Transcriptional dysregulation of Interferome in experimental and human Multiple Sclerosis

Abstract

Recent evidence indicates that single multiple sclerosis (MS) susceptibility genes involved in interferon (IFN) signaling display altered transcript levels in peripheral blood of untreated MS subjects, suggesting that responsiveness to endogenous IFN is dysregulated during neuroinflammation. To prove this hypothesis we exploited the systematic collection of IFN regulated genes (IRG) provided by the Interferome database and mapped Interferome changes in experimental and human MS. Indeed, central nervous system tissue and encephalitogenic CD4 T cells during experimental autoimmune encephalomyelitis were characterized by massive changes in Interferome transcription. Further, the analysis of almost 500 human blood transcriptomes showed that (i) several IRG changed expression at distinct MS stages with a core of 21 transcripts concordantly dysregulated in all MS forms compared with healthy subjects; (ii) 100 differentially expressed IRG were validated in independent case-control cohorts; and (iii) 53 out of 100 dysregulated IRG were targeted by IFN-beta treatment in vivo. Finally, ex vivo and in vitro experiments established that IFN-beta administration modulated expression of two IRG, ARRB1 and CHP1, in immune cells. Our study confirms the impairment of Interferome in experimental and human MS, and describes IRG signatures at distinct disease stages which can represent novel therapeutic targets in MS.

CHP1 reduction ameliorates spinal muscular atrophy pathology by restoring calcineurin activity and endocytosis

“…Since endocytosis defects and Ca 2+ misregulation have also been reported in Parkinson's disease, amyotrophic lateral sclerosis, and hereditary spastic paraplegias ( Schreij et al , 2016 ), CHP1 downregulation might be beneficial for the treatment of other neurodegenerative diseases. Strikingly, in multiple sclerosis patients, interferon-β treatment—a first line therapy for multiple sclerosis—was found to downregulate CHP1 mRNA expression ( Srinivasan et al , 2017 ), suggesting a beneficial effect of CHP1 reduction in multiple sclerosis too. Moreover, calcineurin-related pathways like NGF signalling are involved in neurodegeneration of Down syndrome ( Cooper et al , 2001 ).…”

Significant enrichment of Herpesvirus interactors in GWAS data suggests causal inferences for the association between Epstein Barr virus and multiple sclerosis

“…Human peripheral blood mononuclear cell (PBMC) microarray datasets analyzed in this study were published in Srinivasan et al, 2017a;Srinivasan et al, 2017b) and deposited at EBI Array express database. The dataset was generated by Illumina Human Ref-8 v2 microarrays and contained PBMC transcriptomes of persons with MS (46 with clinically isolated syndromes, 52 with relapsing-remitting, 23 with primary-progressive, 21 with secondary-progressive disease) and 40 healthy controls.…”

“…To investigate the functional consequences of these findings we matched the 741 MS-AIG with gene expression data obtained from the peripheral blood of healthy subjects and persons with different MS phenotypes, including clinically isolated syndrome (CIS), relapsing-remitting (RR), secondary progressive (SP) and primary progressive (PP) MS (Srinivasan et al, 2017b). We calculated whether the MS-AIG were significantly enriched in the lists of genes differentially expressed in each MS forms.…”

Loss of Circulating CD8+ CD161high T Cells in Primary Progressive Multiple Sclerosis

“…PBMC were isolated using a discontinuous density gradient (Lymphoprep, Nycomed, Oslo, Norway) as already described (3, 4, 11). Viable cells were counted by Trypan Blue (Sigma-Aldrich, Milan, Italy) exclusion.…”

“…This information may lay the basis for novel knowledge-driven therapeutic immune checkpoints for each MS stage. As a first step in this direction, we have investigated blood transcriptomics changes in MS and recently demonstrated that peripheral blood mononuclear cells (PBMC) carry important transcriptional information whose monitoring may indeed emphasize dysregulations in genes and pathways at specific stages of MS (3, 4). In this paper we focused our attention on transcript and protein levels of CD161, also called KLRB1, a C-type lectin expressed by NK cells as well as T lymphocytes.…”