Clinical and Laboratory Features in Anti-NF155 Autoimmune Nodopathy

Abstract

Background and ObjectivesTo study the clinical and laboratory features of antineurofascin-155 (NF155)–positive autoimmune nodopathy (AN).MethodsPatients with anti-NF155 antibodies detected on routine immunologic testing were included. Clinical characteristics, treatment response, and functional scales (modified Rankin Scale [mRS] and Inflammatory Rasch-built Overall Disability Scale [I-RODS]) were retrospectively collected at baseline and at the follow-up. Autoantibody and neurofilament light (NfL) chain levels were analyzed at baseline and at the follow-up.ResultsForty NF155+ patients with AN were included. Mean age at onset was 42.4 years. Patients presented with a progressive (75%), sensory motor (87.5%), and symmetric distal-predominant weakness in upper (97.2%) and lower extremities (94.5%), with tremor and ataxia (75%). Patients received a median of 3 (2–4) different treatments in 46 months of median follow-up. Response to IV immunoglobulin (86.8%) or steroids (72.2%) was poor in most patients, whereas 77.3% responded to rituximab. HLA-DRB1*15 was detected in 91.3% of patients. IgG4 anti-NF155 antibodies were predominant in all patients; anti-NF155 titers correlated with mRS within the same patient (r = 0.41, p = 0.004). Serum NfL (sNfL) levels were higher in anti-NF155+ AN than in healthy controls (36.47 vs 7.56 pg/mL, p < 0.001) and correlated with anti-NF155 titers (r = 0.43, p = 0.001), with I-RODS at baseline (r = −0.88, p < 0.001) and with maximum I-RODS achieved (r = −0.58, p = 0.01). Anti-NF155 titers and sNfL levels decreased in all rituximab-treated patients.DiscussionAnti-NF155 AN presents a distinct clinical profile and good response to rituximab. Autoantibody titers and sNfL are useful to monitor disease status in these patients. The use of untagged-NF155 plasmids minimizes the detection of false anti-NF155+ cases.Classification of EvidenceThis study provides Class IV evidence that anti-NF155 antibodies associate with a specific phenotype and response to rituximab.

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

“…Based on passive transfer experiments, anti-Nfasc155 IgG4 and anti-CNTN1 IgG4 cause paranodal disorganization but act differently. In contrast to anti-CNTN1 that cause functional blockade by inhibiting the interaction of Nfasc155 with the CNTN1/CASPR1 complex dismantling the paranodal axoglial contact, the anti-Nfasc155 IgG4 seems to bind to the Schwann cell surface causing Nfasc155 aggregation and depletion [15][16][17][18][19][20][21][22]. Furthermore, anti-CNTN1 autoantibodies can cause reduction in contactin-1 surface expression on dorsal root ganglionic and cerebellar neurons and decrease the sodium currents in the dorsal root ganglionic cells without affecting the sodium channel density, providing a pathophysiologic correlate of sensory ataxia often seen in these patients [21]; the antibody subclass in this study was not however specified.…”

“…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]. 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].…”

“…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.…”

“…The autoimmune nodopathy patients may have the typical clinical phenotype of CIDP but most often have distinct characteristics highlighted by subacute onset of severe neuropathy, tremor, and sensory ataxia. Most importantly, and in contrast to their IgG1-3 counterparts, they respond poorly to IVIg and plasmapheresis but excellently to rituximab that induces long-lasting remissions, necessitating increased awareness to identify them from the outset [1,7,[15][16][17][18][19][20][21]. Because subclass switch from IgG1-3 to IgG4 can also occur, as discussed later, an IgG4 nodopathy/paranodopathy should be considered when a CIDP patient previously responding to IVIg becomes IVIg unresponsive [1].…”