Neurofascin antibodies in autoimmune, genetic, and idiopathic neuropathies

Abstract

Objective: To measure the frequency, persistence, isoform specificity, and clinical correlates of neurofascin antibodies in patients with peripheral neuropathies.

Methods: We studied cohorts of patients with Guillain-Barre syndrome (GBS) or chronic inflammatory demyelinating polyneuropathy (CIDP) (n = 59), genetic neuropathy (n = 111), and idiopathic neuropathy (n = 43) for immunoglobulin (Ig) G and IgM responses to 3 neurofascin (NF) isoforms (NF140, NF155, and NF186) using cell-based assays.

Results: Neurofascin antibodies were more common in patients with GBS/CIDP (14%, 8 of 59) compared to genetic neuropathy controls (3%, 3 of 111, p = 0.01). Seven percent (3 of 43) of patients with idiopathic neuropathy also had neurofascin antibodies. NF155 IgG4 antibodies were associated with CIDP refractory to IV immunoglobulin but responsive to rituximab, and some of these patients had an acute onset resembling GBS. NF186 IgG and IgM to either isoform were less specific. A severe form of CIDP, approaching a locked-in state, was seen in a patient with antibodies recognizing all 3 neurofascin isoforms.

Conclusions: Neurofascin antibodies were 4 times more frequent in autoimmune neuropathy samples compared to genetic neuropathy controls. Persistent IgG4 responses to NF155 correlated with severe CIDP resistant to usual treatments but responsive to rituximab. IgG4 antibodies against the common domains shared by glial and axonal isoforms may portend a particularly severe but treatable neuropathy. The prognostic implications of neurofascin antibodies in a subset of idiopathic neuropathy patients and transient IgM responses in GBS require further investigation.

Figure 1. Neurofascin (NF) isoforms and cell-based assay

(A) NF155, NF186, and NF140 are isoforms of neurofascin that share common extracellular domains (immunoglobulin [Ig], fibronectin [FN], transmembrane [TM], and mucin), as illustrated (adapted from Zhang et al. with permission). (B) HEK293 cells were transfected to express either NF155 or NF186, immunolabeled live with sera, fixed, permeabilized, and immunolabeled with a commercial neurofascin antibody, followed by appropriate secondary fluorescent antibodies. This example shows human IgG staining of cells transfected to express NF155 for a patient with chronic inflammatory demyelinating polyneuropathy (case 4) and a control. Scale = 10 μmol/L.

Figure 2. Isoform specificity of neurofascin (NF) responses

HEK293 cells were transfected to express NF155 (A), NF186 (B), or NF140 (C), immunolabeled live with sera, fixed, permeabilized, and immunolabeled with a commercial neurofascin antibody, followed by appropriate secondary fluorescent antibodies. Most cases with neurofascin antibodies, like case 4, were specific to NF155 or NF186. Case 2 is so far unique in recognizing all 3 isoforms. See text. Scale 10 μmol/L.