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Sera from Remitting and Secondary Progressive Multiple Sclerosis Patients Disrupt the Blood-Brain Barrier

BACKGROUND: Pathological destruction of blood-brain barrier (BBB) has been thought to be the initial key event in the process of developing multiple sclerosis (MS). The purpose of the present study was to clarify the possible molecular mechanisms responsible for the malfunction of BBB by sera from r...

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Autores principales: Shimizu, Fumitaka, Tasaki, Ayako, Sano, Yasuteru, Ju, Mihua, Nishihara, Hideaki, Oishi, Mariko, Koga, Michiaki, Kawai, Motoharu, Kanda, Takashi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3970956/
https://www.ncbi.nlm.nih.gov/pubmed/24686948
http://dx.doi.org/10.1371/journal.pone.0092872
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author Shimizu, Fumitaka
Tasaki, Ayako
Sano, Yasuteru
Ju, Mihua
Nishihara, Hideaki
Oishi, Mariko
Koga, Michiaki
Kawai, Motoharu
Kanda, Takashi
author_facet Shimizu, Fumitaka
Tasaki, Ayako
Sano, Yasuteru
Ju, Mihua
Nishihara, Hideaki
Oishi, Mariko
Koga, Michiaki
Kawai, Motoharu
Kanda, Takashi
author_sort Shimizu, Fumitaka
collection PubMed
description BACKGROUND: Pathological destruction of blood-brain barrier (BBB) has been thought to be the initial key event in the process of developing multiple sclerosis (MS). The purpose of the present study was to clarify the possible molecular mechanisms responsible for the malfunction of BBB by sera from relapse-remitting MS (RRMS) and secondary progressive MS (SPMS) patients. METHODS: We evaluated the effects of sera from the patients in the relapse phase of RRMS (RRMS-R), stable phase of RRMS (RRMS-S) and SPMS on the expression of tight junction proteins and vascular cell adhesion protein-1 (VCAM-1), and on the transendothelial electrical resistance (TEER) in human brain microvascular endothelial cells (BMECs). RESULTS: Sera from the RRMS-R or SPMS patients decreased the claudin-5 protein expression and the TEER in 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, the immunoglobulin G (IgG) purified from patients' sera also decreased the claudin-5 protein expression and the TEER in BMECs. The sera and purified IgG from all MS patients increased the VCAM-1 protein expression in BMECs. CONCLUSIONS: 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. Both RRMS-S and SPMS sera increased the VCAM-1 expression in the BBB, thus indicating that targeting the VCAM-1 in the BBB could represent a possible therapeutic strategy for even the stable phase of MS and SPMS.
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spelling pubmed-39709562014-04-04 Sera from Remitting and Secondary Progressive Multiple Sclerosis Patients Disrupt the Blood-Brain Barrier Shimizu, Fumitaka Tasaki, Ayako Sano, Yasuteru Ju, Mihua Nishihara, Hideaki Oishi, Mariko Koga, Michiaki Kawai, Motoharu Kanda, Takashi PLoS One Research Article BACKGROUND: Pathological destruction of blood-brain barrier (BBB) has been thought to be the initial key event in the process of developing multiple sclerosis (MS). The purpose of the present study was to clarify the possible molecular mechanisms responsible for the malfunction of BBB by sera from relapse-remitting MS (RRMS) and secondary progressive MS (SPMS) patients. METHODS: We evaluated the effects of sera from the patients in the relapse phase of RRMS (RRMS-R), stable phase of RRMS (RRMS-S) and SPMS on the expression of tight junction proteins and vascular cell adhesion protein-1 (VCAM-1), and on the transendothelial electrical resistance (TEER) in human brain microvascular endothelial cells (BMECs). RESULTS: Sera from the RRMS-R or SPMS patients decreased the claudin-5 protein expression and the TEER in 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, the immunoglobulin G (IgG) purified from patients' sera also decreased the claudin-5 protein expression and the TEER in BMECs. The sera and purified IgG from all MS patients increased the VCAM-1 protein expression in BMECs. CONCLUSIONS: 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. Both RRMS-S and SPMS sera increased the VCAM-1 expression in the BBB, thus indicating that targeting the VCAM-1 in the BBB could represent a possible therapeutic strategy for even the stable phase of MS and SPMS. Public Library of Science 2014-03-31 /pmc/articles/PMC3970956/ /pubmed/24686948 http://dx.doi.org/10.1371/journal.pone.0092872 Text en © 2014 Shimizu et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Shimizu, Fumitaka
Tasaki, Ayako
Sano, Yasuteru
Ju, Mihua
Nishihara, Hideaki
Oishi, Mariko
Koga, Michiaki
Kawai, Motoharu
Kanda, Takashi
Sera from Remitting and Secondary Progressive Multiple Sclerosis Patients Disrupt the Blood-Brain Barrier
title Sera from Remitting and Secondary Progressive Multiple Sclerosis Patients Disrupt the Blood-Brain Barrier
title_full Sera from Remitting and Secondary Progressive Multiple Sclerosis Patients Disrupt the Blood-Brain Barrier
title_fullStr Sera from Remitting and Secondary Progressive Multiple Sclerosis Patients Disrupt the Blood-Brain Barrier
title_full_unstemmed Sera from Remitting and Secondary Progressive Multiple Sclerosis Patients Disrupt the Blood-Brain Barrier
title_short Sera from Remitting and Secondary Progressive Multiple Sclerosis Patients Disrupt the Blood-Brain Barrier
title_sort sera from remitting and secondary progressive multiple sclerosis patients disrupt the blood-brain barrier
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3970956/
https://www.ncbi.nlm.nih.gov/pubmed/24686948
http://dx.doi.org/10.1371/journal.pone.0092872
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