Neurofascin antibodies in autoimmune, genetic, and idiopathic neuropathies

Abstract

ObjectiveTo measure the frequency, persistence, isoform specificity, and clinical correlates of neurofascin antibodies in patients with peripheral neuropathies.MethodsWe 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.ResultsNeurofascin 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.ConclusionsNeurofascin 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.

Neurofascin-155 IgM autoantibodies in patients with inflammatory neuropathies

“…In contrast to a recent study also describing anti-neurofascin-155 IgM,7 we did not detect any IgM autoantibodies in patients with non-inflammatory neuropathies and thus found a significant difference of autoantibody frequency between inflammatory neuropathies and controls. This supports the idea of a pathogenic or at least disease-associated role of IgM autoantibodies.…”

“…A patient with a combination of IgM, IgA and IgG3 anti-neurofascin-155 autoantibodies has been reported,4 but subsequent studies focused on the detection of IgG autoantibodies. Only recently a cohort of patients with inflammatory and non-inflammatory neuropathies was published that had been screened for anti-neurofascin IgM and IgG by cell-based assays 7. These authors found IgM autoantibodies in 8% of patients with inflammatory neuropathy, but also in 5% of patients with idiopathic neuropathy.…”

Remarkable Rituximab Response on Tremor Related to Acute‐Onset Chronic Inflammatory Demyelinating Polyradiculoneuropathy in an Antineurofascin155 Immunoglobulin G4–Seropositive Patient

“…Our patient manifested a severe clinical phenotype very similar to those typical of anti‐NF‐155 antibody–associated CIDP. A GBS‐like onset of the disease, as well as good responses to rituximab, have also been reported. However, the heterogeneity in clinical severity and phenotypes (e.g., disabling tremor was absent in some cases) makes the comparative evaluations of rituximab efficacy difficult.…”

Boundaries of chronic inflammatory demyelinating polyradiculoneuropathy

“…IgG3 antibodies against all 3 neurofascin isoforms were detected in 3 cases presenting with a fulminant neuropathy with tetraplegia and cranial nerve palsy, and with respiratory failure and autonomic involvement in 2 of these . Similar findings were observed in 2 patients with pan‐neurofascin IgG3 antibodies, but also in 2 patients with IgG4 antibodies . The latter suggests that the unique clinical picture may be mostly explained by a unique epitope, a common domain of nodal NF140/186 and paranodal NF155, but may also be associated with the IgG3 subclass.…”