Anti-pan-neurofascin antibodies induce subclass-related complement activation and nodo-paranodal damage

Abstract

Autoimmune neuropathy associated with antibodies against pan-neurofascin is a new subtype of nodo-paranodopathy. It is relevant because it is associated with high morbidity and mortality. Affected patients often require intensive care unit treatment for several months, and data on the reversibility and long-term prognosis are limited. The pathogenicity including IgG subclass-associated mechanisms has not been unraveled, nor been directly compared to anti-neurofascin-155 IgG4 related pathology. Understanding the underlying pathology might have a direct impact on treatment of these severely affected patients. By a multicenter combined pro- and retrospective approach, we provide clinical data of a large cohort of patients with anti-neurofascin associated neuropathy (n = 18) including longitudinal titre and neurofilament light chain assessment via Ella® and relate clinical data to in vitro pathogenicity studies of anti-neurofascin antibodies. We assessed antibody binding characteristics and the pathogenic effects of anti-pan-neurofascin vs. neurofascin-155 antibodies on living myelinating dorsal root ganglia co-cultures. Additionally, we analyzed the IgG subclass profile and the complement binding capacity and effector functions considering the effects of intravenous immunoglobulin preparations via ELISA and cell-based assays. In contrast to chronic, neurofascin-155 IgG4 associated neuropathy, anti-pan-neurofascin associated disease presented with a high morbidity and mortality, but as a monophasic and potentially reversible disorder. During follow-up, antibodies were no longer detectable in 8/11 patients. Anti-pan-neurofascin had direct access to the nodes of Ranvier in myelinating cultures titre-dependently, most probably inducing this severe phenotype. Antibody preincubation lead to impaired paranode formation, destruction of paranodal architecture and alterations on paranodal myelin and sensory neurons in the cultures, with more severe effects than neurofascin-155 antibodies. Besides IgG4, subclass IgG3 was detected and associated with complement binding and cytotoxic effects in vitro. As a possible correlate of axonal damage in vivo, we detected highly increased serum neurofilament light chain levels (sNF-L), correlating to serum C3a. Still, sNF-L was not identified as a marker for poor prognosis, but rather as an inter-individual and intra-individual marker for acuteness, severity, and course, with a strong decrease during recovery. Our data provide evidence that anti-pan-neurofascin antibodies directly attack the node and induce severe and acute, but potentially reversible nodo-paranodal pathology, possibly involving complement-mediated mechanisms. Screening for autoantibodies thus is crucial to identify this subset of patients who benefit from early antibody-depleting therapy. Titre and sNF-L might serve as valuable follow-up parameters. The prospect of a favourable outcome has high relevance for physicians, patients and relatives during months of critical care.

Paraneoplastic Syndrome Presenting Combined Central and Peripheral Demyelination Associated with Anti-CV2/CRMP5 and Anti-NF186 Antibodies: A Case Report

“…An antibody against the glial neurofascin isoform, NF155, was predominantly of IgG4 subtype, which lacks the ability to activate a conventional complement-mediated or cellular immune response. A recent study revealed that anti-NF155 IgG4 was pathogenic because it rendered NF155 degeneration directly, whereas the anti-NF186 antibody may be more widely distributed in different antibody isotypes or IgG subtypes, and it may be pathogenic in a complement dependent manner, similar to the pathogenic mechanism of anti-pan-neurofascin antibody [ 6 , 22 ]. This may also be the underlying mechanism of the effective glucocorticoids and IVIG treatment as shown by both this study and other studies.…”

Autoimmune nodo‐paranodopathies 10 years later: Clinical features, pathophysiology and treatment

“…The course was usually monophasic. Some patients improved with IVIg, but showed a fulminant relapse in few days/weeks 37 . Response to plasmapheresis was partial and not sustained; response to corticosteroids was poor.…”

“…Response to plasmapheresis was partial and not sustained; response to corticosteroids was poor. The mortality in patient with antibodies to panNF was high even though some patients showed spontaneous remission 37 . After responses to standard treatment were deemed inadequate (often several months into the illness) the surviving patients received rituximab with a good response till to functional independence.…”

Nodes of Ranvier in health and disease

“…Another type of auto antibodies targeting the paranode is anti‐pan neurofascin (panNF), which recognize both glial and neuronal isoforms of neurofascin. As these antibodies can target both nodes and paranodes, it is not surprising that the affected patients present with the most severe nodopathy 92 . Starting as GBS with a short recovery, they then develop a severe disease with tetraplegia, autonomic instability, cranial nerve involvement, respiratory failure, and a high mortality.…”

“…As these antibodies can target both nodes and paranodes, it is not surprising that the affected patients present with the most severe nodopathy. 92 Starting as GBS with a short recovery, they then develop a severe disease with tetraplegia, autonomic instability, cranial nerve involvement, respiratory failure, and a high mortality. Anti-NFpan antibodies can activate complement in vitro.…”