RT Journal Article
SR Electronic
T1 Autocrine TNF-α Increases Penetration of Myelin-Associated Glycoprotein Antibodies Across the Blood-Nerve Barrier in Anti-MAG Neuropathy
JF Neurology - Neuroimmunology Neuroinflammation
JO Neurol Neuroimmunol Neuroinflamm
FD Lippincott Williams & Wilkins
SP e200086
DO 10.1212/NXI.0000000000200086
VO 10
IS 3
A1 Ryota Sato
A1 Fumitaka Shimizu
A1 Motoi Kuwahara
A1 Yoichi Mizukami
A1 Kenji Watanabe
A1 Toshihiko Maeda
A1 Yasuteru Sano
A1 Yukio Takeshita
A1 Michiaki Koga
A1 Susumu Kusunoki
A1 Takashi Kanda
YR 2023
UL http://nn.neurology.org/content/10/3/e200086.abstract
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