Antibodies to neurofascin, contactin-1, and contactin-associated protein 1 in CIDP: Clinical relevance of IgG isotype.
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Cortese Andrea, Lombardi Raffaella, Briani Chiara, Callegari Ilaria, Benedetti Luana, Manganelli Fiore, Luigetti Marco, Ferrari Sergio, Clerici Angelo M, Marfia Girolama Alessandra, Rigamonti Andrea, Carpo Marinella, Fazio Raffaella, Corbo Massimo, Mazzeo Anna, Giannini Fabio, Cosentino Giuseppe, Zardini Elisabetta, Currò Riccardo, Gastaldi Matteo, Vegezzi Elisa, Alfonsi Enrico, Berardinelli Angela, Kouton Ludivine, Manso Constance, Giannotta Claudia, Doneddu Pietro, Dacci Patrizia, Piccolo Laura, Ruiz Marta, Salvalaggio Alessandro, De Michelis Chiara, Spina Emanuele, Topa Antonietta, Bisogni Giulia, Romano Angela, Mariotto Sara, Mataluni Giorgia, Cerri Federica, Stancanelli Claudia, Sabatelli Mario, Schenone Angelo, Marchioni Enrico, Lauria Giuseppe, Nobile-Orazio Eduardo, Devaux Jérôme, Franciotta Diego
Аннотация
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%).