No conduction blocks were detectable in the rats injected with IgG of the low titre patient. cases. There is evidence that anti-contactin-1 prevents adhesive interaction, and chronic exposure to anti-contactin-1 IgG4 leads to structural changes at the nodes accompanied by neuropathic symptoms. However, the pathomechanism of acute onset of disease and the pathogenic role of IgG3 anti-contactin-1 is largely unknown. Methods Amadacycline methanesulfonate In the present study, we aimed to model acute autoantibody exposure by intraneural injection of IgG of patients with anti-contacin-1 autoantibodies to Lewis rats. Patient IgG obtained during acute onset of disease (IgG3 predominant) and IgG from the chronic phase of disease (IgG4 predominant) were studied in comparison. Results Conduction blocks were measured in rats injected with the acute IgG more often than after injection of chronic IgG (83.3% versus 35%) and proved to be reversible within a week after injection. Impaired nerve conduction was accompanied by motor deficits in rats after injection of the acute IgG but only minor structural changes of the nodes. Paranodal complement deposition was detected after injection of the acute IgG. We did not detect any inflammatory infiltrates, arguing against an inflammatory cascade as cause of damage to the nerve. We also did not observe dispersion of paranodal proteins or sodium channels to the juxtaparanodes as seen in patients after chronic exposure to anti-contactin-1. Conclusions Our data suggest that anti-contactin-1 IgG3 induces an acute conduction block that is most probably mediated by autoantibody binding and subsequent complement deposition and may account for acute onset of disease in these patients. This supports the notion of anti-contactin-1-associated neuropathy as a paranodopathy with the nodes of Ranvier as the site of pathogenesis. Electronic supplementary material The online version of this article (10.1186/s12974-019-1462-z) contains supplementary material, which is available to authorized users. Keywords: Paranodopathy, Anti-contactin-1, CIDP, Passive transfer, Autoantibody, Complement deposition Background Neuropathies with autoantibodies against paranodal proteins comprise a recently described subgroup Amadacycline methanesulfonate of inflammatory Rabbit Polyclonal to NDUFA4 neuropathies. So far, autoantibodies against the paranodal proteins contactin-1 (CNTN1), neurofascin-155 and contactin-associated protein (Caspr) have been identified [1C5]. Most patients with anti-CNTN1 autoantibodies show a distinct clinical phenotype of acute-onset severe sensorimotor peripheral neuropathy, in some associated with a disabling tremor and/or sensory ataxia [3, 4, 6]. Neuropathies with antibodies against paranodal proteins are often referred to as paranodopathies as the paranode is the site of immune attack [7, 8]. However, this term was originally introduced to classify anti-ganglioside autoantibody-associated acute motor axonal neuropathy with reversible conduction failure and referred to the pathophysiological concept of complement-mediated reversible conduction block [9, 10]. Autoantibodies Amadacycline methanesulfonate against paranodal proteins mostly belong to the IgG4 subclass that does not activate complement, but IgG1, IgG2 and IgG3 autoantibodies have also been described either in combination with IgG4 or as the predominant subclass [3, 4]. Pathogenicity of IgG4, but not of IgG1, was recently demonstrated by intravenous passive transfer of anti-CNTN1 IgG4 to rats immunised with P2 peptide [2]. Further indicators of a pathogenic role of paranodal autoantibodies are the destruction of paranodal architecture detectable in patients with anti-CNTN1 associated neuropathy, the excellent Amadacycline methanesulfonate therapeutic response to rituximab and the uniform clinical phenotype of Amadacycline methanesulfonate the patients [4]. There is striking evidence that IgG4 autoantibodies play a pathogenic role during the course of disease and it was shown in vitro that anti-CNTN1 autoantibodies inhibit cell adhesion, which may account for anti-CNTN1 IgG4-induced structural damage of the paranodes [11]. However, the pathomechanism of acute onset of disease in these patients is.
No conduction blocks were detectable in the rats injected with IgG of the low titre patient