Antibodies to the Caspr1/contactin-1 complex in chronic inflammatory demyelinating polyradiculoneuropathy

Abstract

Previous studies have described the clinical, serological and pathological features of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and antibodies directed against the paranodal proteins neurofascin-155, contactin-1 (CNTN1), contactin-associated protein-1 (Caspr1), or nodal forms of neurofascin. Such antibodies are useful for diagnosis and potentially treatment selection. However, antibodies targeting Caspr1 only or the Caspr1/CNTN1 complex have been reported in few patients with CIDP. Moreover, it is unclear if these patients belong to the same pathophysiological subgroup. Using cell-based assays in routine clinical testing, we identified sera from patients with CIDP showing strong membrane reactivity when both CNTN1 and Caspr1 were co-transfected (but not when CNTN1 was transfected alone). Fifteen patients (10 male; aged between 40 and 75) with antibodies targeting Caspr1/CNTN1 co-transfected cells were enrolled for characterization. The prevalence of anti-Caspr1/CNTN1 antibodies was 1.9% (1/52) in the Sant Pau CIDP cohort, and 4.3% (1/23) in a German cohort of acute-onset CIDP. All patients fulfilled European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) definite diagnostic criteria for CIDP. Seven (47%) were initially diagnosed with Guillain-Barré syndrome due to an acute-subacute onset. Six (40%) patients had cranial nerve involvement, eight (53%) reported neuropathic pain and 12 (80%) ataxia. Axonal involvement and acute denervation were frequent in electrophysiological studies. Complete response to intravenous immunoglobulin was not observed, while most (90%) responded well to rituximab. Enzyme-linked immunosorbent assay (ELISA) and teased nerve fibre immunohistochemistry confirmed reactivity against the paranodal Caspr1/CNTN1 complex. Weaker reactivity against Caspr1 transfected alone was also detected in 10/15 (67%). Sera from 13 of these patients were available for testing by ELISA. All 13 samples reacted against Caspr1 by ELISA and this reactivity was enhanced when CNTN1 was added to the Caspr1 ELISA. IgG subclasses were also investigated by ELISA. IgG4 was the predominant subclass in 10 patients, while IgG3 was predominant in other three patients. In conclusion, patients with antibodies to the Caspr1/CNTN1 complex display similar serological and clinical features and constitute a single subgroup within the CIDP syndrome. These antibodies likely target Caspr1 primarily and are detected with Caspr1-only ELISA, but reactivity is optimal when CNTN1 is added to Caspr1 in cell-based assays and ELISA.

Clinical and Laboratory Features in Anti-NF155 Autoimmune Nodopathy

“…Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a clinically and pathologically diverse autoimmune syndrome of the peripheral nervous system, causing significant disability. 1 , 2 Disease-specific antibodies targeting proteins at the node and paranode of Ranvier, such as neurofascin 155 (NF155), 3 nodal neurofascins (NF186 and NF140), 4 contactin-1 (CNTN1), 5 or CNTN-1/caspr-1, 6 , 7 have been described in small subsets of patients with CIDP sharing immunopathologic mechanisms, clinical features, and treatment response and differing from those of typical CIDP. 8 , 9 This has led to the appearance of the autoimmune nodopathy (AN) diagnostic category in the recent update of the European Academy of Neurology/Peripheral Nerve Society CIDP diagnostic guidelines.…”

Novel Immunological and Therapeutic Insights in Guillain-Barré Syndrome and CIDP

“…Recently, our group, in collaboration with others, has published a study analyzing the clinical and immunological characteristics of 15 AN patients with antibodies against the CASPR1/CNTN1 complex. We observed that patients presented with a rapid onset neuropathy with cranial nerve involvement, early axonal damage, and poor response to IVIg demonstrated that these antibodies target primarily CASPR1 protein, but binding is stronger when CNTN1 is also present [49]. Pathogenicity of these autoantibodies remains to be confirmed.…”

Autoimmune Neurological Disorders with IgG4 Antibodies: a Distinct Disease Spectrum with Unique IgG4 Functions Responding to Anti-B Cell Therapies

“…A breakthrough in CIDP antibody autoimmunity has been the remarkable observation that a subset of patients who do not respond to IVIg or plasmapheresis have IgG4 antibodies to nodal/paranodal antigens directed against neurofascin-155 (Nfasc155), neurofascin-140/186 (Nfasc140/186), contactin-1 (CNTN1), and contactin-associated protein 1 (Caspr1) [1,7,[15][16][17][18][19]. These IgG4 antibodies form a clinicopathologically distinct CIDP subset, comprising 10% of all CIDP patients, often referred to as autoimmune nodopathies [20].…”

“…These IgG4 antibodies form a clinicopathologically distinct CIDP subset, comprising 10% of all CIDP patients, often referred to as autoimmune nodopathies [20]. Most commonly, CIDP nodopathies are associated with anti-Nfasc155, followed by Caspr1 and CNTN1, and rarely against both Nfasc140/186 and Nfasc155 [1,7,[15][16][17][18][19][20][21][22]. In contrast to common CIDP characterized by macrophagemediated demyelination, complement activation and myelin destruction, in patients with CIDP nodopathy, except of rare exceptions, the IgG4 nodal/paranodal antibodies do not cause macrophage activation and demyelination, do not fix complement to internalize specific nodal/paranodal antigens, and do not elicit an inflammatory response; instead, they affect protein-protein interaction exerting a functional blockade by disrupting the paranodal axoglial contact leading to conduction failure [1,7,[18][19][20][21].…”

“…NF155 is a Schwann cell adhesion protein that, at the paranodal terminal myelin loops, interacts with CNTN1/ Caspr1 complex anchoring myelin to axon, forming a protein complex critical for maintaining the integrity of the nodal structures ensuring rapid impulse propagation [18][19][20][21]. The antibodies against these proteins are pathogenic by binding distinct epitopes associated with cell adhesion, disrupting the NF155/CNTN1 components by affecting glycosylation and sodium currents or dissecting the axoglial junction resulting in disturbed conduction [7,[15][16][17][18][19][20][21][22]. Based on passive transfer experiments, anti-Nfasc155 IgG4 and anti-CNTN1 IgG4 cause paranodal disorganization but act differently.…”