Expression profiling identifies responder and non‐responder phenotypes to interferon‐β in multiple sclerosis

Stürzebecher, S; Wandinger, Klaus‐Peter; Rosenwald, Andreas; Sathyamoorthy, Mohan; Tzou, Abraham; Mattar, Pierre; Frank, Joseph A.; Staudt, Louis M.; Martin, Roland; McFarland, Henry F.

doi:10.1093/brain/awg147

Cited by 168 publications

(100 citation statements)

References 32 publications

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“…An interesting conclusion held by the author is the exclusion of the hypothesis that interferon β treatment in MS actually shifts immunity from a Th1 to Th2 shift. This is in concordance with the work of Wandinger (Wandinger et al, 2001 andSturzebecher et al, 2003). Sturzebecher investigated the gene expression profile of PBMCs ex vivo and in vitro from 10 RRMS patients with interferon therapy.…”

Section: Major Peripheral Blood Mononuclear Cell Gene Expression Micrsupporting

confidence: 83%

Gene Expression Pattern Characterises Development of Multiple Sclerosis

Tajouri¹,

Brenu²,

Ashton³

et al. 2013

Genes and Autoimmunity - Intracellular Signaling and Microbiome Contribution

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Section: Major Peripheral Blood Mononuclear Cell Gene Expression Micrsupporting

confidence: 83%

Gene Expression Pattern Characterises Development of Multiple Sclerosis

Tajouri¹,

Brenu²,

Ashton³

et al. 2013

Genes and Autoimmunity - Intracellular Signaling and Microbiome Contribution

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“…Our study has detected a significant inhibition of IL-17C expression, which was recently reported to induce STAT3 expression, and in cooperation with RORgt and RORa induces Th17 cell differentiation and enhances EAE disease activity (37). Multiple studies have reported on the IFN-b treatment-induced gene expression changes in RRMS patients (38)(39)(40), however our study reports on the Th17 gene expression changes in CIS patients following IFN-b-1a therapy. The findings are consistent with the results of Durelli et al (11), who reported that Th17 cells have a higher IFNAR1 expression than Th1 cells and are selectively susceptible to inhibition by IFN-b-1a.…”

Section: Ifn-b-1a Treatment Of Rrms Patients Induced Ifnar1 Signalingmentioning

confidence: 50%

The Role of Endogenous IFN-β in the Regulation of Th17 Responses in Patients with Relapsing-Remitting Multiple Sclerosis

Tao

Zhang

Chopra

et al. 2014

The Journal of Immunology

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IFN-β has been used as a first-line therapy for relapsing-remitting multiple sclerosis (RRMS). Because only a few studies have addressed the role of endogenous IFN-β in the pathogenesis of the disease, our objective was to characterize its role in the transcriptional regulation of pathogenic Th17 cytokines in patients with RRMS. In vitro studies have demonstrated that IFN-β inhibits IL-17A, IL-17F, IL-21, IL-22, and IFN-γ secretion in CD4+ lymphocytes through the induction of suppressor of cytokine secretion 1 and suppressor of cytokine secretion 3. We found that patients with RRMS have increased serum and cerebrospinal fluid Th17 (IL-17A and IL-17F) cytokine levels in comparison with the control subjects, suggesting that deficient endogenous IFN-β secretion or signaling can contribute to the dysregulation of those pathogenic cytokines in CD4+ cells. We identified that the endogenous IFN-β from serum of RRMS patients induced a significantly lower IFN-inducible gene expression in comparison with healthy controls. In addition, in vitro studies have revealed deficient endogenous and exogenous IFN-β signaling in the CD4+ cells derived from patients with MS. Interestingly, upon inhibition of the endogenous IFN-β signaling by silencing IFN regulatory factor (IRF) 7 gene expression, the resting CD4+ T cells secreted significantly higher level of IL-17A, IL-17F, IL-21, IL-22, and IL-9, suggesting that endogenous IFN-β suppresses the secretion of these pathogenic cytokines. In vivo recombinant IFN-β–1a treatment induced IFNAR1 and its downstream signaling molecules’ gene expression, suggesting that treatment reconstitutes a deficient endogenous IFN-β regulation of the CD4+ T cells’ pathogenic cytokine production in patients with MS.

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“…40,41 As anticipated, the one patient receiving IFN-b therapy clustered together with the RRMS high patients and showed an upregulation of IFN-induced genes. Although transcription-based prediction of IFN-b therapy has been studied, 42,43 future research in a large cohort of patients is needed to sort out whether the absence or presence of a type-I IFN response in the PB of patients with RRMS is a prognostic factor for successful treatment with IFN-b.…”

Section: Discussionmentioning

confidence: 99%

A subtype of multiple sclerosis defined by an activated immune defense program

et al. 2006

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Given the heterogeneous nature of multiple sclerosis (MS), we applied DNA microarray technology to determine whether variability is reflected in peripheral blood (PB) cells. In this study, we studied whole-blood gene expression profiles of 29 patients with relapsing-remitting MS (RRMS) and 25 age-and sex-matched healthy controls. We used microarrays with a complexity of 43K cDNAs. The data were analyzed using sophisticated pathway-level analysis in order to provide insight into the deregulated peripheral immune response programs in MS. We found a remarkable elevated expression of a spectrum of genes known to be involved in immune defense in the PB of MS patients compared to healthy individuals. Cluster analysis revealed that the increased expression of these genes was characteristic for approximately half of the patients. In addition, the gene signature in this group of patients was comparable with a virus response program. We conclude that the transcriptional signature of the PB cells reflects the heterogeneity of MS and defines a sub-population of RRMS patients, who exhibit an activated immune defense program that resembles a virus response program, which is supportive for a link between viruses and MS.

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Expression profiling identifies responder and non‐responder phenotypes to interferon‐β in multiple sclerosis

Cited by 168 publications

References 32 publications

Gene Expression Pattern Characterises Development of Multiple Sclerosis

Gene Expression Pattern Characterises Development of Multiple Sclerosis

The Role of Endogenous IFN-β in the Regulation of Th17 Responses in Patients with Relapsing-Remitting Multiple Sclerosis

A subtype of multiple sclerosis defined by an activated immune defense program

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