Neurofascin IgG4 antibodies in CIDP associate with disabling tremor and poor response to IVIg

Abstract

Objective: To describe the frequency of antibodies against neurofascin in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and the associated clinical features.

Methods: Immunocytochemistry was used to identify antibodies to neurofascin 155 (NF155) and 186. Serum reactivity with paranodes and brain tissue was tested with immunohistochemistry of teased-nerve fibers and rat brain. Antibody titers and immunoglobulin (Ig) G isotypes were determined using ELISA. Clinical information was obtained retrospectively.

Results: Two of 53 patients, but none of 204 controls, had antibodies to NF155 (p = 0.041). The 2 patients with NF155 antibodies developed severe polyradiculoneuropathy with predominant distal weakness that was refractory to IVIg. Eight additional patients with IVIg-refractory CIDP were then identified from a national database; 2 of them with the same clinical features also had NF155 antibodies. Overall, 3 of the 4 patients with NF155 antibodies had a disabling and characteristic tremor (high amplitude, low frequency, postural, and intention). Patients' antibodies reacted with the paranodes in teased-nerve fibers and with the neuropil of rat cerebellum, brain, and brainstem. Anti-NF155 antibodies were predominantly of the IgG4 isotype in all patients.

Conclusion: Patients with CIDP positive for IgG4 NF155 antibodies constitute a specific subgroup with a severe phenotype, poor response to IVIg, and disabling tremor. Autoantibodies against paranodal structures associate with distinct clinical features in CIDP and their identification has diagnostic, prognostic, and therapeutic implications.

Classification of evidence: This study provides Class IV evidence that autoantibodies to NF155 identify a CIDP subtype characterized by severe neuropathy, poor response to IVIg, and disabling tremor.

Figure 1. Immunocytochemistry and immunohistochemistry of anti-NF155+ patients

(A–C) Commercial anti–neurofascin 155 (NF155) antibody (A) and patient 3 serum (B) signals colocalize (C) in immunocytochemistry using NF155-transfected HEK293 cells. (D–F) Commercial anti-NF155 antibody (D) and patient 1 serum (E) signals colocalize (F) at the paranode in immunohistochemistry using teased-nerve fibers. (G–I) Patient 2 serum reactivity against the paranode (G) is abrogated when it is preincubated with NF155-transfected HEK cells.

Figure 2. Comparison of reactivity against NF155 and anti-NF155 IgG isotypes measured using ELISA

Reactivity against NF155 measured using ELISA (A) was significantly different in patients with anti-NF155 antibodies (tested by immunocytochemistry) than in patients with CIDP without anti-NF155 antibodies (p < 0.01) or in normal controls (p < 0.01) at a serum dilution of 1:100. The predominant anti-NF155 IgG isotype in anti-NF155+ patients was IgG4 (B). CIDP = chronic inflammatory demyelinating polyradiculoneuropathy; CRLS = normal controls; IgG = immunoglobulin G; NF155 = neurofascin 155; NF155+ = CIDP patients with anti-NF155 antibodies detected by immunocytochemistry; OD = optical density.

Figure 3. Demonstration of anti–neurofascin 155 antibodies in the serum of a patient with chronic inflammatory demyelinating polyradiculoneuropathy, disabling tremor, and poor response to IV immunoglobulin

The reactivity of the patient's serum antibodies using immunohistochemistry of rat brain is shown by brown staining in hippocampus (A) and in cerebellum (B). (C, D) Lack of reactivity of serum from an individual without neurofascin antibodies, who served as a control. Original magnification ×2 (A, C) and ×4 (B, D). Counterstained with hematoxylin. Bar = 500 µm.