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Keywords:

  • autoantibody;
  • chronic inflammatory demyelinating polyradiculoneuropathy;
  • combined central and peripheral demyelination;
  • immunoglobulin superfamily;
  • multiple sclerosis;
  • neurofascin

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Molecular structure and functions of neurofascins
  5. Anti-neurofascin antibody in MS, CIDP and GBS
  6. Anti-neurofascin antibody in CCPD
  7. Conclusion
  8. Disclosure
  9. References

Neurofascin (NF), a cell adhesion molecule expressed in both the central nervous system (CNS) and the peripheral nervous system (PNS), plays important roles in developing and maintaining neural structures. There are several subtypes of NF resulting from post-translational modifications: NF155, 166, 180 and 186. Among them, NF155 and NF186 are expressed in the mature CNS/PNS. NF155 is present on the oligodendroglial cell surface in the CNS and on the Schwann cell surface in the PNS at paranodes, where it tightly connects with contactin and caspr on the axonal surface of the paranode, and acts as a stabilizer of the nodes of Ranvier. NF186 exists on the axonal surface at the nodes of Ranvier. NF186 is associated with voltage-gated Na channels (Nav), whereas both NF186 and Nav are anchored by ankyrin G. NF186 contributes to the clustering of Nav at the node. Combined central and peripheral demyelination (CCPD) is an inflammatory demyelinating disorder affecting both the CNS and PNS tissues. Distinct mechanisms including multiple sclerosis and chronic inflammatory demyelinating polyradiculoneuropathy have been hypothesized to play a role in this condition on the basis of distinctive clinical and laboratory findings. We detected anti-NF155 antibody by cell-based assay, enzyme-linked immunosorbent assay, and western blot in both the sera and cerebrospinal fluids of CCPD patients at high frequencies, but did not detect it in patients with other neurological disease or healthy controls. Herein, basic aspects and the clinical significance of NF as indispensable regulators and autoimmune target molecules are summarized.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Molecular structure and functions of neurofascins
  5. Anti-neurofascin antibody in MS, CIDP and GBS
  6. Anti-neurofascin antibody in CCPD
  7. Conclusion
  8. Disclosure
  9. References

Inflammatory demyelinating disorders, such as multiple sclerosis (MS), neuromyelitis optica (NMO), Guillain–Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), are supposed to be autoimmune disorders. In these conditions, some autoantibodies are assumed to be causative; for example, antiganglioside antibodies in GBS[1] and anti-AQP-4 antibodies in NMO.[2] Even in MS, several autoantibodies have been proposed to be operative.[3] The mechanisms underlying inflammatory demyelinating disorders are thought to involve multiple immune steps from antigen presentation by dendritic cells to actual neuronal and myelin damage induced by cellular and humoral factors, such as T cells, macrophages, autoantibodies and complements. As the disease stage progresses, new antigens could be liberated by massive destruction of nervous tissue, and thereafter, these could secondarily induce inter- and intramolecular epitope spreading.[4] Thus, different kinds of novel autoantibodies could appear in the chronic stage of diseases. Therefore, it is critical to identify novel autoantibodies as effector factors for specific disease conditions. In the present review, combined central and peripheral demyelination (CCPD), a rare demyelinating condition affecting both central nervous system (CNS) and peripheral nervous system (PNS) tissues, is introduced, and neurofascin as an autoimmune target antigen in this condition is proposed.

Molecular structure and functions of neurofascins

  1. Top of page
  2. Abstract
  3. Introduction
  4. Molecular structure and functions of neurofascins
  5. Anti-neurofascin antibody in MS, CIDP and GBS
  6. Anti-neurofascin antibody in CCPD
  7. Conclusion
  8. Disclosure
  9. References

Neurofascin (NF) was initially found in the embryonic chick brain as a neuronal cell surface molecule. As antibodies against this molecule can inhibit formation of neurite fasciculations/bundles, this molecule was named “neuro-fascin”.[5] Later, NF was revealed as a member of the immunoglobulin superfamily (IgSF).[6]

The IgSF is one of the cell adhesion molecules, such as integrins, cadherins, and gap junction and tight junction proteins. IgSF molecules commonly have an immunoglobulin (Ig)-like domain, which consists of two beta sheet structures connected by a disulfide bond, producing a ball-like shape.[7] Ig-like domains play a major role in cell–cell recognition.[8] IgSF molecules expressed in the nervous system fall into four different subgroups according to their molecular structures, namely, groups I–IV.[9] NF belongs to the L1 subgroup of IgSF group II. The L1 subgroup consists of L1, a close homolog of L1 (CHL1), NF and neuron-glia cell adhesion molecule-related cell adhesion molecule (NrCAM). These molecules have common structures, with six Ig-like domains, up to five fibronectin III (FNIII)-like domains, a transmembrane domain and a cytoplasmic domain (Fig. 1).[10] The NF gene (NFASC) is located on chromosome 1,[11] and products of the gene are generated by alternative splicing of its pre-mRNA. Thus, NF has several isoforms: NF155, NF166, NF180 and NF186 (Fig. 2).[12]

image

Figure 1. Schematic structures of immunoglobulin superfamily members. (a) P0; (b) Thy-1; (c) Nectin-1,2,3,4, Necl-1,2,3,4,5, Afadin, IL1RAcP, IL1RAPL1; (d) OBCAM, LAMP, Neurotrimin, Klon; (e) MAG, SC1, Kirrel1,2,3; (f) Telencephalin; (g) NCAM, OCAM; (h) Robo 1,2,3; (i) DCC, Neogenin; (j) Contactin, TAG1, BIG-1,2, NB-2,3; (k) L1, NrCAM, *Neurofascin, CHL1; (l) DSCAM, DSCAML1; (m) Sidekick-1,2; (n) FGFR1,2,3,4; (o) PDGFR-α, β, Kit, Fms, Flt3; (p) TrkA,B,C; (q) Axl, Sky, Mer; (r) Ror1,2; (s) PTPμκ, PCP-2; (t) LAR, PTPδσ; (u) Unc5H1,2,3; (v) Semaphorin3,4,7; (w) Neuregulin-1,2; (x) SALM1,2,3,4,5, Pal1,2,3; (y) LINGO1,2,3,4, AMIGO1,2,3; (z) MDGA1,2. Fn, fibronectin; Ig, immunoglobulin; IgTK, immunoglobulin tyrosine kinase; IgTP, immunoglobulin tyrosine phosphatase.

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image

Figure 2. Different isoforms of neurofascins. Six common immunoglobulin (Ig)-like domains with modified fibronectin III (FNIII) domains. NF180 and NF186 include PAT (proline-, alanine-, threonine-rich) domain (also referred as mucin-like domain), which is thought to be a flexible structure, as well as the third and the fifth FNIII-like repeats.

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NF166 and NF180 are found in chick dorsal root ganglia and embryonic brain, respectively.[12] The interaction between NF180 and NrCAM is essential for neurite outgrowth in central tectal neurons.[13] NF166 and contactin-2 (IgSF group II) function in the neurite outgrowth of dorsal root ganglion cells.[14] NF186 is expressed on mature neurons at the nodes of Ranvier and at the initial segment of axons (axon hillock).[15] NF155, in contrast, is expressed on oligodendrocytes and Schwann cells at the paranodes (Fig. 3).[16] NF186 interacts with a cytoskeletal component, ankyrinG, as well as voltage-gated Na channels (Nav) at the axon hillock and the nodes of Ranvier, suggesting an important role in generating and propagating action potentials.[17] The interaction between NF186 and Nav through beta-1 and beta-3 subunits of Nav was also confirmed in vivo.[18] In NF186-depleted knockout mice, the number of GABAergic synapses at the mature axon hillock was reduced, showing an important role for NF186 in axo-axonic innervation.[15] NF155, a glial isoform of NF, has distinct roles in maintaining the nodes. Glial NF155, which is expressed in oligodendrocytes and Schwann cells, interacts with an axonal contactin/caspr complex to stabilize the paranode.[19] NF155 deficiency in vivo causes disintegration of the paranodal complex.[20] Expression and distribution patterns in the rodent brain also differ between NF155 and NF186; NF155 is expressed mainly in the brain white matter, whereas NF186 is expressed diffusely in both gray and white matter.[21] In the rat spinal cord, the expression level of NF186 gradually decreases according to age, whereas expression of NF155 increases.[22] Such differences are rational, because NF155 is important for nodal formation and stability, which contribute to the maintaining of myelinated fiber structures, whereas NF186 is crucial for axo-axonal stability, as well as integration of GABAergic neuronal systems.

image

Figure 3. Schematic illustration of node–paranode structures. At the nodes of Ranvier, voltage-gated Na channels are clustered together with NF186 and anchored by ankyrin G. NF186 also associates with neuron-glia cell adhesion molecule-related cell adhesion molecule (NrCAM). NF186 interacts with gliomedin expressed on Schwann cell microvilli in the peripheral nervous system. At the paranode, glial NF155 associates with caspr and contactin-1 expressed on the axon.

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In summary, NF are distributed throughout the nervous system, and have important roles in the formation and stabilization of neuro-neuronal and neuro-glial complexes. Each isoform produced by post-transcriptional alternative splicing has a distinct expression pattern and function.

Pan-neurofascin-deficient mice (Nfasc−/−) die suddenly at 6–7 postnatal days when saltatory conduction takes place in the CNS and PNS. In the sciatic nerves of Nfasc−/− mice, the myelin sheaths appeared grossly normal, but the nodal structures are disrupted. The expression levels of other components in the paranodal junction (caspr, contactin, Nav, NrCAM) are unchanged. These findings suggest a role for NF in stabilizing the nodes.[16] Transgenic expression of NF155 in Nfasc−/− mice rescued nodal formation in the CNS, but failed to rescue nodal complex formation in the PNS; there was no Nav localization at the nodes in the PNS. In contrast to NF155, transgenic expression of NF186 rescued the nodal complex, including the correct localization of Nav at the nodes, in both CNS and PNS. These results suggest that NF155 is dispensable for PNS nodal formation, whereas NF186 is indispensable for nodal complex formation in the PNS and CNS.[23] These findings provide important insights into the pathomechanisms underlying inflammatory demyelinating disorders associated with anti-NF antibody, as mentioned in the following section.

Anti-neurofascin antibody in MS, CIDP and GBS

  1. Top of page
  2. Abstract
  3. Introduction
  4. Molecular structure and functions of neurofascins
  5. Anti-neurofascin antibody in MS, CIDP and GBS
  6. Anti-neurofascin antibody in CCPD
  7. Conclusion
  8. Disclosure
  9. References

Mathey et al.[24] first reported the existence of an autoantibody against NF in MS patients. They screened the sera of 26 MS patients including 13 patients with relapse-remitting MS (RRMS), nine patients with chronic progressive MS (CPMS) and four patients with possible MS by enzyme-linked immunosorbent assay (ELISA), and found that approximately one-third of MS patients had high titer anti-NF155 antibodies. The mean optical density (OD) value was highest in the CPMS group. They also found that the sera of three patients reacted with NF186.[24] Prüss et al.[25] measured anti-NF antibody titer in 52 GBS patients and 44 healthy controls, and found significantly higher mean anti-NF antibody titers in the GBS group. Devaux et al. examined 100 GBS patients, 50 CIDP patients, 80 disease controls and 50 healthy controls, and showed that 15% of GBS patients and 12% of CIDP patients were anti-NF186 antibody-seropositive, whereas none of the disease controls and just 2% of the healthy controls were anti-NF186 antibody-seropositive. They also pointed out the possibility of cross-reactivity of the anti-NF186 autoantibody with NF155 based on the characteristic staining patterns of the nodes and paranodes using their sera.[26] Ng et al. examined sera from 119 CIDP patients, 65 acute inflammatory demyelinating polyneuropathy (AIDP) patients, 50 acute motor axonal neuropathy (AMAN) patients, 20 other neuropathy patients, 63 other neurological disease controls and 77 healthy controls by ELISA, and found that 4% of patients with AIDP and CIDP were seropositive for NF (five with CIDP and three with AIDP). Among them, only one serum sample was positive for both anti-NF155 and anti-NF186 ELISA. Four CIDP samples and two AIDP samples were seropositive for anti-NF155 antibody, whereas two AIDP samples were anti-NF186 antibody-seropositive. Among them, one AIDP patient was double-positive for both isoforms of NF.[27] These reports suggest that a fraction of patients with idiopathic inflammatory demyelinating diseases are seropositive for NF. As aforementioned, the loss of NF155 mainly influences the CNS, but not the PNS, whereas a deficit of NF186 affects both the CNS and PNS in rodents. If anti-NF antibodies with different epitope specificities were associated with any clinical features, anti-NF antibody would be clinically more relevant.

Anti-neurofascin antibody in CCPD

  1. Top of page
  2. Abstract
  3. Introduction
  4. Molecular structure and functions of neurofascins
  5. Anti-neurofascin antibody in MS, CIDP and GBS
  6. Anti-neurofascin antibody in CCPD
  7. Conclusion
  8. Disclosure
  9. References

Patients presenting demyelination in both the CNS and PNS, in other words, combined cases of MS and CIDP/GBS, have occasionally been reported under various terminologies, namely, CCPD, chronic demyelinating peripheral neuropathy associated with multifocal CNS demyelination, peripheral neuropathy with MS, CIDP with CNS involvement, and relapsing demyelinating disease affecting both the CNS and PNS.[28] There are currently no established definitions or diagnostic criteria for CCPD. CCPD patients who fulfil the diagnostic criteria for both MS[29] and CIDP[30] are rarely experienced. In these patients, clinical and laboratory features of “MS” could be atypical; that is, bilateral optic neuritis, absence of oligoclonal immunoglobulin G bands (OCB) and gray matter involvement.[31-33]

These characteristic features of CCPD encouraged us to explore distinctive causative factors from MS and CIDP. We studied seven consecutive CCPD patients referred to our clinic who had both CNS demyelinating lesions confirmed by magnetic resonance imaging (MRI) and PNS demyelination confirmed by nerve conduction studies (Table 1).[34]

Table 1. Summary of the clinical and laboratory findings in seven combined central and peripheral demyelination patients
Patients' informationCCPD (n = 7)
Sex (male : female)3:4
Initial symptoms (CNS : PNS : simultaneous)2:2:3
Mean age at onset (years)CNSPNS
 29.328.9
Lab datan (%)
Anti-NF155 antibody
ELISA (serum)6/7 (85.7)
CBA (serum)5/7 (71.4)
CBA (CSF)3/3 (100)
CSF oligoclonal IgG bands1/7 (14.3)
MRI abnormality (brain)7/7 (100)
Multifocal: diffuse6: 1
MRI abnormality (spinal cord)4/7 (57.1)
NCS (fulfilled criteria for CIDPa)6/7 (85.7)
VEP abnormality4/5 (80)
Treatmentn (%)
  1. CBA, cell-based assay; CCPD, combined central and peripheral demyelination; CNS, central nervous system; CS, corticosteroids; CSF, cerebrospinal fluid; ELISA, enzyme-linked immunosorbent assay; IgG, immunoglobulin G; IVIg, intravenous immunoglobulin; MRI, magnetic resonance imaging; NCS, nerve conduction study; PNS, peripheral nervous system; VEP, visual-evoked potential.

  2. a

    According to the diagnostic criteria for and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).[30]

CS pulse
Effective for CNS6/7 (85.7)
Effective for PNS4/7 (57.1)
IVIg effective4/4 (100)

At screening, sera from two CCPD patients reacted with rat sciatic nerve specimens showing unique cross-like appearances with a regular interval along the nerve fibers. This finding suggested the presence of some sort of autoantibody against components of the nodes of Ranvier in the sera; based on the similarity of the staining pattern obtained using the sera from these CCPD patients with that obtained using anti-NF antibodies, we identified anti-NF155 antibody as a relevant autoantibody in CCPD.[34] We also carried out western blot assays using rat brain homogenates. The sera from our two CCPD patients reacted with rat brain extracts as two dense bands. These sera also reacted with a rat recombinant NF155 peptide. When these sera were mixed with rat recombinant NF155 and subjected to western blotting, the two dense bands disappeared. These results thus confirmed the presence of an anti-NF155 antibody in the sera of these two CCPD patients.

Next we examined the presence of anti-NF155 antibody in seven CCPD patients together with patients with CIDP, MS, GBS and other neurological disorders, as well as healthy controls by a cell-based assay (CBA). By ELISA, six of the seven CCPD patients (85.7%) had high OD values, whereas two of the 20 MS patients (10%), four of the 16 CIDP patients (25%) and three of the 20 GBS patients (15%) were weakly positive. None of the patients with other neurological diseases (n = 21) and none of the healthy controls (n = 23) were anti-NF155 antibody-seropositive. By CBA, five of seven CCPD patients' sera (71.4%) were also positive, whereas none of the other patients' sera were positive (Fig. 4). Cerebrospinal fluid (CSF) samples were available for three CCPD cases; when these were subjected to CBA, all samples were found to be positive for anti-NF155 antibody. These results suggest a high specificity of anti-NF155 antibody for CCPD.

image

Figure 4. Cell-based assay for NF155. (a) Human embryonic kidney 293 cells expressing human NF155 conjugated with green fluorescent protein are visualized as green signal. (b) The same cells are also labeled by a patient's serum. (c) Staining patterns merge well. Bar, 10 μm. IgG, immunoglobulin G.

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As summarized in Table 1, three CCPD patients experienced CNS and PNS symptoms simultaneously. Brain MRI showed MS-like multiple lesions in six patients, whereas one had a diffuse white-matter lesion (Fig. 5). The results of a nerve conduction study (NCS) showed that six of seven patients fulfilled the CIDP criteria. Visual-evoked potential (VEP) examination also showed abnormalities in four of five patients examined. Four of five anti-NF155 antibody-seropositive CCPD patients were treated with intravenous immunoglobulin (IVIg), which was more effective than corticosteroid (CS) therapy. MRI abnormalities were also alleviated in some patients (Fig. 5). Interestingly, the clinical course of one CCPD patient who was negative for anti-NF155 antibody in serum, but positive for anti-NF155 antibody in CSF, was somewhat different from the courses in the other CCPD patients. In particular, CS therapy was more effective than IVIg. She was treated for MS before the onset of “CIDP”. Interferon (IFN) beta-1b was administrated to prevent MS relapse, which might have influenced the onset of PNS symptoms.[35] Previous reports have also suggested the existence of relationships between IFN beta and CIDP onset.[32, 33] IFN beta-1a/b are effective and safe disease-modifying drugs that have been used for more than 20 years. The relationship between IFN beta therapy and the development of PNS demyelinating diseases in MS patients still remains to be solved.

image

Figure 5. Representative magnetic resonance imaging (MRI) images of a combined central and peripheral demyelination (CCPD) patient. (a–e) MRI images of a 16-year-old female CCPD patient with high-titer anti-NF155 antibody. (a,b,d,e): Brain MRI (fluid attenuated inversion recovery [FLAIR]) images. Note the multiple ovoid lesions in the white matter indicated by the arrowheads. (c) Magnetic resonance neurography of cervical roots and brachial plexus based on maximum intensity projection (MIP) images. Arrows indicate bilateral hypertrophic C3 roots. C4–7 roots and bilateral brachial plexuses are also hypertrophic. (f,g) Brain MRI (FLAIR) images of a 25-year-old male CCPD patient. (f) Diffuse white matter lesions are observed (arrows). (g) After treatment with plasma exchange (PE) and intravenous immunoglobulin, the white matter lesions show partial recovery in accordance with the resolution of his symptoms.

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As mentioned in the previous section, NF186 could also be very important. The sera of CCPD patients occasionally cross-reacted with both NF155 and NF186. The cross-like staining pattern seen when CCPD patients' sera were used to label rat sciatic nerve specimens indicates the presence of an autoantibody reacting to both nodal and paranodal molecules; these could be NF186 and NF155, respectively. Our preliminary experiments also show the presence of anti-NF186 antibody in some patients' sera. We are now trying to measure anti-NF186 antibody titers in these patients. IgG subclass analyses of these antibodies are also in progress. Analyses of the relationships of antibody titers and subclasses with clinical features could shed light on the molecular mechanisms underlying nervous tissue damage in CCPD, and thereby, provide clues to the indications for different sorts of immunotherapies in this condition.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Molecular structure and functions of neurofascins
  5. Anti-neurofascin antibody in MS, CIDP and GBS
  6. Anti-neurofascin antibody in CCPD
  7. Conclusion
  8. Disclosure
  9. References

Neurofascin is expressed throughout the nervous system from before birth until death. Each isoform, which is derived from strictly controlled alternative splicing, has pivotal roles in the development and maintenance of the CNS and PNS. Disturbances of these molecules can result in disorganization of both the CNS and PNS. We are at the beginning of investigations into these key molecules, a deeper understanding of which will be of benefit for deciphering not only the mechanisms underlying demyelinating diseases, but also those underlying neurodegenerative disorders.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Molecular structure and functions of neurofascins
  5. Anti-neurofascin antibody in MS, CIDP and GBS
  6. Anti-neurofascin antibody in CCPD
  7. Conclusion
  8. Disclosure
  9. References

Dr Yamasaki has received research support from Bayer Schering Pharma, Biogen Idec, Novartis Pharma and Mitsubishi Tanabe Pharma. These sponsors had no influence over the interpretation, writing or publication of this manuscript.

References

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  2. Abstract
  3. Introduction
  4. Molecular structure and functions of neurofascins
  5. Anti-neurofascin antibody in MS, CIDP and GBS
  6. Anti-neurofascin antibody in CCPD
  7. Conclusion
  8. Disclosure
  9. References
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