Anti-Neurofascin-155 IgG4 antibodies prevent paranodal complex formation in vivo

J Clin Invest. 2019 Mar 14;129(6):2222-2236. doi: 10.1172/JCI124694.

Abstract

Neurofascin-155 (Nfasc155) is an essential glial cell adhesion molecule expressed in paranodal septate-like junctions of peripheral and central myelinated axons. The genetic deletion of Nfasc155 results in the loss of septate-like junctions and in conduction slowing. In humans, IgG4 antibodies against Nfasc155 are implicated in the pathogenesis of chronic inflammatory demyelinating polyneuropathy (CIDP). These antibodies are associated with an aggressive onset, a refractoriness to intravenous immunoglobulin, and tremor of possible cerebellar origin. Here, we examined the pathogenic effects of patient-derived anti-Nfasc155 IgG4. These antibodies did not inhibit the ability of Nfasc155 to complex with its axonal partners contactin-1/CASPR1 or induce target internalization. Passive transfer experiments revealed that IgG4 antibodies target Nfasc155 on Schwann cell surface, and diminished Nfasc155 protein levels and prevented paranodal complex formation in neonatal animals. In adult animals, chronic intrathecal infusions of antibodies also induced the loss of Nfasc155 and of paranodal specialization and resulted in conduction alterations in motor nerves. These results indicate that anti-Nfasc155 IgG4 perturb conduction in absence of demyelination, validating the existence of paranodopathy. These results also shed light on the mechanisms regulating protein insertion at paranodes.

Keywords: Autoimmune diseases; Autoimmunity; Neurological disorders; Neuromuscular disease; Neuroscience.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / immunology*
  • Axons / pathology
  • Cell Adhesion Molecules / antagonists & inhibitors*
  • Cell Adhesion Molecules / immunology
  • Chronic Disease
  • Female
  • HEK293 Cells
  • Humans
  • Immunoglobulin G / immunology
  • Immunoglobulin G / pharmacology*
  • Male
  • Motor Neurons / immunology
  • Motor Neurons / pathology
  • Nerve Growth Factors / antagonists & inhibitors*
  • Nerve Growth Factors / immunology
  • Polyneuropathies* / drug therapy
  • Polyneuropathies* / immunology
  • Polyneuropathies* / pathology
  • Polyradiculoneuropathy* / drug therapy
  • Polyradiculoneuropathy* / immunology
  • Polyradiculoneuropathy* / pathology
  • Rats
  • Rats, Inbred Lew
  • Schwann Cells / immunology
  • Schwann Cells / pathology

Substances

  • Cell Adhesion Molecules
  • Immunoglobulin G
  • NFASC protein, human
  • Nerve Growth Factors
  • Nfasc protein, rat

Grant support

Pla Estratègic de Recerca i Innovació en Salut (PERIS) 2016-2020