Cargando…

S100A6 Promotes B Lymphocyte Penetration Through the Blood–Brain Barrier in Autoimmune Encephalitis

Autoimmune encephalitis (AE) is a severe neurological disease. The brain of the AE patient is attacked by a dysregulated immune system, which is caused by the excessive production of autoantibodies against neuronal receptors and synaptic proteins. AE is also characterized by the uncontrolled B lymph...

Descripción completa

Detalles Bibliográficos
Autores principales: Tsai, Meng-Han, Lin, Chih-Hsiang, Tsai, Kuo-Wang, Lin, Ming-Hong, Ho, Chen-Jui, Lu, Yan-Ting, Weng, Ken-Pen, Lin, Yuyu, Lin, Pei-Hsien, Li, Sung-Chou
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901080/
https://www.ncbi.nlm.nih.gov/pubmed/31850060
http://dx.doi.org/10.3389/fgene.2019.01188
_version_ 1783477450647273472
author Tsai, Meng-Han
Lin, Chih-Hsiang
Tsai, Kuo-Wang
Lin, Ming-Hong
Ho, Chen-Jui
Lu, Yan-Ting
Weng, Ken-Pen
Lin, Yuyu
Lin, Pei-Hsien
Li, Sung-Chou
author_facet Tsai, Meng-Han
Lin, Chih-Hsiang
Tsai, Kuo-Wang
Lin, Ming-Hong
Ho, Chen-Jui
Lu, Yan-Ting
Weng, Ken-Pen
Lin, Yuyu
Lin, Pei-Hsien
Li, Sung-Chou
author_sort Tsai, Meng-Han
collection PubMed
description Autoimmune encephalitis (AE) is a severe neurological disease. The brain of the AE patient is attacked by a dysregulated immune system, which is caused by the excessive production of autoantibodies against neuronal receptors and synaptic proteins. AE is also characterized by the uncontrolled B lymphocyte infiltration through the blood–brain barrier (BBB) layer, and the investigation of the underlying mechanism involved in this infiltration may facilitate the discovery of novel therapies for AE. However, few AE-related studies have focused on this issue. In this study, we aimed to identify the factors involved in B lymphocyte infiltration in AE. For this purpose, we first enrolled four healthy control and five AE subjects, collecting their serum and/or total white blood cell samples. The white blood cell samples were further used for collecting RNA and DNA. Then, we simulated the in vivo B lymphocyte infiltration with an in vitro leukocyte transendothelial migration model. It turned out that AE serum treatment significantly and specifically promoted B cells to penetrate the BBB endothelial layer without affecting neutrophils. Next, through genome-wide DNA methylation assays on bisulfite-conversion DNA samples, we identified S100A6 and S100A11 as potential hypo-methylated disease genes in the AE samples. Further qPCR assays demonstrated their upregulation in AE samples, reflecting the negative correlations between gene expression and DNA methylation. Finally, recombinant S100A6 protein treatment significantly increased B lymphocyte infiltration through the BBB endothelial layer, which partially recapitulated the effect of AE serum. In summary, by using an in vitro leukocyte transendothelial migration model, we confirmed that S100A6 promoted B lymphocyte to penetrate the BBB endothelial layer, which is similar to the in vivo clinical manifestations of AE. Therefore, further studies on how the S100A6 protein facilitates B lymphocyte infiltration and on whether other factors in serum also contribute to this phenomenon are likely to improve our understanding of AE and hopefully to reveal novel therapeutic targets for this emerging treatable neurological disorder.
format Online
Article
Text
id pubmed-6901080
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-69010802019-12-17 S100A6 Promotes B Lymphocyte Penetration Through the Blood–Brain Barrier in Autoimmune Encephalitis Tsai, Meng-Han Lin, Chih-Hsiang Tsai, Kuo-Wang Lin, Ming-Hong Ho, Chen-Jui Lu, Yan-Ting Weng, Ken-Pen Lin, Yuyu Lin, Pei-Hsien Li, Sung-Chou Front Genet Genetics Autoimmune encephalitis (AE) is a severe neurological disease. The brain of the AE patient is attacked by a dysregulated immune system, which is caused by the excessive production of autoantibodies against neuronal receptors and synaptic proteins. AE is also characterized by the uncontrolled B lymphocyte infiltration through the blood–brain barrier (BBB) layer, and the investigation of the underlying mechanism involved in this infiltration may facilitate the discovery of novel therapies for AE. However, few AE-related studies have focused on this issue. In this study, we aimed to identify the factors involved in B lymphocyte infiltration in AE. For this purpose, we first enrolled four healthy control and five AE subjects, collecting their serum and/or total white blood cell samples. The white blood cell samples were further used for collecting RNA and DNA. Then, we simulated the in vivo B lymphocyte infiltration with an in vitro leukocyte transendothelial migration model. It turned out that AE serum treatment significantly and specifically promoted B cells to penetrate the BBB endothelial layer without affecting neutrophils. Next, through genome-wide DNA methylation assays on bisulfite-conversion DNA samples, we identified S100A6 and S100A11 as potential hypo-methylated disease genes in the AE samples. Further qPCR assays demonstrated their upregulation in AE samples, reflecting the negative correlations between gene expression and DNA methylation. Finally, recombinant S100A6 protein treatment significantly increased B lymphocyte infiltration through the BBB endothelial layer, which partially recapitulated the effect of AE serum. In summary, by using an in vitro leukocyte transendothelial migration model, we confirmed that S100A6 promoted B lymphocyte to penetrate the BBB endothelial layer, which is similar to the in vivo clinical manifestations of AE. Therefore, further studies on how the S100A6 protein facilitates B lymphocyte infiltration and on whether other factors in serum also contribute to this phenomenon are likely to improve our understanding of AE and hopefully to reveal novel therapeutic targets for this emerging treatable neurological disorder. Frontiers Media S.A. 2019-11-22 /pmc/articles/PMC6901080/ /pubmed/31850060 http://dx.doi.org/10.3389/fgene.2019.01188 Text en Copyright © 2019 Tsai, Lin, Tsai, Lin, Ho, Lu, Weng, Lin, Lin and Li http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Tsai, Meng-Han
Lin, Chih-Hsiang
Tsai, Kuo-Wang
Lin, Ming-Hong
Ho, Chen-Jui
Lu, Yan-Ting
Weng, Ken-Pen
Lin, Yuyu
Lin, Pei-Hsien
Li, Sung-Chou
S100A6 Promotes B Lymphocyte Penetration Through the Blood–Brain Barrier in Autoimmune Encephalitis
title S100A6 Promotes B Lymphocyte Penetration Through the Blood–Brain Barrier in Autoimmune Encephalitis
title_full S100A6 Promotes B Lymphocyte Penetration Through the Blood–Brain Barrier in Autoimmune Encephalitis
title_fullStr S100A6 Promotes B Lymphocyte Penetration Through the Blood–Brain Barrier in Autoimmune Encephalitis
title_full_unstemmed S100A6 Promotes B Lymphocyte Penetration Through the Blood–Brain Barrier in Autoimmune Encephalitis
title_short S100A6 Promotes B Lymphocyte Penetration Through the Blood–Brain Barrier in Autoimmune Encephalitis
title_sort s100a6 promotes b lymphocyte penetration through the blood–brain barrier in autoimmune encephalitis
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901080/
https://www.ncbi.nlm.nih.gov/pubmed/31850060
http://dx.doi.org/10.3389/fgene.2019.01188
work_keys_str_mv AT tsaimenghan s100a6promotesblymphocytepenetrationthroughthebloodbrainbarrierinautoimmuneencephalitis
AT linchihhsiang s100a6promotesblymphocytepenetrationthroughthebloodbrainbarrierinautoimmuneencephalitis
AT tsaikuowang s100a6promotesblymphocytepenetrationthroughthebloodbrainbarrierinautoimmuneencephalitis
AT linminghong s100a6promotesblymphocytepenetrationthroughthebloodbrainbarrierinautoimmuneencephalitis
AT hochenjui s100a6promotesblymphocytepenetrationthroughthebloodbrainbarrierinautoimmuneencephalitis
AT luyanting s100a6promotesblymphocytepenetrationthroughthebloodbrainbarrierinautoimmuneencephalitis
AT wengkenpen s100a6promotesblymphocytepenetrationthroughthebloodbrainbarrierinautoimmuneencephalitis
AT linyuyu s100a6promotesblymphocytepenetrationthroughthebloodbrainbarrierinautoimmuneencephalitis
AT linpeihsien s100a6promotesblymphocytepenetrationthroughthebloodbrainbarrierinautoimmuneencephalitis
AT lisungchou s100a6promotesblymphocytepenetrationthroughthebloodbrainbarrierinautoimmuneencephalitis