scholarly journals Dysregulation of MS risk genes and pathways at distinct stages of disease

2017 ◽  
Vol 4 (3) ◽  
pp. e337 ◽  
Author(s):  
Sundararajan Srinivasan ◽  
Marco Di Dario ◽  
Alessandra Russo ◽  
Ramesh Menon ◽  
Elena Brini ◽  
...  
Keyword(s):  
Gene Expression ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Gene List ◽  
Literature Mining ◽  
Specific Gene ◽  
Healthy Population ◽  
Gene Expressions ◽  
Altered Expression ◽  
Risk Genes

Objective:To perform systematic transcriptomic analysis of multiple sclerosis (MS) risk genes in peripheral blood mononuclear cells (PBMCs) of subjects with distinct MS stages and describe the pathways characterized by dysregulated gene expressions.Methods:We monitored gene expression levels in PBMCs from 3 independent cohorts for a total of 297 cases (including clinically isolated syndromes (CIS), relapsing-remitting MS, primary and secondary progressive MS) and 96 healthy controls by distinct microarray platforms and quantitative PCR. Differential expression and pathway analyses for distinct MS stages were defined and validated by literature mining.Results:Genes located in the vicinity of MS risk variants displayed altered expression in peripheral blood at distinct stages of MS compared with the healthy population. The frequency of dysregulation was significantly higher than expected in CIS and progressive forms of MS. Pathway analysis for each MS stage–specific gene list showed that dysregulated genes contributed to pathogenic processes with scientific evidence in MS.Conclusions:Systematic gene expression analysis in PBMCs highlighted selective dysregulation of MS susceptibility genes playing a role in novel and well-known pathogenic pathways.

scholarly journals Molecular Profiling of Glatiramer Acetate Early Treatment Effects in Multiple Sclerosis

2009 ◽  
Vol 27 (2) ◽  
pp. 63-73 ◽  
Author(s):  
Anat Achiron ◽  
Anna Feldman ◽  
Michael Gurevich
Keyword(s):  
Gene Expression ◽  
Multiple Sclerosis ◽  
Glatiramer Acetate ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Molecular Signature ◽  
Specific Gene ◽  
Altered Expression

Background: Glatiramer acetate (GA, Copaxone®) has beneficial effects on the clinical course of relapsing-remitting multiple sclerosis (RRMS). However, the exact molecular mechanisms of GA effects are only partially understood.Objective: To characterized GA molecular effects in RRMS patients within 3 months of treatment by microarray profiling of peripheral blood mononuclear cells (PBMC).Methods: Gene-expression profiles were determined in RRMS patients before and at 3 months after initiation of GA treatment using Affimetrix (U133A-2) microarrays containing 14,500 well-characterized human genes. Most informative genes (MIGs) of GA-induced biological convergent pathways operating in RRMS were constructed using gene functional annotation, enrichment analysis and pathway reconstruction bioinformatic softwares. Verification at the mRNA and protein level was performed by qRT-PCR and FACS.Results: GA induced a specific gene expression molecular signature that included altered expression of 480 genes within 3 months of treatment; 262 genes were up-regulated, and 218 genes were down-regulated. The main convergent mechanisms of GA effects were related to antigen-activated apoptosis, inflammation, adhesion, and MHC class-I antigen presentation.Conclusions: Our findings demonstrate that GA treatment induces alternations of immunomodulatory gene expression patterns that are important for suppression of disease activity already at three months of treatment and can be used as molecular markers of GA activity.

scholarly journals Expression of CYP24A1 and other multiple sclerosis risk genes in peripheral blood indicates response to vitamin D in homeostatic and inflammatory conditions

2021 ◽  
Author(s):  
Samantha P. L. Law ◽  
Prudence N. Gatt ◽  
Stephen D. Schibeci ◽  
Fiona C. McKay ◽  
Steve Vucic ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Vitamin D ◽  
Immune Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Immunological Response ◽  
Response To Treatment ◽  
Peripheral Blood Mononuclear ◽  
Risk Genes ◽  
Inflammatory Models

AbstractAlthough genetic and epidemiological evidence indicates vitamin D insufficiency contributes to multiple sclerosis (MS), and serum levels of vitamin D increase on treatment with cholecalciferol, recent metanalyses indicate that this vitamin D form does not ameliorate disease. Genetic variation in genes regulating vitamin D, and regulated by vitamin D, affect MS risk. We evaluated if the expression of vitamin D responsive MS risk genes could be used to assess vitamin D response in immune cells. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy controls and people with MS treated with dimethyl fumarate. We assayed changes in expression of vitamin D responsive MS risk (VDRMS) genes in response to treatment with 25 hydroxy vitamin D in the presence or absence of inflammatory stimuli. Expression of CYP24A1 and other VDRMS genes was significantly altered in PBMCs treated with vitamin D in the homeostatic and inflammatory models. Gene expression in MS samples had similar responses to controls, but lower initial expression of the risk genes. Vitamin D treatment abrogated these differences. Expression of CYP24A1 and other MS risk genes in blood immune cells indicate vitamin D response and could enable assessment of immunological response to vitamin D in clinical trials and on therapy.

scholarly journals Peripheral Blood Gene Expression and IgG Glycosylation Profiles as Markers of Tocilizumab Treatment in Rheumatoid Arthritis

2012 ◽  
Vol 39 (5) ◽  
pp. 916-928 ◽  
Author(s):  
BERTALAN MESKO ◽  
SZILARD POLISKA ◽  
SZILVIA SZAMOSI ◽  
ZOLTAN SZEKANECZ ◽  
JANOS PODANI ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Peripheral Blood ◽  
Multiple Testing ◽  
Mononuclear Cells ◽  
Expression Profiles ◽  
Quantitative Polymerase Chain Reaction ◽  
Response To Treatment ◽  
Peripheral Blood Mononuclear ◽  
Gene Sets

Objective.Tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, has recently been approved as a biological therapy for rheumatoid arthritis (RA) and other diseases. It is not known if there are characteristic changes in gene expression and immunoglobulin G glycosylation during therapy or in response to treatment.Methods.Global gene expression profiles from peripheral blood mononuclear cells of 13 patients with RA and active disease at Week 0 (baseline) and Week 4 following treatment were obtained together with clinical measures, serum cytokine levels using ELISA, and the degree of galactosylation of the IgG N-glycan chains. Gene sets separating responders and nonresponders were tested using canonical variates analysis. This approach also revealed important gene groups and pathways that differentiate responders from nonresponders.Results.Fifty-nine genes showed significant differences between baseline and Week 4 and thus correlated with treatment. Significantly, 4 genes determined responders after correction for multiple testing. Ten of the 12 genes with the most significant changes were validated using real-time quantitative polymerase chain reaction. An increase in the terminal galactose content of N-linked glycans of IgG was observed in responders versus nonresponders, as well as in treated samples versus samples obtained at baseline.Conclusion.As a preliminary report, gene expression changes as a result of tocilizumab therapy in RA were examined, and gene sets discriminating between responders and nonresponders were found and validated. A significant increase in the degree of galactosylation of IgG N-glycans in patients with RA treated with tocilizumab was documented.

Abstract 3259: Leukocyte Subset Specific Gene Expression In Acute Stroke Patients

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Mateusz G Adamski ◽  
Yan Li ◽  
Hua Yu ◽  
Erin Wagner ◽  
Sareen Amarjeet ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Stroke ◽  
Whole Blood ◽  
Peripheral Blood ◽  
Fold Increase ◽  
Specific Gene ◽  
Related Gene ◽  
Stroke Patients ◽  
Leukocyte Subset ◽  
Control Subjects

Background: Alterations in gene expression in the peripheral blood of patients with acute stroke have been demonstrated using microarray technology. Whole blood and peripheral blood mononuclear cells (PBMCs) were used in prior studies in which panels of genes diagnostic for stroke were developed. We aimed to determine the cellular sources of alterations in gene expression by studying individual leukocyte subsets. Methods: The expression of four genes previously found to be upregulated in ischemic and hemorrhagic stroke (IL1R2, S100A9, ETS2 and F5) was measured in four leukocyte subsets: CD14+ monocytes, CD4+ T cell lymphocytes, CD20+ B cell lymphocytes and PBMCs. These four genes had been reported in at least two of the previously published stroke-related gene panels. Peripheral blood was obtained from six acute stroke patients (all <48 hours from symptom onset) and 6 age, race and sex matched control subjects. Leukocytes were separated from whole blood using density gradient centrifugation and column magnetic bead cell sorting. The purity of separated leukocyte subsets exceeded 90% and was verified with flow cytometry. Messenger RNA was isolated from each leukocyte subset and analyzed by two step RT PCR and qPCR. The expression of the four stroke-related genes was compared to the expression of a housekeeping gene (GAPDH). The relative expression of individual genes and of the 4 gene panel within cellular subsets was compared between stroke patients and control subjects. Results: Individually, IL1R2 and S100A9 were significantly over-expressed in stroke patients with a 10 fold increase for IL1R2 in PBMCs (p<0.05) and a 3 fold increase for S100A9 in the CD4+ T and CD20+ B lymphocyte subsets (p<0.05). When analyzed as a panel of four genes the expression of IL1R2, S100A9, ETS2 and F5 was significantly higher in both the CD4+ T lymphocytes (p<0.05) and CD20+ B lymphocytes (p<0.05) of stroke patients but not in the monocytes or the PBMCs. Conclusion: These results show the potential diagnostic value of selected genes from panels previously found in microarray studies in stroke patients. They also emphasize the value of panel analysis over that of single gene expression and the potential cellular specificity of alterations in gene expression. Analysis of whole blood and PBMCs alone may not reflect important dynamic changes in stroke-related gene expression.

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