Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Expression data of multiple sclerosis patients receiving Interferon-beta therapy

ABSTRACT: The purpose of this study was to characterize the transcriptional effects induced by subcutaneous IFN-beta-1b treatment (Betaferon, 250 µg every other day) in patients with relapsing-remitting form of multiple sclerosis (MS). By using Affymetrix DNA microarrays, we obtained genome-wide expression profiles of peripheral blood mononuclear cells from 25 MS patients within the first two years of IFN-beta administration. EDTA blood samples were drawn from all patients immediately before first, second, month 1, 12, and 24 IFN-beta injection. Total RNA of Ficoll-isolated peripheral blood mononuclear cells from each sample was extracted, labelled and hybridized to Affymetrix Human Genome U133 A and B arrays to quantify the mRNA levels.

ORGANISM(S): Homo sapiens

SUBMITTER: Robert Goertsches

PROVIDER: E-GEOD-24427 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Long-term genome-wide blood RNA expression profiles yield novel molecular response candidates for IFN-beta-1b treatment in relapsing remitting MS.

Goertsches Robert H RH Hecker Michael M Koczan Dirk D Serrano-Fernandez Pablo P Moeller Steffen S Thiesen Hans-Juergen HJ Zettl Uwe K UK

Pharmacogenomics 20100201 2

<h4>Aims</h4>In multiple sclerosis patients, treatment with recombinant IFN-beta (rIFN-beta) is partially efficient in reducing clinical exacerbations. However, its molecular mechanism of action is still under scrutiny.<h4>Materials & methods</h4>We used DNA microarrays (Affymetrix, CA, USA) and peripheral mononuclear blood cells from 25 relapsing remitting multiple sclerosis patients to analyze the longitudinal transcriptional profile within 2 years of rIFN-beta administration. Sets of differen ...[more]

PMID: 20136355

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Project description:Background: Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system and the leading cause of lasting neurological disabilities in young adults. Increasing evidence suggests that early treatment prevents the development of disability. However, there have been no reliable serum markers to assist the early diagnosis. In addition, interferon (IFN)-β, which is the major treatment for MS, is not always effective. Therefore, the development of simple serological test to help the early diagnosis and predict responsiveness to IFN-β is of clinical importance. On the other hand, a transmembrane-type semaphorin, Sema4A, has been implicated in experimental autoimmune encephalomyelitis (EAE) by regulating helper T (Th) cell differentiation. Thus, we aimed to identify the implications of Sema4A in diagnosis and pathogenesis of MS. Methods: We assayed serum Sema4A in 59 patients with relapsing-remitting MS (RRMS), 22 patients with clinically isolated syndrome (CIS) and 126 patients with other neurological diseases (OND) by developing a sandwich ELISA. To identify a source of soluble Sema4A and characteristics of MS patients with high levels of Sema4A, we analyzed peripheral blood mononuclear cells (PBMCs) from MS patients and healthy controls by flow cytometry (FACS) and gene chip analysis. The effect of Sema4A was examined in vitro and in vivo using an EAE model. Findings: Sema4A was significantly increased in sera of patients with MS and CIS compared to controls. Sema4A expression was increased on the surface of DCs in MS patients and shed from these cells in a metalloproteinase-dependent manner, affecting the Th17skewing. In addition, patients with high Sema4A levels exhibited more severe disabilities, and IFN-β treatment was not beneficial to those patients. Interpretation: Measuring Sema4A is a practical laboratory test to help diagnose MS and to predict responsiveness to IFN-β therapy. Microarray analysis showed that metalloproteinases such as ADAM 10 and MMPs 1, 3, 9, 12 and 25, which are reported to be involved in the pathogenesis of MS, were increased in PBMCs from MS patients with high Sema4A levels compared to those with low Sema4A and healthy controls. However, ADAM 17 and MMP 2 and 7 did not correlate with Sema4A levels. Taken together, these findings strongly suggest that Sema4A, abundantly expressed on monocytes and DCs in MS patients, is enzymatically cleaved and shed in a portion of the patients, which contributes to the high soluble Sema4A detected by the ELISA. Multiple sclerosis patients were classified according to Serum Sema4A levels. RNA from peripheral blood from 4 healthy controls, 3 MS patients with high serum Sema4A levels and 3 MS patients with low serum Sema4A levels was extracted and hybridized on Affymetrix microarrays. We sought to see whether there is corrlated genes with serum Sema4A levels or not, especially for genes for varions proteases.

Project description:Compared to primary human monocytes in whole blood cultures, few B cells activated STAT1 in response to stimulation of 2000 IU/ml IFN-beta for 45 minutes. Because activation of STAT1 leads to apoptosis induction, we tested the hypothesis that less pro-apoptotic genes are induced in B cells as compared to monocytes. Manuscript titled: Major differences in the responses of primary human leukocyte subsets to IFN-beta. Abstract: Treatment of cell lines with type I IFNs activates the formation of ISGF3 (STAT1/STAT2/ IRF9), which induces the expression of many genes. To study this response in primary cells, we treated fresh human blood with IFN-beta and used flow cytometry to analyze phosphorylated STATs1, 3 and 5 in CD4+ and CD8+ T cells, B cells, and monocytes. The activation of STAT1 was remarkably different among these leukocyte subsets. In contrast to monocytes, CD4+ and CD8+ T cells, few B cells activated STAT1 in response to IFN-beta, a finding that could not be explained by decreased levels of IFNAR2 or STAT1 or enhanced levels of SOCS1 or relevant protein tyrosine phosphatases in B cells. Micro-array and real-time PCR analyses revealed the induction of STAT1-dependent pro-apoptotic mRNAs in monocytes but not in B cells. These data show that ISGF3 or STAT1 homodimers are not the main activators of gene expression in primary B cells of healthy humans. Notably, in B cells and especially in CD4+ T cells, IFN-beta activated STAT5 in addition to STAT3, with biological effects often opposite from those driven by activated STAT1. These data help to explain why IFN-beta increases the survival of primary human B cells and CD4+ T cells, but enhances the apoptosis of monocytes, and also to understand how leukocyte subsets are differentially affected by endogenous type I IFNs during viral or bacterial infections, and by type I IFN treatment of patients with multiple sclerosis, hepatitis or cancer. Undiluted whole blood of 2 healthy individuals (HI) was used, and either stimulated with IFN-beta or left untreated (control) for 3 hrs. After 3 hrs, both B cells and monocytes were isolated from whole blood of the first healthy individual, and only B cells were isolated from whole blood of the second healthy individual.

Dataset Information

Expression data of multiple sclerosis patients receiving Interferon-beta therapy

Publications

Long-term genome-wide blood RNA expression profiles yield novel molecular response candidates for IFN-beta-1b treatment in relapsing remitting MS.

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