PT  - JOURNAL ARTICLE
AU  - Ryota Sato
AU  - Fumitaka Shimizu
AU  - Motoi Kuwahara
AU  - Yoichi Mizukami
AU  - Kenji Watanabe
AU  - Toshihiko Maeda
AU  - Yasuteru Sano
AU  - Yukio Takeshita
AU  - Michiaki Koga
AU  - Susumu Kusunoki
AU  - Takashi Kanda
TI  - Autocrine TNF-α Increases Penetration of Myelin-Associated Glycoprotein Antibodies Across the Blood-Nerve Barrier in Anti-MAG Neuropathy
AID  - 10.1212/NXI.0000000000200086
DP  - 2023 May 01
TA  - Neurology - Neuroimmunology Neuroinflammation
PG  - e200086
VI  - 10
IP  - 3
4099  - http://nn.neurology.org/content/10/3/e200086.short
4100  - http://nn.neurology.org/content/10/3/e200086.full
SO  - Neurol Neuroimmunol Neuroinflamm2023 May 01; 10
AB  - 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.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