Anti-neurofascin antibody in patients with combined central and peripheral demyelination

Kawamura, Nobutoshi; Yamasaki, Ryo; Yonekawa, Tomomi; Matsushita, Takuya; Kusunoki, Susumu; Nagayama, Shigemi; Ogata, Hidenori; Matsuse, Dai; Murai, Hiroyuki; Kira, Jun Ichi

doi:10.1212/wnl.0b013e3182a1aa9c

Cited by 162 publications

(161 citation statements)

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“…16 Recent reports showed that 46% (5/11) and 71% (5/7) of Japanese patients with CCPD carried anti-NF155 IgG antibodies. 7,8 The age at onset was between 10 and 48 years in their cohorts and was in keeping with our observations (21-33 years for ours). However, the patients with CCPD in our cohort did not always respond to IVIg, whereas those in their cohort did.…”

Section: Association Of Cidp With Anti-nf155 Igg4 Antibodiessupporting

confidence: 90%

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Neurofascin-155 IgG4 in chronic inflammatory demyelinating polyneuropathy

et al. 2016

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Objective: We report the clinical and serologic features of Japanese patients with chronic inflammatory demyelinating polyneuropathy (CIDP) displaying anti-neurofascin-155 (NF155) immunoglobulin G4 (IgG4) antibodies. Methods:In sera from 533 patients with CIDP, anti-NF155 IgG4 antibodies were detected by ELISA. Binding of IgG antibodies to central and peripheral nerves was tested.Results: Anti-NF155 IgG4 antibodies were identified in 38 patients (7%) with CIDP, but not in disease controls or normal participants. These patients were younger at onset as compared to 100 anti-NF155-negative patients with CIDP. Twenty-eight patients (74%) presented with sensory ataxia, 16 (42%) showed tremor, 5 (13%) presented with cerebellar ataxia associated with nystagmus, 3 (8%) had demyelinating lesions in the CNS, and 20 of 25 (80%) had poor response to IV immunoglobulin. The clinical features of the antibody-positive patients were statistically more frequent as compared to negative patients with CIDP (n 5 100). Anti-NF155 IgG antibodies targeted similarly central and peripheral paranodes.Conclusion: Anti-NF155 IgG4 antibodies were associated with a subgroup of patients with CIDP showing a younger age at onset, ataxia, tremor, CNS demyelination, and a poor response to IV immunoglobulin. The autoantibodies may serve as a biomarker to improve patients' diagnosis and guide treatments. Neurology ® 2016;86:800-807 GLOSSARY Caspr1 5 contactin-associated protein-1; CCPD 5 combined central and peripheral demyelination; CI 5 confidence interval; CIDP 5 chronic inflammatory demyelinating polyneuropathy; CNTN1 5 contactin 1; GBS 5 Guillain-Barré syndrome; IgG4 5 immunoglobulin G4; IVIg 5 IV immunoglobulin; MS 5 multiple sclerosis; NF155 5 neurofascin-155; OR 5 odds ratio; PNS 5 peripheral nervous system.Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common acquired immune-mediated neuropathy worldwide and is clinically heterogeneous.1 Proven treatments for CIDP include corticosteroids, plasma exchange, and IV immunoglobulin (IVIg). However, the response rates to treatments are highly heterogeneous between patients. This emphasizes that patients and clinicians require biomarkers to identify CIDP subgroups and guide specific immunotherapeutic options.Immunoglobulin G4 (IgG4) autoantibodies to neurofascin-155 (NF155) were recently documented in patients with CIDP.2,3 NF155 belongs to the L1 family of adhesion molecules and is expressed at paranodes by the terminal loops of myelin and associates with the axonal cell adhesion molecules CNTN1 and contactin-associated protein-1 (Caspr1). 4 This ternary complex of glycoproteins is required for the rapid propagation of the nerve impulses along myelinated axons. 5,6 Three of 4 patients with anti-NF155 IgG4 showed disabling tremor and all showed poor response to IVIg. 3 This suggested that IgG4 autoantibodies participate in CIDP pathogenesis; nonetheless, the low number of reactive patients precluded statistical correlation.

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Section: Association Of Cidp With Anti-nf155 Igg4 Antibodiessupporting

confidence: 90%

“…7,8 However, it is unclear whether these autoantibodies belong to the IgG4 subclass, and whether these CCPD cases are considered as definite CIDP cases with CNS involvement. To answer these questions, we have examined the clinical and serologic features of 38 Japanese patients with CIDP and anti-NF155 IgG4 antibodies including 3 patients with CCPD.…”

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confidence: 99%

Neurofascin-155 IgG4 in chronic inflammatory demyelinating polyneuropathy

et al. 2016

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“…Besides, antibodies to several proteins in the nodal area of the peripheral nerves -in particular, gliomedin, neurofascin, contactin (63,64), and moesin (65) -were found in the blood stream of some AIDP patients. We also tested blood samples against the CAM proteins whose fragments we observed.A slightly enhanced titer of autoantibodies was found only against NrCAM and the difference was not as evident as in other classic autoimmune diseases with their autoantigens (53,66).…”

Section: Discussionmentioning

confidence: 99%

The Pathogenesis of the Demyelinating Form of Guillain-Barre Syndrome (GBS): Proteo-peptidomic and Immunological Profiling of Physiological Fluids

Ziganshin

Ivanova

Lomakin

et al. 2016

Molecular & Cellular Proteomics

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Acute inflammatory demyelinating polyneuropathy (AIDP) -the main form of Guillain-Barre syndrome-is a rare and severe disorder of the peripheral nervous system with an unknown etiology. One of the hallmarks of the AIDP pathogenesis is a significantly elevated cerebrospinal fluid (CSF) protein level. In this paper CSF peptidome and proteome in AIDP were analyzed and compared with multiple sclerosis and control patients. A total protein concentration increase was shown to be because of even changes in all proteins rather than some specific response, supporting the hypothesis of protein leakage from blood through the blood-nerve barrier. The elevated CSF protein level in AIDP was complemented by activization of protein degradation and much higher peptidome diversity. Because of the studies of the acute motor axonal form, Guillain-Barre syndrome as a whole is thought to be associated with autoimmune response against neurospecific molecules. Thus, in AIDP, autoantibodies against cell adhesion proteins localized at Ranvier's nodes were suggested as possible targets in AIDP. Indeed, AIDP CSF peptidome analysis revealed cell adhesion proteins degradation, however no reliable dependence on the corresponding autoantibodies levels was found. Proteome analysis revealed overrepresentation of Gene Ontology groups related to responses to bacteria and virus infections, which were earlier suggested as possible AIDP triggers. Immunoglobulin blood serum analysis against most common neuronal viruses did not reveal any specific pathogen; however, AIDP patients were more immunopositive in average and often had polyinfections. Cytokine analysis of both AIDP CSF and blood did not show a systemic adaptive immune response or general inflammation, whereas innate immunity cytokines were up-regulated. To supplement the widely-accepted though still unproven autoimmunity-based AIDP mechanism we propose a hypothesis of the primary peripheral nervous system damaging initiated as an innate immunity-associated local inflammation following neurotropic viruses egress, whereas the autoantibody production might be an optional complementary secondary process. Molecular & Cellular

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“…61 Antibodies to neurofascin and contactin-1, which are concentrated near the nodes of Ranvier, are found in a small population of patients with CIDP. 62 In a few patients, IgG4 antibodies to the paranodal proteins contactin and NF155 have been associated with severe, intravenous immunoglobulin (IVIG)-resistant CIDP. 63,64 A subset of IVIG-resistant patients with contactin or NF-155 antibodies have responded to rituximab.…”

Section: Autoantigens In Chronic Inflammatory Demyelinating Polyradicmentioning

confidence: 99%

Chronic Inflammatory Demyelinating Polyradiculoneuropathy 101—Pitfalls and Pearls of Diagnosis and Treatment

Beydoun¹,

Brannagan²,

Donofrio³

et al. 2017

US Neurology

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Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), which is caused by demyelination of the peripheral nerves, is characterized by progressive weakness and impaired sensory function in the arms and legs. CIDP is a treatable condition in which early diagnosis is crucial to limit chronic disability. CIDP can mimic other neuropathies and it is important to identify these in order to ensure prompt treatment. Patients with other causes of neuropathy should be suspected of having CIDP if there is rapid progress or proximal weakness. Intravenous immunoglobulin (IVIG), corticosteroids, and plasma exchange are first-line therapies. The IVIG CIDP Efficacy (ICE) trial, the largest trial reported of any CIDP treatment, demonstrated that IVIG therapy reduced disability and functional impairment, as well as improved quality of life. Autoantibodies against membrane proteins of the peripheral nerve axons or the myelin sheath have been reported recently, and an improved understanding of antibody responses in CIDP may enable the development of future targeted therapeutic interventions.

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Anti-neurofascin antibody in patients with combined central and peripheral demyelination

Abstract: Anti-neurofascin antibody is frequently present in patients with CCPD. Recognition of this antibody may be important, because patients with CCPD who are antibody positive respond well to IV immunoglobulin or plasma exchange.

Cited by 162 publications

References 18 publications

Neurofascin-155 IgG4 in chronic inflammatory demyelinating polyneuropathy

Neurofascin-155 IgG4 in chronic inflammatory demyelinating polyneuropathy

The Pathogenesis of the Demyelinating Form of Guillain-Barre Syndrome (GBS): Proteo-peptidomic and Immunological Profiling of Physiological Fluids

Chronic Inflammatory Demyelinating Polyradiculoneuropathy 101—Pitfalls and Pearls of Diagnosis and Treatment

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