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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Genet. | doi: 10.3389/fgene.2019.01188

S100A6 promotes B lymphocytes penetration through blood-brain barrier in autoimmune encephalitis

 Meng-Han Tsai1,  Chih-Hsiang Lin1, Ming-Hong Lin2,  Chen-Jui Ho1, Yan-Ting Lu1, Yuyu Lin1, Pei-Hsien Lin1 and  Sung-Chou Li1*
  • 1Kaohsiung Chang Gung Memorial Hospital, Taiwan
  • 2Kaohsiung Medical University, Taiwan

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 (HC) and five AE subjects, collecting their serum and/or total white blood cell (WBC) samples. The WBC 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 (LTEM) 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 LTEM 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.

Keywords: autoimmune encephalitis, DNA Methylation, leukocyte trans-endothelial migration, B cell infiltration, Blood-Brain Barrier, S100A6

Received: 30 May 2019; Accepted: 28 Oct 2019.

Copyright: © 2019 Tsai, Lin, Lin, Ho, Lu, Lin, Lin and Li. 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.

* Correspondence: Mx. Sung-Chou Li, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 833, Taiwan, raymond.pinus@gmail.com