10.1212/NXI.0000000000000639