IgG1 pan-neurofascin antibodies identify a severe yet treatable neuropathy with a high mortality

Abstract

Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy are umbrella terms for a number of pathologically distinct diseases involving disabling, immune-mediated injury to peripheral nerves. Current treatments involve non-specific immunomodulation. Prospective identification of patients with specific disease mechanisms should increasingly inform the use of more targeted disease modifying therapies and may lead to improved outcomes. In this cohort study, we tested serum for antibodies directed against nodal/paranodal protein antigens. The clinical characteristics of antibody positive and seronegative patients were then compared. Eight patients with IgG1-subclass antibodies directed against both isoforms of the nodal/paranodal cell-adhesion molecule neurofascin were identified. All developed rapidly progressive tetraplegia. Cranial nerve deficits (100% versus 26%), autonomic dysfunction (75% versus 13%) and respiratory involvement (88% versus 14%) were more common than in seronegative patients. The response to intravenous immunoglobulin, steroids and/or plasmapheresis was poor. Four patients received the B-cell-depleting therapy rituximab. After several weeks, these patients began to show progressive functional improvements, became seronegative, and were ultimately discharged home. Four patients who did not receive rituximab did not improve and died following the development of infectious complications and/or withdrawal of intensive care support. IgG1 panneurofascin antibodies define a very severe autoimmune neuropathy. We urgently recommend trials of targeted immunotherapy for this serologically-classified patient group.

Guillain-Barré syndrome following Zika virus infection is associated with a diverse spectrum of peripheral nerve reactive antibodies

“…[27] Although we observed one case of anti-pan-NF protein isotype IgG1 autoantibodies in our Colombian cohort (ZIKV-GBS patient A), prodromal infection is not a consistent feature of this rare and potentially fatal peripheral neuropathy subtype. [28] By employing a comprehensive series of peripheral nerve cell culture models and antigen expression systems, we reveal a surprisingly heterogeneous autoantibody response in patients' sera. Overall, IgG reactivity to rat SCs and the cell co-cultures was significantly higher, albeit infrequently, in the ZIKV-GBS patient group compared to all controls.…”

Autoimmune nodopathies, an emerging diagnostic category

“…These findings are suggestive of reversible conduction failure due to nodal pathology. CSF protein levels are either normal or mildly elevated at presentation and significantly lower than in patients with paranodal antibodies [35 ▪▪ ]. Again, patients responded poorly to IVIG but well to rituximab (even anti-pan-NF-IgG1 cases) and antibodies became negative during follow up.…”

“…IgG4 and IgG3 antibodies against NF140 and NF186 isoforms located at the node of Ranvier were initially reported in patients with severe subacute onset neuropathy with conduction blocks that reversed after immunotherapy and nephrotic syndrome [7]. Recently, anti-pan-NF IgG1 [35 ▪▪ ] and IgG3 [8 ▪▪ ] antibodies targeting an immunoglobulin domain found in all three NF isoforms (NF140, NF155 and NF186), have been associated with an aggressive-onset neuropathy with severe phenotype, including tetraplegia (or almost locked-in syndrome), cranial nerve involvement, respiratory failure, autonomic dysfunction and nephrotic syndrome. Anti-pan-NF AN may have a dramatic monophasic course and may be misdiagnosed as GBS.…”

“…Again, patients responded poorly to IVIG but well to rituximab (even anti-pan-NF-IgG1 cases) and antibodies became negative during follow up. Nephrotic syndrome (peripheral oedema and hypoalbuminaemia) appears in a third of patients in parallel with their neuropathy and is also responsive to rituximab [35 ▪▪ ].…”

“…Passive transfer of human anti-CNTN1 IgG3 antibodies to animal models cause weakness, reversible conduction blocks and paranodal complement deposition [25]. Similarly, anti-pan-NF IgG1 or IgG3 antibodies associate with a GBS-like fulminant course [8 ▪▪ ,35 ▪▪ ]. Complement deposition induced by patients’ derived anti-pan-NF IgG3 can be detected by complement binding assays [8 ▪▪ ] and may contribute to the more severe acute course of disease observed in these cases.…”