University of Edinburgh
Characteristic ultrastructural lesions of the paranodal regions in CIDP associated with anti-Neurofascin 155 antibodies.Running head: Paranodal alterations in Nfasc155 CIDPJean-Michel Vallat,1 Nobuhiro Yuki,2 Kenji Sekiguchi,3 Norito Kokubun,4 Nobuyuki Oka,5 Diane L. Sherman,6 Peter J. Brophy,6 and Jér?me J. Devaux.7From 1 Department of Neurology and ‘Centre de Référence des neuropathies rares’, CHU Limoges; 2 Department of Neurology, Mishima Hospital, Niigata, Japan; 3 Division of neurology, Kobe University Graduate School of Medicine, Kobe, Japan; 4 Department of Neurology, Dokkyo Medical University, Tochigi, Japan; 5 Department of Neurology, National Hospital Organization Minami-Kyoto Hospital, Joyo, Kyoto, Japan; 6 Centre for Neuroregeneration, University of Edinburgh, Edinburgh EH16 4SB, United Kingdom; 7 Aix-Marseille Université, CNRS, CRN2M-UMR 7286, Marseille, France; Corresponding author: Pr. Vallat, Department of Neurology, Centre de référence “neuropathies périphériques rares”, CHU Limoges, 2 Avenue Martin Luther-King, 87042 Limoges, France.E-mail: jean-michel.vallat@unilim.frAuthor email addresses: JMV, jean-michel.vallat@unilim.fr; NY, gbs.yuki.cidp@; KS, sekiguch@med.kobe-u.ac.jp; NK, kokubun@dokkyomed.ac.jp; NO, dkajo904@kyoto.zaq.ne.jp; DLS, Diane.Sherman@ed.ac.uk; PJB, Peter.Brophy@ed.ac.uk; JJD, JD jerome.devaux@univ-amu.frTitle, 120 characters with spaces; running head, 38 characters with spaces; abstract, 197 words; manuscript, 1524 words; figures, 2; tables, 1; references, 18.Study funding: Supported by the Agence Nationale pour la Recherche (ACAMIN; JJD) under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases, and the Association Fran?aise contre les Myopathies (MNM1 2012-14580; JJD) and by the Medical Research Council and the Wellcome Trust (DLS and PJB).Keywords: autoantibody, chronic inflammatory demyelinating polyneuropathy, NF155, nodes of Ranvier, myelinAbbreviations: Caspr1 = Contactin-associated protein-1, CIDP = chronic inflammatory demyelinating polyneuropathy, EM = electron microscopy, Nfasc155 = Neurofascin 155Financial disclosure statement: JMV, KS, NK, NO, DLS, PJB, and JJD report no relevant disclosures. NY serves as an editorial board member of Expert Review of Neurotherapeutics, The Journal of the Neurological Sciences, The Journal of Peripheral Nervous System, Journal of Neurology, Neurosurgery & Psychiatry, and Journal of Alzheimer’s Disease.Author contributions: Drafting/revising the manuscript for content, including medical writing for content, JMV, NY, KS, NK, NO, DLS, PJB, and JJD. Study concept and design, JMV, NY and JD. Acquisition of data, JMV, NY, KS, NK, NO, and JJD. Analysis and interpretation of data, JMV, NY, KS, NK, NO, DLS, PJB, and JJD. ABSTRACTAntibodies to Contactin-1 and Neurofascin 155 (Nfasc155) have recently been associated with subsets of patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Contactin-1 and Nfasc155 are cell adhesion molecules that constitute the septate-like junctions observed by electron microscopy in the paranodes of myelinated axons. Antibodies to Contactin-1 have been shown to affect the localization of paranodal proteins both in patient nerve biopsies and in animal models after passive transfer. However, it is unclear whether these antibodies alter the paranodal ultrastructure. We examined by electron microscopy sural nerve biopsies from two patients presenting with anti-Nfasc155 antibodies, and also four patients lacking antibodies, three normal controls, and five patients with other neuropathies. We found that patients with anti-Nfasc155 antibodies presented a selective loss of the septate-like junctions at all paranodes examined. Further, cellular processes penetrated into the expanded spaces between the paranodal myelin loops and the axolemma in these patients. These patients presented with important nerve conduction slowing and demyelination. Also, the reactivity of anti-Nfasc155 antibodies from these patients was abolished in?neurofascin-deficient mice, confirming that the antibodies specifically target paranodal proteins. Our data indicate that anti-Nfasc155 destabilizes the paranodal axo-glial junctions and may participate in conduction deterioration.INTRODUCTIONChronic inflammatory demyelinating polyneuropathy (CIDP) is the commonest acquired immune-mediated neuropathy worldwide and is clinically heterogeneous ADDIN EN.CITE <EndNote><Cite><Author>Vallat</Author><Year>2010</Year><RecNum>23207</RecNum><DisplayText>(Vallat<style face="italic"> et al.</style>, 2010)</DisplayText><record><rec-number>23207</rec-number><foreign-keys><key app="EN" db-id="prw5v0stjvs9x2e0wxpvd0rjtwzwsp0r09ap" timestamp="1467887517">23207</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vallat, J. M.</author><author>Sommer, C.</author><author>Magy, L.</author></authors></contributors><auth-address>Service de Neurologie, Centre de Reference Neuropathies peripheriques rares, CHU Limoges, France.</auth-address><titles><title>Chronic inflammatory demyelinating polyradiculoneuropathy: diagnostic and therapeutic challenges for a treatable condition</title><secondary-title>Lancet Neurol</secondary-title></titles><periodical><full-title>Lancet Neurol</full-title><abbr-1>Lancet neurology</abbr-1></periodical><pages>402-12</pages><volume>9</volume><number>4</number><keywords><keyword>Animals</keyword><keyword>Diagnosis, Differential</keyword><keyword>Disease Progression</keyword><keyword>Humans</keyword><keyword>Polyradiculoneuropathy, Chronic Inflammatory</keyword><keyword>Demyelinating/*diagnosis/epidemiology/*therapy</keyword><keyword>Prognosis</keyword></keywords><dates><year>2010</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1474-4465 (Electronic)
1474-4422 (Linking)</isbn><accession-num>20298964</accession-num><urls><related-urls><url>(10)70041-7</electronic-resource-num></record></Cite></EndNote>(Vallat et al., 2010). Anti-Neurofascin 155 (Nfasc155) and anti-Contactin-1 IgG4 antibodies have recently been associated with subgroups of CIDP patients showing ataxia, tremor, and a poor response to intravenous immunoglobulin PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZXZhdXg8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Doppler et al., 2015) and in animals models ADDIN EN.CITE <EndNote><Cite><Author>Manso</Author><Year>2016</Year><RecNum>23202</RecNum><DisplayText>(Manso<style face="italic"> et al.</style>, 2016)</DisplayText><record><rec-number>23202</rec-number><foreign-keys><key app="EN" db-id="prw5v0stjvs9x2e0wxpvd0rjtwzwsp0r09ap" timestamp="1465200871">23202</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Manso, C.</author><author>Querol, L.</author><author>Mekaouche, M.</author><author>Illa, I.</author><author>Devaux, J. J.</author></authors></contributors><auth-address>Aix-Marseille Universite, CNRS, CRN2M-UMR7286, Marseille, France.
Neuromuscular Diseases Unit, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain.
Aix-Marseille Universite, CNRS, CRN2M-UMR7286, Marseille, France jerome.devaux@univ-amu.fr.</auth-address><titles><title>Contactin-1 IgG4 antibodies cause paranode dismantling and conduction defects</title><secondary-title>Brain</secondary-title></titles><periodical><full-title>Brain</full-title><abbr-1>Brain</abbr-1></periodical><pages>1700-12</pages><volume>139</volume><number>Pt 6</number><keywords><keyword>Cidp</keyword><keyword>autoantibody</keyword><keyword>caspr</keyword><keyword>dysimmune</keyword><keyword>neuritis</keyword></keywords><dates><year>2016</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1460-2156 (Electronic)
0006-8950 (Linking)</isbn><accession-num>27017186</accession-num><urls><related-urls><url>;(Manso et al., 2016). However, the pathogenic effects of anti-Nfasc155 IgG4 are yet unclear. We present here characteristic ultrastructural modifications of the paranodal junctions in sural nerve biopsies from two patients with anti-Nfasc155 IgG4 antibodies. These lesions have not been described before in nerves of CIDP patients and are likely to contribute significantly to the conduction deficits observed.METHODSNerve biopsies. A portion of each sural nerve biopsy from two CIDP patients with anti-Nfasc155 antibodies was fixed in buffered glutaraldehyde, embedded in Epon, and prepared for light (semi-thin sections) and ultrastructural examination. To study specifically the node of Ranvier, several longitudinal sections of each nerve biopsy were systematically examined by electron microscopy (EM) and compared with longitudinal sections of sural nerve biopsies from three normal controls, five patients with non-CIDP acquired neuropathies (two cases of vasculitic neuropathy, one case of nutritional neuropathy, and two cases of lymphomatous neuropathy), and from four CIDP patients showing no reactivity to paranodal proteins.Nerve staining. Teased fibers from sciatic nerves of 7-day-old neurofascin-deficient (Nfasc-/-) and Nfasc+/+ mice were prepared as previously described PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGVybWFuPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48
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ADDIN EN.CITE.DATA (Sherman et al., 2005). Teased fibers were immersed in -20°C acetone for 10 min, blocked for 1 hr in blocking solution containing 5% fish skin gelatin, 0.1% Triton X-100 in phosphate buffer saline and incubated overnight at 4°C with anti-Nfasc155 CIDP sera diluted at 1:200, rabbit antisera against Contactin-associated protein-1 (Caspr1; 1:2,000) and chicken antibody against Myelin Protein Zero (1:2,000; Abcam). The slides were washed and incubated with the appropriate Alexa-conjugated secondary antibodies (1:500; Jackson Immunoresearch, West Grove, PA). Slides were mounted and examined using an ApoTome fluorescence microscope (Carl Zeiss MicroImaging GmbH).Biochemistry. Brains from 7-day-old Nfasc+/+ and Nfasc-/- mice were homogenized as previously described ADDIN EN.CITE <EndNote><Cite><Author>Devaux</Author><Year>2010</Year><RecNum>22513</RecNum><DisplayText>(Devaux, 2010)</DisplayText><record><rec-number>22513</rec-number><foreign-keys><key app="EN" db-id="prw5v0stjvs9x2e0wxpvd0rjtwzwsp0r09ap" timestamp="0">22513</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Devaux, J.J.</author></authors></contributors><titles><title>The C-terminal domain of betaIV-spectrin is crucial for KCNQ2 aggregation and excitability at nodes of Ranvier</title><secondary-title>J Physiol London</secondary-title><alt-title>Journal of Physiology - London</alt-title></titles><periodical><full-title>J Physiol London</full-title><abbr-1>Journal of Physiology - London</abbr-1></periodical><alt-periodical><full-title>J Physiol London</full-title><abbr-1>Journal of Physiology - London</abbr-1></alt-periodical><pages>4719-4730</pages><volume>588</volume><number>23</number><keywords><keyword>AXON INITIAL SEGMENTS</keyword><keyword>SODIUM-CHANNEL</keyword><keyword>ANKYRIN-G</keyword><keyword>K+ CHANNELS</keyword><keyword>MOLECULAR-ORGANIZATION</keyword><keyword>DOMINANT DEAFNESS</keyword><keyword>MYELINATED AXONS</keyword><keyword>SUBUNIT</keyword><keyword>NEUROMYOTONIA</keyword><keyword>MUTATION</keyword></keywords><dates><year>2010</year></dates><pub-location>Commerce Place, 350 Main St, Malden 02148, MA, USA</pub-location><publisher>Wiley-Blackwell Publishing, Inc</publisher><isbn>0022-3751</isbn><urls></urls></record></Cite></EndNote>(Devaux, 2010). 100 ?g of proteins were loaded on 7.5% SDS-PAGE gels, transferred, and immunoblotted with a rabbit recognizing all Neurofascin isoforms (PanNfasc; 1:2,000; Abcam), a rabbit antiserum against Actin (1:2,000; Sigma-Aldrich) or anti-Nfasc155 CIDP sera (1:500). Immunoreactivity was revealed using peroxidase-coupled secondary antibodies (1:5,000; Jackson ImmunoResearch) and BM chemiluminescence kit (Roche).RESULTSIn a previous study, we detailed the clinical data of two CIDP patients showing IgG4 antibodies to Nfasc155 (patients 10 and 24; Devaux et al., 2016). The serum IgG from these patients stained the paranodal regions of mouse sciatic nerve fibers (Fig. 1A). To further confirm the specificity of this reactivity in these patients, we tested these samples on nerves from the Nfasc-/- mice PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGVybWFuPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48
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ADDIN EN.CITE.DATA (Sherman et al., 2005). As expected, CIDP sera did not stain paranodes from Nfasc-/- mice (Fig. 1A), and immunoreactivity to Nfasc155 was abolished in immunoblots of brain samples from Nfasc-/- mice (Fig. 1B). To determine whether these autoantibodies are associated with specific morphological abnormalities, we examined sural nerve biopsies from these two patients. On semi-thin sections, there was a decreased number of both large and small diameter myelinated fibers compared to controls (Fig. 2A-B). This decrease was heterogeneous between fascicles. Some myelinated axons presented thin myelin sheaths suggestive of demyelinating/remyelinating process. Myelin ovoids attesting to nerve fiber destruction were also seen. No inflammatory cells were noted. EM examination confirmed these aspects. Myelin debris in the cytoplasm of some Schwann cells and in a few macrophages in the endoneurial space were present. No proliferation of Schwann cell profiles like onion bulbs was seen. On longitudinal sections, we observed frequent and significant widenings of the nodes of Ranvier (Fig. 2C). High magnification study of all the paranodal regions showed an absence of transverse bands at paranodes in Nfasc155-positive patients (Fig. 2D-E). In these areas there was a loss of the attachment of the myelin loops to the axon, and an irregular widening of the periaxonal space by comparison to controls. Transverse bands could be readily observed at paranodes in nerve biopsies from normal controls or CIDP patients lacking antibodies to paranodal proteins (Fig. 2F). In case 2 (patient 24), cellular processes often penetrated the paranodal region perhaps contributing to the dissociated attachment between the axon and the paranodal loops (Fig. 2D). In case 1 (patient 10), only a few small axonal processes penetrated the first paranodal loops located near the nodal area. No such alterations were ever seen in normal controls, in non-CIDP acquired neuropathies or CIDP patients lacking antibodies to paranodal proteins. The nerve conduction studies showed diffuse, but heterogeneous conduction slowing in motor nerves as all nerves were not similarly affected. F-waves were detectable with prolonged latency in both patients (Table 1). Sensory nerve action potentials could not be detected in all tested nerves in both patients. In case 2, prolonged distal latencies and reduced conduction velocities with probable conduction block were found in the forearm segment of the median nerve (Table 1). These results indicated that the demyelinating process was diffuse along the nerve.DISCUSSIONNfasc155 is a cell adhesion molecule playing an essential function in paranodal formation and in nerve conduction PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGVybWFuPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48
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ADDIN EN.CITE.DATA (Charles et al., 2002). This ternary complex of glycoproteins is required for the formation and stability of the paranodal transverse bands also known as septate-like junctions PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaGF0PC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Bhat et al., 2001; Boyle et al., 2001; Sherman et al., 2005; Zonta et al., 2008). Recently, we screened a large cohort of CIDP patients and identified anti-Nfasc155 IgG4 antibodies in a subgroup of CIDP patients ADDIN EN.CITE <EndNote><Cite><Author>Manso</Author><Year>2016</Year><RecNum>23202</RecNum><DisplayText>(Manso<style face="italic"> et al.</style>, 2016)</DisplayText><record><rec-number>23202</rec-number><foreign-keys><key app="EN" db-id="prw5v0stjvs9x2e0wxpvd0rjtwzwsp0r09ap" timestamp="1465200871">23202</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Manso, C.</author><author>Querol, L.</author><author>Mekaouche, M.</author><author>Illa, I.</author><author>Devaux, J. J.</author></authors></contributors><auth-address>Aix-Marseille Universite, CNRS, CRN2M-UMR7286, Marseille, France.
Neuromuscular Diseases Unit, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain.
Aix-Marseille Universite, CNRS, CRN2M-UMR7286, Marseille, France jerome.devaux@univ-amu.fr.</auth-address><titles><title>Contactin-1 IgG4 antibodies cause paranode dismantling and conduction defects</title><secondary-title>Brain</secondary-title></titles><periodical><full-title>Brain</full-title><abbr-1>Brain</abbr-1></periodical><pages>1700-12</pages><volume>139</volume><number>Pt 6</number><keywords><keyword>Cidp</keyword><keyword>autoantibody</keyword><keyword>caspr</keyword><keyword>dysimmune</keyword><keyword>neuritis</keyword></keywords><dates><year>2016</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1460-2156 (Electronic)
0006-8950 (Linking)</isbn><accession-num>27017186</accession-num><urls><related-urls><url>;(Devaux et al., 2016). Here, we further show using Nfasc-/- mice that the reactivity to Nfasc155 is specific and that autoantibodies target Nfasc155 at paranodes. In addition, we describe paranodal alterations in nerve biopsies from two of these patients.At the ultrastructural level on longitudinal sections from control human nerve biopsies, we observed the presence of transverse bands, which correspond to small linear structures spiraling around the axon between the terminal myelin loops and the axolemma. In the two nerve biopsies from CIDP patients with anti-Nfasc155 antibodies, these transverse bands were absent in all the paranodes that we have examined. In addition, the periaxonal space between the axon and the paranodal loops was irregularly widened. In case 2, cytoplasm processes were detected in this widened space penetrating between the axons and the loops. In this case, the nerve biopsy was performed several years after the first clinical signs appeared. In case 1, this penetration of cell cytoplasm between the paranodal loops and the axon seemed to be just beginning. This could be due to the shorter duration of the polyneuropathy (about 5 months) at the time of the nerve biopsy. These alterations were highly reminiscent of the alterations found in mice deficient for Contactin-1, Caspr1, or Neurofascin PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaGF0PC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Sima et al., 1986; Giannini and Dyck, 1996) or in experiment allergic neuritis ADDIN EN.CITE <EndNote><Cite><Author>Allt</Author><Year>1975</Year><RecNum>13015</RecNum><DisplayText>(Allt, 1975)</DisplayText><record><rec-number>13015</rec-number><foreign-keys><key app="EN" db-id="prw5v0stjvs9x2e0wxpvd0rjtwzwsp0r09ap" timestamp="0">13015</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Allt, G.</author></authors></contributors><titles><title>The node of Ranvier in experiemntal allergic neuritis: an electron microscope study</title><secondary-title>J. Neurocytol.</secondary-title></titles><periodical><full-title>Journal of Neurocytology</full-title><abbr-1>J. Neurocytol.</abbr-1></periodical><pages>63-76</pages><volume>4</volume><keywords><keyword>nodes</keyword></keywords><dates><year>1975</year></dates><urls></urls></record></Cite></EndNote>(Allt, 1975). These were mostly partial loss involving some paranodes or some paranodal loops. This was not the case here, because all paranodes were affected. In addition, we carefully examined serial sections at high magnification to make sure that transverse band alterations were not preparation artifacts.The patients presented with diffuse and heterogeneous nerve conduction slowing along the nerves. Because all paranodes were affected, it is plausible that transverse band loss accounts for the diffuse conduction defects. However, significant node widenings and demyelination were also observed and likely participate in conduction slowing. Both cases also presented a rarefaction of myelinated axons. The absence of sensory nerve action potentials may therefore be due to both axonal loss and distal demyelination. Axonal loss is a common phenomenon in CIDP and is likely related to the demyelination process. The patients showed a prominent IgG4 response to Nfasc155, which did not activate the complement pathway (Devaux et al., 2016) and are unlikely to induce axonal degeneration. In addition, no immune cell infiltration was found in nerve biopsies. In conclusion, our data indicate that patients with IgG4 antibodies to Nfasc155 present typical electrophysiological and morphological aspects of CIDP, but in presence of specific paranodal alterations. These results suggest that multiple mechanisms can be responsible for the physiopathology of CIDP, including IgG4-mediated demyelination.REFERENCES ADDIN EN.REFLIST Allt G. The node of Ranvier in experimental allergic neuritis: an electron microscope study. J Neurocytol 1975; 4: 63-76.Bhat MA, Rios JC, Lu Y, Garcia-Fresco GP, Ching W, St Martin M, et al. Axon-glia interactions and the domain organization of myelinated axons require Neurexin IV/Caspr/Paranodin. Neuron 2001; 30(2): 369-83.Boyle MET, Berglund EO, Murai KK, Weber L, Peles E, Ranscht B. Contactin orchestrates assembly of the septate-like junctions at the paranode in myelinated peripheral nerve. Neuron 2001; 30(2): 385-97.Charles P, Tait S, Faivre-Sarrailh C, Barbin G, Gunn-Moore F, Denisenko-Nehrbass N, et al. Neurofascin is a glial receptor for the paranodin/Caspr-contactin axonal complex at the axoglial junction. Curr Biol 2002; 12(3): 217-20.Devaux JJ. The C-terminal domain of betaIV-spectrin is crucial for KCNQ2 aggregation and excitability at nodes of Ranvier. J Physiol 2010; 588(23): 4719-30.Devaux JJ, Miura Y, Fukami Y, Inoue T, Manso C, Belghazi M, et al. Neurofascin-155 IgG4 in chronic inflammatory demyelinating polyneuropathy. Neurology 2016; 86(9): 800-7.Doppler K, Appeltshauser L, Wilhelmi K, Villmann C, Dib-Hajj SD, Waxman SG, et al. Destruction of paranodal architecture in inflammatory neuropathy with anti-contactin-1 autoantibodies. J Neurol Neurosurg Psychiatry 2015.Giannini C, Dyck PJ. Axoglial dysjunction: a critical appraisal of definition, techniques, and previous results. Microsc Res Technique 1996; 34(5): 436-44.Manso C, Querol L, Mekaouche M, Illa I, Devaux JJ. Contactin-1 IgG4 antibodies cause paranode dismantling and conduction defects. Brain 2016; 139(Pt 6): 1700-12.Miura Y, Devaux JJ, Fukami Y, Manso C, Belghazi M, Wong AH, et al. Contactin 1 IgG4 associates to chronic inflammatory demyelinating polyneuropathy with sensory ataxia. Brain 2015; 138(Pt 6): 1484-91.Ng JK, Malotka J, Kawakami N, Derfuss T, Khademi M, Olsson T, et al. Neurofascin as a target for autoantibodies in peripheral neuropathies. Neurology 2012; 79(23): 2241-8.Querol L, Nogales-Gadea G, Rojas-Garcia R, Diaz-Manera J, Pardo J, Ortega-Moreno A, et al. Neurofascin IgG4 antibodies in CIDP associate with disabling tremor and poor response to IVIg. Neurology 2014; 82(10): 879-86.Querol L, Nogales-Gadea G, Rojas-Garcia R, Martinez-Hernandez E, Diaz-Manera J, Suarez-Calvet X, et al. Antibodies to contactin-1 in chronic inflammatory demyelinating polyneuropathy. Ann Neurol 2012; 73(3): 370-80.Querol L, Rojas-Garcia R, Diaz-Manera J, Barcena J, Pardo J, Ortega-Moreno A, et al. Rituximab in treatment-resistant CIDP with antibodies against paranodal proteins. Neurol Neuroimmunol Neuroinflamm 2015; 2(5): e149.Sherman DL, Tait S, Melrose S, Johnson R, Zonta B, Court FA, et al. Neurofascins are required to establish axonal domains for saltatory conduction. Neuron 2005; 48(5): 737-42.Sima AF, Lattimer SA, Yagihashi S, Greene DA. Axo-glial dysjunction: novel structural lesion that accounts for poorly reversible slowing of nerve conduction in the spontaneously diabetic bio-breeding rat. J Clin Invest 1986; 77: 474-84.Vallat JM, Sommer C, Magy L. Chronic inflammatory demyelinating polyradiculoneuropathy: diagnostic and therapeutic challenges for a treatable condition. Lancet Neurol 2010; 9(4): 402-12.Zonta B, Tait S, Melrose S, Anderson H, Harroch S, Higginson J, et al. Glial and neuronal isoforms of Neurofascin have distinct roles in the assembly of nodes of Ranvier in the central nervous system. J Cell Biol 2008; 181(7): 1169-77.FIGURE LEGENDSFigure 1: Autoantibodies in CIDP patients specifically bind Nfasc155 at paranodes. (A) These are teased sciatic nerve fibers from 7 day old Nfasc+/+ (upper panel) and Nfasc-/- mice (lower panel) stained with CIDP sera (red), Caspr1 (green), and Myelin Protein Zero (P0; blue). IgG from Nfasc155 CIDP patients stained the paranodal regions of wild-type animals, but not in Nfasc-/- mice. Scale bars: 10 μm.(B) Brain proteins (100 ?g) from Nfasc+/+ and Nfasc-/- mice were immunoblotted with a Nfasc155 CIDP serum, a rabbit antiserum recognizing all Neurofascin isoforms (PanNfasc), or a rabbit antiserum against Actin. The CIDP serum recognized two protein bands in Nfasc+/+ but not in Nfasc-/- mice. These two bands likely represent Nfasc155 high and low forms. The PanNfasc antibody revealed several protein bands corresponding to Nfasc186 and Nfasc155 in Nfasc+/+ but not in Nfasc-/- mice. Molecular weight markers are indicated in kDa on the left.Figure 2: Paranodal alterations in sural nerve biopsy from Nfasc155 CIDP patients.(A-B) These are transverse semithin sections of sural nerve biopsy from a CIDP patient with anti-Nfasc155 antibodies (A) and normal nerve biopsy of a patient of the same age (B). Note the significant rarefaction of large myelinated axons by comparison to the normal nerve.(C, D, E) Longitudinal ultrathin sections showing ultrastructural alterations at paranodes in CIDP patients with anti-Nfasc155 antibodies (case 2). Widening of nodes of Ranvier (C) were observed suggesting demyelinating process. Paranodal regions were severely disrupted and cellular processes (colored in blue) interposed between the paranodal myelin loops (ml) and the axon (a). The periaxonal space between the axon and the paranodal loops were abnormally widened (D-E) and lacked transverse bands (arrow).(F) Longitudinal sections of a paranode showing transverse bands in a normal control nerve.Table 1: Electrophysiological characteristics of CIDP patients with anti-Nfasc155 IgG4Case 1Case 2Median nerveDML (ms)6.56.9dCMAP amplitude (mV)4.25.0MCV (m.s-1)2421F wave latency (ms)6271.8SNAP amplitude (?v)NDNDUlnar nerveDML (ms)4.05.1dCMAP amplitude (mV)8.27.3MCV (m.s-1)2522F wave latency (ms)55-SNAP amplitude (?v)2.0NDTibial nerveDML (ms)ND15.4dCMAP amplitude (mV)ND0.4MCV (m.s-1)NDUnmeasurableF wave latency (ms)NDNDSural nerveSNAP amplitude (?v)1.5NDdCMAP = distal compound muscle action potential; DML = distal motor latency; MCV = motor conduction velocity; ND = not detected; SNAP = sensory nerve action potential. ................
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