Neurofascin-155 IgG4 in chronic inflammatory demyelinating polyneuropathy

Abstract

Objective: We report the clinical and serologic features of Japanese patients with chronic inflammatory demyelinating polyneuropathy (CIDP) displaying anti-neurofascin-155 (NF155) immunoglobulin G4 (IgG4) antibodies. Methods:In sera from 533 patients with CIDP, anti-NF155 IgG4 antibodies were detected by ELISA. Binding of IgG antibodies to central and peripheral nerves was tested.Results: Anti-NF155 IgG4 antibodies were identified in 38 patients (7%) with CIDP, but not in disease controls or normal participants. These patients were younger at onset as compared to 100 anti-NF155-negative patients with CIDP. Twenty-eight patients (74%) presented with sensory ataxia, 16 (42%) showed tremor, 5 (13%) presented with cerebellar ataxia associated with nystagmus, 3 (8%) had demyelinating lesions in the CNS, and 20 of 25 (80%) had poor response to IV immunoglobulin. The clinical features of the antibody-positive patients were statistically more frequent as compared to negative patients with CIDP (n 5 100). Anti-NF155 IgG antibodies targeted similarly central and peripheral paranodes.Conclusion: Anti-NF155 IgG4 antibodies were associated with a subgroup of patients with CIDP showing a younger age at onset, ataxia, tremor, CNS demyelination, and a poor response to IV immunoglobulin. The autoantibodies may serve as a biomarker to improve patients' diagnosis and guide treatments. Neurology ® 2016;86:800-807 GLOSSARY Caspr1 5 contactin-associated protein-1; CCPD 5 combined central and peripheral demyelination; CI 5 confidence interval; CIDP 5 chronic inflammatory demyelinating polyneuropathy; CNTN1 5 contactin 1; GBS 5 Guillain-Barré syndrome; IgG4 5 immunoglobulin G4; IVIg 5 IV immunoglobulin; MS 5 multiple sclerosis; NF155 5 neurofascin-155; OR 5 odds ratio; PNS 5 peripheral nervous system.Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common acquired immune-mediated neuropathy worldwide and is clinically heterogeneous.1 Proven treatments for CIDP include corticosteroids, plasma exchange, and IV immunoglobulin (IVIg). However, the response rates to treatments are highly heterogeneous between patients. This emphasizes that patients and clinicians require biomarkers to identify CIDP subgroups and guide specific immunotherapeutic options.Immunoglobulin G4 (IgG4) autoantibodies to neurofascin-155 (NF155) were recently documented in patients with CIDP.2,3 NF155 belongs to the L1 family of adhesion molecules and is expressed at paranodes by the terminal loops of myelin and associates with the axonal cell adhesion molecules CNTN1 and contactin-associated protein-1 (Caspr1). 4 This ternary complex of glycoproteins is required for the rapid propagation of the nerve impulses along myelinated axons. 5,6 Three of 4 patients with anti-NF155 IgG4 showed disabling tremor and all showed poor response to IVIg. 3 This suggested that IgG4 autoantibodies participate in CIDP pathogenesis; nonetheless, the low number of reactive patients precluded statistical correlation.

Paranodal dissection in chronic inflammatory demyelinating polyneuropathy with anti-neurofascin-155 and anti-contactin-1 antibodies

“…As for the light microscopy observations of the transverse sections of the sural nerve biopsy specimens, similar findings have been reported previously in the assessment of two patients with anti-neurofascin-155 antibodies 20. Photographs taken from two other patients in a subsequent report also revealed similar features, although the presence of demyelination was also mentioned 21. Three sural nerve biopsy specimens taken from patients with CIDP with anti-contactin-1 antibodies also seemed to show similar pathological findings 18.…”

“…Patients with these antibodies are characterised by sensory ataxia, tremor and poor response to IVIg treatment 16 17 19–21. As pathological assessments of patients with these antibodies have been performed in only a small number of patients,18 20 21 the morphological abnormalities leading to the observed damage to the peripheral nervous system have not been clarified.…”

Autoimmune nodo-paranodopathies of peripheral nerve: the concept is gaining ground

“…The Spanish group reported also four patients with antibodies to NF155 presenting severe distal sensorimotor neuropathy, disabling tremor and poor response to intravenous Ig 4. This observation was confirmed in 7% of 533 Japanese patients with CIDP showing ataxia, tremor, poor response to intravenous Ig and, in 3 patients, central nervous system demyelination 52. Finally, antibodies directed exclusively to Caspr1 were described in one patient with CIDP with prominent neuropathic pain 5.…”

Teaching Neuro Images : Cranial nerve hypertrophy in IgG4 anti-neurofascin 155 antibody–positive polyneuropathy

“…1 Nerve hypertrophy has been reported in up to half of patients with CIDP, particularly in anti-NF155 antibody-positive patients. Hypertrophy of cervical and lumbosacral roots/plexuses has also been observed.…”