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神経科学学会-神経学会合同シンポジウム:Neuroimmunology Cutting Edge Symposium: Mechanisms of Immune-mediated Neurological Disease
Joint Symposium of the Japan Neuroscience Society and the Japanese Society of Neurology:Neuroimmunology Cutting Edge Symposium:
Mechanisms of Immune-mediated Neurological Disease

開催日 2014/9/13
時間 9:00 - 11:00
会場 Room A(Main Hall)
Chairperson(s) 吉良 潤一 / Jun-ichi Kira (九州大学大学院医学系研究院 神経内科学 / Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Japan)
神田 隆 / Takashi Kanda (山口大学大学院医学系研究科神経内科学 / Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Japan)

自己免疫を介したneurovascular unitの破綻メカニズム
Immune-mediated disruption of neurovascular units in neuroimmunological diseases

  • S3-A-1-4
  • 神田 隆 / Takashi Kanda:1 
  • 1:山口大学大学院医学系研究科神経内科学 / Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Japan 

The neurovascular unit (NVU) controls brain homeostasis and is composed by neurons, endothelial cells, pericytes, astrocytes, and extracelluar matrix components. Because the failure of NVU directly causes brain malfunction and endothelial cells forming blood-brain barrier (BBB) are the sole cells in NVU which directly contact with systemic circulation, immune-mediated disruption of BBB caused by endothelial cell damage is the key step in various neuroimmunological disorders including multiple sclerosis (MS) and neuromyelitis optica (NMO). We evaluated the effects of sera from aquaporin 4 (AQP4) antibody positive NMO patients and from relapse-remitting MS (RRMS) and secondary progressive MS (SPMS) patients against the BBB in vitro, utilizing the parameters including the expression of tight junction proteins and transendothelial electrical resistance (TEER) in human brain microvascular endothelial cells (BMECs).
Results: Claudin-5 protein and TEER in BMECs were significantly decreased after exposure to acute phase NMO sera, and this effect was reversed after MMP-2/9 inhibitor application. Purified IgG obtained from NMO patients' sera did not influence these two BBB properties, but increased the amount of VCAM-1 in BMECs. Sera from relapse phase of MS (RRMS-R) and SPMS patients decreased the claudin-5 protein and the BMECs. In RRMS-R, this effect was restored after adding an MMP inhibitor, and the MMP-2/9 secretion by BMECs was significantly increased after the application of patients' sera. In SPMS, purified IgG from patients' sera also decreased claudin-5 protein and the TEER in BMECs. The total sera and purified IgG from all MS patients increased the VCAM-1 protein in BMECs.
Conclusions: Undetermined substance other than IgG in NMO sera at acute stage disrupt the BBB via autocrine secretion of VEGF and MMP-2/9. Autoantibodies against BMECs other than AQP4 antibody in NMO sera upregulate VCAM-1 and also contribute to the destruction of BBB. In MS, the up-regulation of autocrine MMP-2/9 by BMECs after exposure to sera from RRMS-R patients or the autoantibodies against BMECs from SPMS patients can compromise the BBB. Increased VCAM-1 caused by all MS patients' sera may provide a therapeutic strategy for even stable phase of MS and SPMS.

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