5B and C). By a multicentre combined prospective and retrospective approach, we provide medical data ITI214 of a large cohort of individuals with anti-neurofascin-associated neuropathy (= 18) including longitudinal titre and neurofilament light chain assessment ITI214 via Ella? and relate medical data to pathogenicity studies of anti-neurofascin antibodies. We assessed antibody binding characteristics and the pathogenic effects of anti-pan-neurofascin versus neurofascin-155 antibodies on living myelinating dorsal root ganglia co-cultures. Additionally, we analysed the IgG subclass profile and the match binding capacity and effector functions considering the effects of intravenous immunoglobulin preparations via enzyme-linked immunosorbent and cell-based assays. In contrast to chronic neurofascin-155 IgG4-connected neuropathy, anti-pan-neurofascin-associated disease presented with a high morbidity and mortality, but like a monophasic and potentially reversible disorder. During follow-up, antibodies were no longer detectable in 8 of 11 individuals. Anti-pan-neurofascin had direct access to the nodes of Ranvier in myelinating ethnicities titre-dependently, most probably inducing this severe phenotype. Antibody preincubation led to impaired paranode formation, damage of paranodal architecture and alterations on paranodal myelin and sensory neurons in the ethnicities, with more severe effects than neurofascin-155 antibodies. Besides IgG4, subclass IgG3 was recognized and associated with match binding and cytotoxic effects provide evidence for the pathogenicity of anti-pan-neurofascin autoantibodies in fulminant autoimmune neuropathy. By longitudinal follow-up, they determine serum neurofilament light chain as a disease activity marker and display that prognosis can be favourable despite high morbidity. Intro GuillainCBarr syndrome (GBS) is an acute immune-mediated neuropathy with potentially high morbidity and mortality.1 Individuals present with disabling symptoms including rapid progressive, sensorimotor tetraparesis, autonomic and cranial nerve involvement and at times respiratory insufficiency. Still, the pathophysiology and the medical phenotypes are heterogeneous, imposing great difficulties on medical management.1,2 Inside a subset of individuals initially classifying as GBS, IgG autoantibodies directed against adhesion molecules of the node of Ranvier can be detected. Focuses on are contactin-1 and contactin-1 connected protein (Caspr-1), gliomedin and nodal and paranodal isoforms of neurofascin.3C7 Despite a frequent acute to subacute onset, IgG4 antibodies often associate having a chronic neuropathy, formerly classified as acute-onset chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).8C13 Due to its growing impact, distinct clinical features and distinct pathophysiology compared to GBS or CIDP, autoimmune neuropathies with nodal or paranodal antibodies were recently categorized as a distinct entity termed autoimmune nodopathy.14,15 The pathogenicity of antibodies against neurofascin-155 and contactin-1 offers been shown in various studies.10,16C19 Their detection offers direct implications on diagnostic work-up and clinical management of seropositive patients, who respond poorly to standard therapy but well to rituximab.14,15 Most recently, a shared epitope on different nodo-paranodal neurofascin isoforms 140/155/186 (pan-neurofascin) has been identified as a target in acute-onset immune-mediated neuropathy.12,20 As the disease is rare, anti-pan-neurofascin seropositive individuals possess only been explained at low figures and even in single case studies.12,20C27 A distinct clinical phenotype has been proposed with this subset: they present having a severe, GBS-like onset and after initial short recovery, develop a fulminant course of disease with tetraplegia, autonomic instability, cranial nerve involvement, respiratory failure with prolonged air flow, insufficient response to standard treatment and a high mortality.12,20,21,26,27 So far, knowledge on anti-pan-neurofascin-associated neuropathy is mostly restricted to clinical data. Nevertheless, these reports of single individuals with long term but partly reversible and monophasic program imply different pathogenic mechanisms compared to chronic anti-neurofascin-155-IgG4-mediated neuropathy. Amazingly, anti-pan-neurofascin antibodies can be of the IgG1/3 subclass.12,20,26 Unlike IgG4, IgG1/3 can trigger Fc-mediated effector functions including cross-linking and complement activation, possibly mediating complement-associated pathologies.28,29 Hence, the subclass-related and role of complement needs further attention. Furthermore, the isoform-dependent convenience of nodo-paranodal focuses on to autoantibodies may contribute Rabbit polyclonal to ANGPTL4 to their pathogenic effect, but has not been investigated so far. In this study, we included a large cohort of individuals with certain anti-pan-neurofascin antibodies. We aimed at typifying the medical phenotype including long-term serological and medical follow-up and direct assessment to anti-neurofascin-155 seropositive including the assessment of serum neurofilament light ITI214 chain (sNF-L) like a biomarker for axonal damage at nadir and during follow-up. We quantitatively assessed IgG subclasses, match binding and effector functions under influence of intravenous immunoglobulin preparations, and analysed binding characteristics of the antibodies and pathogenic effects in comparison to neurofascin-155 using myelinating co-cultures, therefore providing a detailed medical and pathophysiological characterization of this rare but severe disease. Materials and methods Patients Individuals with certain anti-neurofascin antibodies (further referred to as seropositive) were recognized from a cohort of individuals who underwent diagnostic screening for anti-paranodal antibodies (observe Supplementary material). Clinical data were collected retrospectively from patient records in seropositive.