Anti-pan-neurofascin IgG3: insights about an emerging autoimmune nodoparanodopathy

Abstract

Neurofascin constitutes a family of cell-surface proteins identified more than 4 decades ago, produced through alternative RNA splicing, with various isoforms expressed in neural tissues. With the emergence of chronic inflammatory demyelinating polyneuropathy (CIDP) subtypes characterized by distinct pathological mechanisms, antineurofascin antibody-mediated neuropathies have gained attention and are now categorized as autoimmune nodoparanodopathies. Among these, the anti-pan-neurofascin immunoglobulin G3 (IgG3) subtype presents a particularly severe and diagnostically-challenging phenotype, marked by a fulminant clinical course, diverse symptomatology, and high rates of morbidity and mortality. Despite its clinical relevance, to date, no comprehensive review has focused specifically on this manifestation, highlighting a significant gap in the literature. To address this, we herein review the seven reported cases and explore the proposed pathophysiological mechanism involving the destruction of the node of Ranvier via hyperactivation of membrane attack complex (MAC) formation. Additionally, we examine emerging evidence supporting the use of eculizumab as a potential therapeutic option, alongside other treatment strategies. Finally, we discuss the role of standardized antibody assays, serological analyses, and neurophysiological studies in improving diagnostic accuracy.

Keywords

Polyneuropathies - Autoantibodies - Immunoglobulin G

Authors' Contributions

Conceptualization: MVMG; Data curation: GE, MEGI; Investigation: GE, MEGI; Methodology: GE, MEGI; Project administration: LFP, GDV; Supervision: GDV, MVMG; Writing – original draft: GE, MEGI, LFP; Writing – review & editing: LFP, GDV, MVMG.

Data Availability Statement

Because our table is based on data extracted from previously-published studies, all data and materials are publicly available. The authors do not have access to individual patient-level data from the studies included in the present review.

Editor-in-Chief: Ayrton Roberto Massaro (https://orcid.org/0000-0002-0487-5299/).

Associate Editor: Wilson Marques Jr. (https://orcid.org/0000-0002-4589-2749/).

Publikationsverlauf

Eingereicht: 07. Januar 2025

Angenommen: 27. Juli 2025

Artikel online veröffentlicht:
15. Oktober 2025

• References

• 1 Uncini A, Susuki K, Yuki N. Nodo-paranodopathy: beyond the demyelinating and axonal classification in anti-ganglioside antibody-mediated neuropathies. Clin Neurophysiol 2013; 124 (10) 1928-1934
• 2 Rathjen FG, Wolff JM, Chang S, Bonhoeffer F, Raper JA. Neurofascin: a novel chick cell-surface glycoprotein involved in neurite-neurite interactions. Cell 1987; 51 (05) 841-849
• 3 Gao Y, Kong L, Liu S, Liu K, Zhu J. Impact of Neurofascin on Chronic Inflammatory Demyelinating Polyneuropathy via Changing the Node of Ranvier Function: A Review. Front Mol Neurosci 2021; 14: 779385
• 4 Appeltshauser L, Doppler K. Pan-Neurofascin autoimmune nodopathy - a life-threatening, but reversible neuropathy. Curr Opin Neurol 2023; 36 (05) 394-401
• 5 Kriebel M, Wuchter J, Trinks S, Volkmer H. Neurofascin: a switch between neuronal plasticity and stability. Int J Biochem Cell Biol 2012; 44 (05) 694-697
• 6 Van den Bergh PYK, Van Doorn PA, Hadden RDM, Avau B, Vankrunkelsven P, Allen JA. et al. European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision. Eur J Neurol 2021; 28 (11) 3556-3583
• 7 Gonçalves MVM, Tomaselli PJ, Marques Junior W. Immune-mediated insights into clinical and specific autoantibodies in acute and chronic immune-mediated nodo-paranodopathies. Arq Neuropsiquiatr 2025; 83 (04) 1-6
• 8 Stengel H, Vural A, Brunder A-M, Heinius A, Appeltshauser L, Fiebig B. et al. Anti-pan-neurofascin IgG3 as a marker of fulminant autoimmune neuropathy. Neurol Neuroimmunol Neuroinflamm 2019; 6 (05) e603
• 9 Olafsdottir TA, Thorleifsson G, Portilla ALdL, Jonsson S, Stefansdottir L, Niroula A. et al. Sequence variants influencing the regulation of serum IgG subclass levels. Nat Commun 2024; 15 (01) 8054
• 10 Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: from structure to effector functions. Front Immunol 2014; 5: 520
• 11 Siber GR, Schur PH, Aisenberg AC, Weitzman SA, Schiffman G. Correlation between serum IgG-2 concentrations and the antibody response to bacterial polysaccharide antigens. N Engl J Med 1980; 303 (04) 178-182
• 12 Schroeder Jr HW, Cavacini L. Structure and function of immunoglobulins. J Allergy Clin Immunol 2010; 125 (2, Suppl 2) S41-S52
• 13 Querol L, Dalakas MC. The Discovery of Autoimmune Nodopathies and the Impact of IgG4 Antibodies in Autoimmune Neurology. Neurol Neuroimmunol Neuroinflamm 2025; 12 (01) e200365
• 14 Stapleton NM, Andersen JT, Stemerding AM, Bjarnarson SP, Verheul RC, Gerritsen J. et al. Competition for FcRn-mediated transport gives rise to short half-life of human IgG3 and offers therapeutic potential. Nat Commun 2011; 2: 599
• 15 Abendstein L, Dijkstra DJ, Tjokrodirijo RTN, Van Veelen PA, Trouw LA, Hensbergen PJ, Sharp TH. Complement is activated by elevated IgG3 hexameric platforms and deposits C4b onto distinct antibody domains. Nat Commun 2023; 14 (01) 4027
• 16 Delmont E, Manso C, Querol L, Cortese A, Berardinelli A, Lozza A. et al. Autoantibodies to nodal isoforms of neurofascin in chronic inflammatory demyelinating polyneuropathy. Brain 2017; 140 (07) 1851-1858
• 17 Appeltshauser L, Junghof H, Messinger J, Linke J, Haarmann A, Ayzenberg I. et al. Anti-pan-neurofascin antibodies induce subclass-related complement activation and nodo-paranodal damage. Brain 2023; 146 (05) 1932-1949
• 18 Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol 2010; 11 (09) 785-797
• 19 Rohrbacher S, Seefried S, Hartmannsberger B, Annabelle R, Appeltshauser L, Arlt FA. et al. Different Patterns of Autoantibody Secretion by Peripheral Blood Mononuclear Cells in Autoimmune Nodopathies. Neurol Neuroimmunol Neuroinflamm 2024; 11 (05) e200295
• 20 Vallat J-M, Mathis S, Magy L, Bounolleau P, Skarzynski M, Heitzmann A. et al. Subacute nodopathy with conduction blocks and anti-neurofascin 140/186 antibodies: an ultrastructural study. Brain 2018; 141 (07) e56
• 21 Martín-Aguilar L, Lleixà C, Pascual-Goñi E. Autoimmune nodopathies, an emerging diagnostic category. Curr Opin Neurol 2022; 35 (05) 579-585
• 22 Lleixà C, Titulaer M, Rohrbacher S, Mgbachi V, Halstead S, Fehmi J. et al. Inter-Laboratory Validation of Nodal/Paranodal Antibody Testing. J Peripher Nerv Syst 2025; 30 (01) e70000
• 23 Hodgens A, Sharman T. Corticosteroids. [Updated 2023 May 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025. . Available from: https://www.ncbi.nlm.nih.gov/books/NBK554612/
• 24 Yasir M, Goyal A, Sonthalia S. Corticosteroid Adverse Effects. [Updated 2023 Jul 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025. . Available from: https://www.ncbi.nlm.nih.gov/books/NBK531462/
• 25 Sergent SR, Ashurst JV. Plasmapheresis. [Updated 2023 Jul 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025. . Available from: https://www.ncbi.nlm.nih.gov/books/NBK560566/
• 26 Mair D, Madi H, Eftimov F, Lunn MP, Keddie S. Novel therapies in CIDP. J Neurol Neurosurg Psychiatry 2024; 96 (01) 38-46
• 27 Pavlasova G, Mraz M. The regulation and function of CD20: an “enigma” of B-cell biology and targeted therapy. Haematologica 2020; 105 (06) 1494-1506
• 28 Zografou C, Vakrakou AG, Stathopoulos P. Short- and Long-Lived Autoantibody-Secreting Cells in Autoimmune Neurological Disorders. Front Immunol 2021; 12: 686466
• 29 Lutz HU, Stammler P, Bianchi V, Trüeb RM, Hunziker T, Burger R. et al. Intravenously applied IgG stimulates complement attenuation in a complement-dependent autoimmune disease at the amplifying C3 convertase level. Blood 2004; 103 (02) 465-472
• 30 Arumugham VB, Rayi A. Intravenous Immunoglobulin (IVIG) [Updated 2023 Jul 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025. . Available from: https://www.ncbi.nlm.nih.gov/books/NBK554446/
• 31 Shelly S, Klein CJ, Dyck PJB, Paul P, Mauermann ML, Berini SE. et al. Neurofascin-155 Immunoglobulin Subtypes: Clinicopathologic Associations and Neurologic Outcomes. Neurology 2021; 97 (24) e2392-e2403
• 32 Davin J-C, Van de Kar NCAJ. Advances and challenges in the management of complement-mediated thrombotic microangiopathies. Ther Adv Hematol 2015; 6 (04) 171-185
• 33 Howard Jr JF, Utsugisawa K, Benatar M, Murai H, Barohn RJ, Illa I. et al; REGAIN Study Group. Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study. Lancet Neurol 2017; 16 (12) 976-986
• 34 Jacob S, Murai H, Utsugisawa K, Nowak RJ, Wiendl H, Fujita KP. et al. Response to eculizumab in patients with myasthenia gravis recently treated with chronic IVIg: a subgroup analysis of REGAIN and its open-label extension study. Ther Adv Neurol Disord 2020; 13: 1756286420911784
• 35 Misawa S, Kuwabara S, Sato Y, Yamaguchi N, Nagashima K, Katayama K. et al; Japanese Eculizumab Trial for GBS (JET-GBS) Study Group. Safety and efficacy of eculizumab in Guillain-Barré syndrome: a multicentre, double-blind, randomised phase 2 trial. Lancet Neurol 2018; 17 (06) 519-529