Auto-antibodies to contactin-associated protein 1 (Caspr) in two patients with painful inflammatory neuropathy

Abstract

Auto-antibodies against the paranodal proteins neurofascin-155 and contactin-1 have recently been described in patients with chronic inflammatory demyelinating polyradiculoneuropathy and are associated with a distinct clinical phenotype and response to treatment. Contactin-associated protein 1 (Caspr, encoded by CNTNAP1) is a paranodal protein that is attached to neurofascin-155 and contactin-1 (CNTN1) but has not yet been identified as a sole antigen in patients with inflammatory neuropathies. In the present study, we screened a cohort of 35 patients with chronic inflammatory demyelinating polyradiculoneuropathy (age range 20-80, 10 female, 25 male) and 22 patients with Guillain-Barré syndrome (age range 17-86, eight female, 14 male) for autoantibodies against paranodal antigens. We identified two patients, one with chronic inflammatory demyelinating polyradiculoneuropathy and one with Guillain-Barré syndrome, with autoantibodies against Caspr by binding assays using Caspr transfected human embryonic kidney cells and murine teased fibres. IgG3 was the predominant autoantibody subclass in the patient with Guillain-Barré syndrome, IgG4 was predominant in the patient with chronic inflammatory demyelinating polyradiculoneuropathy. Accordingly, complement deposition after binding to HEK293 cells was detectable in the patient with IgG3 autoantibodies only, not in the patient with IgG4. Severe disruption of the paranodal and nodal architecture was detectable in teased fibres of the sural nerve biopsy and in dermal myelinated fibres, supporting the notion of the paranodes being the site of pathology. Deposition of IgG at the paranodes was detected in teased fibre preparations of the sural nerve, further supporting the pathogenicity of anti-Caspr autoantibodies. Pain was one of the predominant findings in both patients, possibly reflected by binding of patients' IgG to TRPV1 immunoreactive dorsal root ganglia neurons. Our results demonstrate that the paranodal protein Caspr constitutes a new antigen that leads to autoantibody generation as part of the novel entity of neuropathies associated with autoantibodies against paranodal proteins.

Rituximab in chronic inflammatory demyelinating polyradiculoneuropathy with associated diseases

“…Our data show efficacy of rituximab in patients with an associated haematological disease (group 1), as reported by Benedetti and et al, and also in a second group of patients with autoimmune diseases. In a similar way, patients with anti‐neurofascin 155 antibodies have been reported to derive benefit from rituximab …”

Autoimmune nodo-paranodopathies of peripheral nerve: the concept is gaining ground

“…This observation was confirmed in 7% of 533 Japanese patients with CIDP showing ataxia, tremor, poor response to intravenous Ig and, in 3 patients, central nervous system demyelination 52. Finally, antibodies directed exclusively to Caspr1 were described in one patient with CIDP with prominent neuropathic pain 5. Overall, the patients harbouring antibodies against proteins of paranodal junctions account for about 10% of all patients classified as CIDP.…”

“…At last, the description of a patient with the clinical picture of GBS and severe neuropathic pain, RCF and IgG3 anti-Caspr1 antibodies activating complement suggested that reactivity to paranodal Caspr1, with a mechanism similar to antiganglioside antibodies, could be also involved in acute autoimmune neuropathies 5. The dichotomous classification of neuropathies into axonal or demyelinating might be inadequate in the diagnosis of GBS subtypes.…”

Neurofascin-155 IgM autoantibodies in patients with inflammatory neuropathies

“…Of some nerve biopsies, one part was used for the preparations of teased nerve fibres by gently teasing the fibres prefixed with paraformaldehyde 4% on a slide. Immunofluorescence double-staining with antibodies against myelin basic protein (GeneTex, 1:200) and Caspr (Abcam, 1:100), pan-neurofascin (Abcam, 1:400) and pan-sodium-channel (Sigma Aldrich, 1:100) was then performed as previously described 6. Skin biopsy sections were stained with the same combinations of antibodies for longitudinal assessment of dermal myelinated fibres according to protocols of a former study 14…”