Using biomarkers to predict progression from clinically isolated syndrome to multiple sclerosis

Tossberg, John T.; Crooke, Philip S.; Henderson, Melodie A.; Subramaniam, Sriram; Mrelashvili, Davit; Vosslamber, Saskia; Verweij, C. L.; Olsen, Nancy J.; Aune, Thomas M.

doi:10.1186/2043-9113-3-18

Cited by 9 publications

(9 citation statements)

References 20 publications

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“…We annotated both mRNAs and lncRNAs using respective references from gencode.v17 40 , 41 . To assess quantitative accuracy of our RNA-seq analysis, we compared expression levels from one individual of 34 protein-coding genes determined by RNA-seq and by quantitative RT-PCR 42 . We found that quantitative transcript determinations were highly correlated across this gene set that exhibited a wide expression range (>10 4 ) ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Expression and functions of long noncoding RNAs during human T helper cell differentiation

et al. 2015

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Long noncoding RNAs (lncRNAs) regulate an array of biological processes in cells and organ systems. Less is known about their expression and function in lymphocyte lineages. Here we have identified >2000 lncRNAs expressed in human T cell cultures and those which display a TH lineage specific pattern of expression and are intragenic or adjacent to TH lineage specific genes encoding proteins with immunologic functions. One lncRNA cluster selectively expressed by the effector TH2 lineage consists of four alternatively spliced transcripts that regulate expression of TH2 cytokines, IL-4, IL-5 and IL-13. Genes encoding this lncRNA cluster in humans overlap the RAD50 gene and thus are contiguous with the previously described TH2 locus control region (LCR) in the mouse. Given its genomic synteny with the TH2 LCR, we refer to this lncRNA cluster as TH2-LCR lncRNA.

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Section: Resultsmentioning

confidence: 99%

Expression and functions of long noncoding RNAs during human T helper cell differentiation

et al. 2015

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“…mRNA studies on the expression of immune and cytokine genes were performed from stored blood obtained from the Accelerated Cure Project (http://www.acceleratedcure.org/about) or the MS center at Vanderbilt and stored in PAX gene tubes. The details of these samples have been reported previously 8, 9, 29 . Flow cytometric assays were performed on freshly isolated peripheral blood mononuclear and serological assays on CSF and serum samples were obtained from stored samples obtained from the MS clinic.…”

Section: Methodsmentioning

confidence: 99%

“…These studies were based on our early studies examining the gene expression profiles of MS patients which showed an increased expression of genes which participate in the innate immune response and the more recent studies showing the expression of IL-33 to be increased in MS 5–9 .…”

Section: Introductionmentioning

confidence: 99%

Expression of IL‐33 and its epigenetic regulation in multiple sclerosis

Zhang

Tossberg

Spurlock

et al. 2014

Ann Clin Transl Neurol

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We examined the expression of IL-33 as an indicator of an innate immune response in relapsing remitting MS (RRMS) and controls. Based on our previous studies we proposed a link between the expression of IL-33 and IL-33 regulated genes to histone deacetylase (HDAC) activity and in particular HDAC3, an enzyme that plays a role in the epigenetic regulation of a number of genes including those which regulate inflammation. Our studies showed that intracellular expressions of IL-33 and IL-33 regulated genes are increased in patients with RRMS. In addition, following in vitro culture with TLR agonist lipopolysaccharide (LPS), there is increased induction of both IL-33 and HDAC3 in RRMS patients over that seen in controls. Also, culture of PBMC with IL-33 led to the expression of genes which overlapped with that seen in RRMS patients suggesting that the gene expression signature seen in RRMS may be driven by innate immune pathways. Expression of levels of IL-33 but not IL-1β (another gene regulated by TLR agonists) is completely inhibited by Trichostatin A (TSA) establishing a closer regulation of IL-33 but not IL-1β with HDAC. These results demonstrate the over expression of innate immune genes in RRMS and offer a causal link between the epigenetic regulation by HDAC and the induction of IL-33.

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“…RA, inflammatory bowel diseases, multiple sclerosis, etc. (12–15). To this end, we analyzed >1,500 CTRLs, subjects with different autoimmune diseases, and subjects with chronic non-inflammatory diseases (disease controls).…”

Section: Resultsmentioning

confidence: 99%

Cutting Edge: Chronic NF-κB Activation in CD4+ T Cells in Rheumatoid Arthritis Is Genetically Determined by HLA Risk Alleles

Spurlock

Tossberg

Olsen

et al. 2015

The Journal of Immunology

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Of identified genetic variants, HLA polymorphisms confer the greatest risk for developing autoimmune diseases, including rheumatoid arthritis (HLA-DRB1*04). There are strong influences of HLA polymorphisms on cell-type specific gene expression in B cells and monocytes. Their influence on gene expression in CD4+ T cells is not known. We determined transcript and proteins levels of target genes in lymphocyte/monocyte subsets in healthy controls and RA subjects as a function of HLA-DRB1*04 haplotype. We identified gene expression dependent upon HLA-DRB1*04 genotype in CD4+ T cells. NF-κB activity in CD4+ T cells was also dependent upon HLA-DRB1*04 genotype and blocking HLA-DR inhibited NF-κB activity in CD4+ T cells and normalized gene expression as did pharmacologic inhibition of NF-κB. We conclude that interactions between TCR and MHC class II encoded by HLA-DRB1*04 create a pro-inflammatory ‘hum’ altering CD4+ T cell phenotype.

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Using biomarkers to predict progression from clinically isolated syndrome to multiple sclerosis

Cited by 9 publications

References 20 publications

Expression and functions of long noncoding RNAs during human T helper cell differentiation

Expression and functions of long noncoding RNAs during human T helper cell differentiation

Expression of IL‐33 and its epigenetic regulation in multiple sclerosis

Cutting Edge: Chronic NF-κB Activation in CD4+ T Cells in Rheumatoid Arthritis Is Genetically Determined by HLA Risk Alleles

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