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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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Full PDF
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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    Figure 1 Reactivity to Nfasc155, CNTN1, and Caspr1 in CIDP by ELISA and CBA

    (A) Serum samples from patients with CIDP (n = 342), MMN (n = 13), GBS (n = 31), genetic PN (n = 18), other noninflammatory PN (n = 52), MS (n = 60) and from HCs (n = 60) were tested for autoantibodies to human Nfasc155 (left) and CNTN1 (right) by ELISA. OD are shown after subtraction of the baseline OD reading to bovine serum albumin. The red line represents the mean OD in HCs plus 3 standard deviations. (B) IgG isotype in Nfasc155- and CNTN1-positive patients. (C) The sera (here case 14) were tested on living HEK cells transfected with CNTN1 and Caspr1 (red) and then revealed with mouse antihuman IgG1, IgG2, IgG3, or IgG4 (green) as indicated. Nuclei were stained with DAPI (blue). (D) These are teased fibers from mouse sciatic nerves immunostained for CNTN1 (red) and the serum from case 14, then revealed with mouse antihuman IgG1, IgG2, IgG3, or IgG4 (green) as indicated. IgG1 and IgG4 from this patient reacted against Caspr1 and bound to the paranodal regions. Scale bars: 10 μm. Caspr1 = contactin-associated protein 1; CBA = cell-based assay; CIDP = chronic inflammatory demyelinating polyradiculoneuropathy; CNTN1 = contactin-1; GBS = Guillain-Barré syndrome; HC = healthy control; HEK = human embryonic kidney; MMN = multifocal motor neuropathy; Nfasc155 = neurofascin-155; OD = Optical density; PN = peripheral neuropathy.

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    Figure 2 Morphological alterations of the nodes of Ranvier in patients with CIDP with IgG4 autoantibodies

    We evaluated skin biopsies from 3 patients with IgG4 anti-Nfasc155 antibodies, 1 patient with IgG3/IgG4 anti-CNTN1 antibodies, 1 patient with IgG4 anti-Caspr1 antibodies, 1 patient with undetectable isotype IgG anti-Nfasc155, and 6 seronegative patients with CIDP. Analysis of myelinated fibers showed elongation of the nodes of Ranvier and loss of paranodal Nfasc155 staining in skin biopsies from patients with anti-Nfasc155 (C) and Caspr1 (E) IgG4. Moderate elongation of the nodes of Ranvier and loss of Nfasc155 paranodal staining were also observed in myelinated fibers of a CNTN1 IgG3/IgG4-positive patient (D). Contrarily, we did not observe similar changes in the patient with undetectable isotype IgG anti-Nfasc155 antibodies (F), in seronegative patients with CIDP (B), or in HCs (A). A complete loss of Caspr1 staining was observed in biopsies from patients with IgG4 antibodies to paranodal proteins (I, L, M), but not in an Nfasc155 seropositive patient with an undetectable isotype (N) and in seronegative CIDP (H) or healthy patients (G). Caspr1 = contactin-associated protein 1; CIDP = chronic inflammatory demyelinating polyradiculoneuropathy; CNTN1 = contactin-1; HC = healthy control; Nfasc155 = neurofascin-155.

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    Figure 3 IgG4 to Caspr1 disrupt the interaction between Nfasc155 and CNTN1/Caspr1

    (A–D) HEK cells transfected with CNTN1 and Caspr1 (green) or Nfasc155 (red) were incubated together for 2 hours in the presence of control IgG4 (B), anti-Caspr1 IgG1 (C), or anti-Caspr1 IgG4 (D). As negative controls, HEK cells transfected with Nfasc155 (red) were incubated with cells transfected with GFP (A). Anti-Caspr1 IgG4, but not anti-Caspr1 IgG1, abrogated the aggregation of Nfasc155-transfected cells with CNTN1/Caspr1. Scale bar: 10 μm. (E–F) The graphs represent the relative frequency of green cells per aggregates (n = 4 experiments for each condition). The percentage of cell clusters with contacts between green and red cells was quantified (F). The percentage of contacts was significantly decreased in the presence of anti-Caspr1 IgG4 (p < 0.005 by unpaired 2-tailed Student t tests and by one-way ANOVA, followed by Bonferroni post hoc tests). Bars represent mean and SEM. ANOVA = analysis of variance; Caspr1 = contactin-associated protein 1; CNTN1 = contactin-1; GFP = green fluorescent protein; HEK = human embryonic kidney; Nfasc155 = neurofascin-155.

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    Figure 4 Anti-Caspr1 IgG4, but not IgG1, invades the paranodal regions

    (A–C) Sciatic nerve fibers were incubated in vitro with purified control IgG4 (A), anti-Caspr1 IgG1 (B), or anti-Caspr1 IgG4 (C) for 3 hours and immunolabeled for IgG (green) and CNTN1 (red). (D–F) Sciatic nerves were fixed 1 or 3 days after intraneural injections of purified control IgG4 (D), anti-Caspr1 IgG4 (E–F), immunolabeled for CNTN1 (red), and human IgG (green). Note that only anti-Caspr1 IgG4 penetrated the paranodes. One or 3 days after injection, IgG4 antibodies were detected at the paranode borders (arrows). Images are representative of 3 independent experiments. Scale bar: 10 μm. Caspr1 = contactin-associated protein 1; CNTN1 = contactin-1.

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