Global transcriptome profiling of blood mononuclear cells from individuals with radiologically isolated syndrome reveals abnormalities characteristic of the rapid manifestation of multiple sclerosis symptoms

Abstract

Objective: to look for differences in the transcriptome profiles in mononuclear blood cells of a group of patients with radiologically isolated syndrome (RIS) who developed symptoms of multiple sclerosis (MS) in the following three years of observation and a group of patients with RIS who did not develop MS during this period.Material and methods. The study included 19 patients with RIS (9 men and 10 women), six of whom developed symptoms of MS during the three-year follow-up period. The transcription profiles of blood mononuclear cells were compared between the groups of patients with RIS who developed or did not develop MS symptoms during this period. The work was conducted in the format of a prospective study; the time of blood collection was taken as the reference point. Full transcriptome profiling was performed using RNA sequencing on an MGISEQ-200 platform. Differential gene expression analysis was performed using the DESeq2 package for the R programming language. Subsequent analysis involved constructing a network of interactions between the protein products of the detected differentially expressed genes based on data from the STRING database, identifying a cluster of interacting proteins, and analyzing the enrichment of this cluster by participants in pathways annotated in the KEGG database.Results. The expression of 146 genes differed significantly (p<0.05; |log2FC| >1) in the studied groups of patients with RIS: in patients with subsequent manifestation of MS symptoms, the expression of 67 genes was lower and expression of 79 genes was higher than in patients without MS symptoms. The decrease in expression of two of the 67 genes (ADGRG7 and LGALS9C) remained significant even after correction for multiple comparisons (padj=2.17⋅10-11 and padj=6.19⋅10-6, respectively). Analyzing the network of interactions between the protein products of the differentially expressed genes allowed the identification of a cluster of 12 genes: APBB2, CCL4, CCL4L2, CDH2, DAZL, FOSB, H2BC17, JUN, KLF4, KLF5, MAPK8IP1, SYCE1; it is over-represented by components of the Toll-like receptor signaling pathway.Conclusion. The transcriptome profiles of blood mononuclear cells differ in groups of patients with RIS who did or did not develop MS symptoms during the three-year follow-up period. The decrease in the expression level of ADGRG7 and LGALS9C genes detected in this study as a sign of rapid conversion of RIS to MS needs to be confirmed in independent samples.

Keywords

• radiologically isolated syndrome
• multiple sclerosis
• rna sequencing
• transcriptome
• peripheral blood mononuclear cells
• pathway analysis