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

Abstract

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.

The Calcium Binding Protein S100A11 and Its Roles in Diseases

“…In another severe neurological disease, autoimmune encephalitis, S100A11 was also found to be up-regulated and hypomethylated. Along with S100A6, in this state specific S100 family members may facilitate B lymphocyte infiltration into the central nervous system through the blood-brain barrier (Tsai et al, 2019). However, it has been suggested that S100A11 does not always play a role in pathogenicity.…”

Eye-color and Type-2 diabetes phenotype prediction from genotype data using deep learning methods

“…Some models use gradient descent procedures and parameter estimation iterative rounds to look for optimal predictive power across the training data space. Machine learning algorithms use multivariate, non-parametric methods that identify patterns from data that are not normally distributed and highly correlated [ 13 , 14 ].…”

DNA Methylation in LIME1 and SPTBN2 Genes Is Associated with Attention Deficit in Children

“…Figure 1 b demonstrated that the most significant CpG dinucleotides were hypo-methylated in disease samples and such result was pretty similar to previous studies. In inflammation-related diseases, such as Kawasaki disease [ 38 ] or autoimmune encephalitis [ 32 ], significant CpG dinucleotides tend to be hypo-methylated in disease samples. Figure 1 b also illustrated that one control sample was clustered into the disease set which was consistent with the result of the PCA plot.…”

“…The generated raw M850K data were first processed with GenomeStudio (Illumina, CA, USA) with the default parameters as suggested by a previous study [ 32 ]. Then, the GenomeStudio output data were subsequently analyzed with Partek Genomics Suite (Qiagen, CA, USA).…”