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May 2023; 10 (3) Research ArticleOpen Access

Autocrine TNF-α Increases Penetration of Myelin-Associated Glycoprotein Antibodies Across the Blood-Nerve Barrier in Anti-MAG Neuropathy

Ryota Sato, Fumitaka Shimizu, Motoi Kuwahara, View ORCID ProfileYoichi Mizukami, Kenji Watanabe, Toshihiko Maeda, Yasuteru Sano, View ORCID ProfileYukio Takeshita, Michiaki Koga, Susumu Kusunoki, Takashi Kanda
First published February 21, 2023, DOI: https://doi.org/10.1212/NXI.0000000000200086
Ryota Sato
From the Department of Neurology and Clinical Neuroscience (R.S., F.S., Y.S., Y.T., Michiaki Koga, T.K.), Yamaguchi University Graduate School of Medicine, Ube; Department of Neurology (Motoi Kuwahara, S.K.), Kindai University Faculty of Medicine, Osaka; Center for Gene Research (Y.M., K.W.), Yamaguchi University, Ube, Japan; and Japan Community Health Care Organization (S.K.).
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Fumitaka Shimizu
From the Department of Neurology and Clinical Neuroscience (R.S., F.S., Y.S., Y.T., Michiaki Koga, T.K.), Yamaguchi University Graduate School of Medicine, Ube; Department of Neurology (Motoi Kuwahara, S.K.), Kindai University Faculty of Medicine, Osaka; Center for Gene Research (Y.M., K.W.), Yamaguchi University, Ube, Japan; and Japan Community Health Care Organization (S.K.).
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Motoi Kuwahara
From the Department of Neurology and Clinical Neuroscience (R.S., F.S., Y.S., Y.T., Michiaki Koga, T.K.), Yamaguchi University Graduate School of Medicine, Ube; Department of Neurology (Motoi Kuwahara, S.K.), Kindai University Faculty of Medicine, Osaka; Center for Gene Research (Y.M., K.W.), Yamaguchi University, Ube, Japan; and Japan Community Health Care Organization (S.K.).
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Yoichi Mizukami
From the Department of Neurology and Clinical Neuroscience (R.S., F.S., Y.S., Y.T., Michiaki Koga, T.K.), Yamaguchi University Graduate School of Medicine, Ube; Department of Neurology (Motoi Kuwahara, S.K.), Kindai University Faculty of Medicine, Osaka; Center for Gene Research (Y.M., K.W.), Yamaguchi University, Ube, Japan; and Japan Community Health Care Organization (S.K.).
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  • ORCID record for Yoichi Mizukami
Kenji Watanabe
From the Department of Neurology and Clinical Neuroscience (R.S., F.S., Y.S., Y.T., Michiaki Koga, T.K.), Yamaguchi University Graduate School of Medicine, Ube; Department of Neurology (Motoi Kuwahara, S.K.), Kindai University Faculty of Medicine, Osaka; Center for Gene Research (Y.M., K.W.), Yamaguchi University, Ube, Japan; and Japan Community Health Care Organization (S.K.).
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Toshihiko Maeda
From the Department of Neurology and Clinical Neuroscience (R.S., F.S., Y.S., Y.T., Michiaki Koga, T.K.), Yamaguchi University Graduate School of Medicine, Ube; Department of Neurology (Motoi Kuwahara, S.K.), Kindai University Faculty of Medicine, Osaka; Center for Gene Research (Y.M., K.W.), Yamaguchi University, Ube, Japan; and Japan Community Health Care Organization (S.K.).
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Yasuteru Sano
From the Department of Neurology and Clinical Neuroscience (R.S., F.S., Y.S., Y.T., Michiaki Koga, T.K.), Yamaguchi University Graduate School of Medicine, Ube; Department of Neurology (Motoi Kuwahara, S.K.), Kindai University Faculty of Medicine, Osaka; Center for Gene Research (Y.M., K.W.), Yamaguchi University, Ube, Japan; and Japan Community Health Care Organization (S.K.).
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Yukio Takeshita
From the Department of Neurology and Clinical Neuroscience (R.S., F.S., Y.S., Y.T., Michiaki Koga, T.K.), Yamaguchi University Graduate School of Medicine, Ube; Department of Neurology (Motoi Kuwahara, S.K.), Kindai University Faculty of Medicine, Osaka; Center for Gene Research (Y.M., K.W.), Yamaguchi University, Ube, Japan; and Japan Community Health Care Organization (S.K.).
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Michiaki Koga
From the Department of Neurology and Clinical Neuroscience (R.S., F.S., Y.S., Y.T., Michiaki Koga, T.K.), Yamaguchi University Graduate School of Medicine, Ube; Department of Neurology (Motoi Kuwahara, S.K.), Kindai University Faculty of Medicine, Osaka; Center for Gene Research (Y.M., K.W.), Yamaguchi University, Ube, Japan; and Japan Community Health Care Organization (S.K.).
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Susumu Kusunoki
From the Department of Neurology and Clinical Neuroscience (R.S., F.S., Y.S., Y.T., Michiaki Koga, T.K.), Yamaguchi University Graduate School of Medicine, Ube; Department of Neurology (Motoi Kuwahara, S.K.), Kindai University Faculty of Medicine, Osaka; Center for Gene Research (Y.M., K.W.), Yamaguchi University, Ube, Japan; and Japan Community Health Care Organization (S.K.).
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Takashi Kanda
From the Department of Neurology and Clinical Neuroscience (R.S., F.S., Y.S., Y.T., Michiaki Koga, T.K.), Yamaguchi University Graduate School of Medicine, Ube; Department of Neurology (Motoi Kuwahara, S.K.), Kindai University Faculty of Medicine, Osaka; Center for Gene Research (Y.M., K.W.), Yamaguchi University, Ube, Japan; and Japan Community Health Care Organization (S.K.).
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Citation
Autocrine TNF-α Increases Penetration of Myelin-Associated Glycoprotein Antibodies Across the Blood-Nerve Barrier in Anti-MAG Neuropathy
Ryota Sato, Fumitaka Shimizu, Motoi Kuwahara, Yoichi Mizukami, Kenji Watanabe, Toshihiko Maeda, Yasuteru Sano, Yukio Takeshita, Michiaki Koga, Susumu Kusunoki, Takashi Kanda
Neurol Neuroimmunol Neuroinflamm May 2023, 10 (3) e200086; DOI: 10.1212/NXI.0000000000200086

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Abstract

Background and Objectives Deposition of myelin-associated glycoprotein (MAG) immunoglobulin M (IgM) antibodies in the sural nerve is a key feature in anti-MAG neuropathy. Whether the blood-nerve barrier (BNB) is disrupted in anti-MAG neuropathy remains elusive.We aimed to evaluate the effect of sera from anti-MAG neuropathy at the molecular level using our in vitro human BNB model and observe the change of BNB endothelial cells in the sural nerve of anti-MAG neuropathy.

Methods Diluted sera from patients with anti-MAG neuropathy (n = 16), monoclonal gammopathies of undetermined significance (MGUS) neuropathy (n = 7), amyotrophic lateral sclerosis (ALS, n = 10), and healthy controls (HCs, n = 10) incubated with human BNB endothelial cells to identify the key molecule of BNB activation using RNA-seq and a high-content imaging system, and exposed with a BNB coculture model to evaluate small molecule/IgG/IgM/anti-MAG antibody permeability.

Results RNA-seq and the high-content imaging system showed the significant upregulation of tumor necrosis factor (TNF-α) and nuclear factor-kappa B (NF-κB) in BNB endothelial cells after exposure to sera from patients with anti-MAG neuropathy, whereas the serum TNF-α concentration was not changed among the MAG/MGUS/ALS/HC groups. Sera from patients with anti-MAG neuropathy did not increase 10-kDa dextran or IgG permeability but enhanced IgM and anti-MAG antibody permeability. Sural nerve biopsy specimens from patients with anti-MAG neuropathy showed higher TNF-α expression levels in BNB endothelial cells and preservation of the structural integrity of the tight junctions and the presence of more vesicles in BNB endothelial cells. Neutralization of TNF-α reduces IgM/anti-MAG antibody permeability.

Discussion Sera from individuals with anti-MAG neuropathy increased transcellular IgM/anti-MAG antibody permeability via autocrine TNF-α secretion and NF-κB signaling in the BNB.

Glossary

ALS=
amyotrophic lateral sclerosis;
ANOVA=
analysis of variance;
BCL-2=
B-cell lymphoma 2;
BNB=
blood-nerve barrier;
B-SNR-B=
blood–spinal nerve root barrier;
CIDP=
chronic inflammatory demyelinating polyneuropathy;
CXCL=
C-X-C motif chemokine ligand;
FITC=
fluorescein isothiocyanate;
HC=
healthy control;
IgM=
immunoglobulin M;
IL=
interleukin-6;
LDL=
low-density lipoprotein;
MAG=
myelin-associated glycoprotein;
MGUS=
monoclonal gammopathies of undetermined significance;
MGUS=
monoclonal gammopathy of uncertain significance;
NF-κB=
nuclear factor-kappa B;
PCA=
principal component analysis;
PNS=
peripheral nervous system;
QALB=
serum albumin quotient;
SGPG=
sulfoglucuronosyl para-globoside;
TNF=
tumor necrosis factor;
vWF=
von Willebrand Factor

Footnotes

  • Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.

  • The Article Processing Charge was funded by the authors.

  • Submitted and externally peer reviewed. The handling editor was Associate Editor Marinos C. Dalakas, MD, FAAN.

  • Received May 10, 2022.
  • Accepted in final form November 28, 2022.
  • Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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