Gene Expression Changes in Multiple Sclerosis Relapse Suggest Activation of T and Non-T Cells

Lindsey, J. W.; Agarwal, Sandeep K.; Tan, Filemon K.

doi:10.2119/molmed.2010.00071

Cited by 14 publications

(9 citation statements)

References 32 publications

(41 reference statements)

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“…Speculatively, the activation of T cells could mirror the processes that occur in vivo in driving relapses, whereas the resting, unactivated cells would represent the steady-state condition during remission. Differences in gene expression during relapse and remission in peripheral immune cells have been found in patients with MS (Brynedal et al 2010, Lindsey et al 2011, although similar studies on isolated CD4 + T cells is, to our knowledge, missing. A network-based modular approach identifies cell activation and chemotaxis as central components in the dysregulated response to T cell activation in MS A network-based modular approach was used to search for functionally related genes among the DR genes to broaden the biological significance and find relevant functional modules that could disclose central processes involved in driving the differential responses in patients versus controls.…”

Section: Response To Tcr-mediated Stimulation In Patients With Msmentioning

confidence: 71%

Effects of Pregnancy and Hormones on T cell Immune Regulation in Multiple Sclerosis

Hellberg

2019

Linköping University Medical Dissertations

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Multiple sclerosis (MS) is characterized by a dysregulated immune system leading to chronic inflammation in the central nervous system. Despite increasing number of treatments, many patients continue to deteriorate. A better understanding of the underlying disease mechanisms involved in driving disease is a prerequisite for finding new biomarkers and new treatment targets. The improvement of MS during pregnancy, comparable to the beneficial effects of the most effective treatment, suggests that the transient and physiological immune tolerance established during pregnancy could serve as a model for successful immune regulation. Most likely the immune-endocrine alterations that take place during pregnancy to accommodate the presence of the semi-allogenic fetus contribute to the observed disease improvement. The aim of this thesis was to characterize the dysregulated immune system in MS and define potential factors and mechanisms established during pregnancy that could be involved in the pregnancy-induced effects in MS, focusing on CD4 + T cells as one of the main drivers in immunity and in the MS pathogenesis. Using a network-based modular approach based on gene expression profiling, we could show that CD4 + T cells from patients with MS displayed an altered dynamic gene response to activation, in line with a dysregulated immune system in MS. The resulting gene module disclosed cell activation and chemotaxis as central components in the deviating response, results that form a basis for further studies on its modulation during pregnancy. Moreover, a combination of secreted proteins (OPN+CXCL1-3+CXCL10-CCL2), identified from the module, could be used to separate patients and controls, predict disease activity after 2 years and discriminate between high and low responders to treatment, highlighting their potential use as biomarkers for predicting disease activity and response to treatment. The pregnancy hormone progesterone (P4), a potential factor involved in the pregnancy-induced amelioration of MS, was found to significantly dampen CD4 + T cell activation. Further detailed transcriptomic profiling revealed that P4 almost exclusively down-regulated immune-related pathways in activated T cells, several related to or downstream of T cell activation such as JAK-STAT signaling, T cell receptor signaling and cytokine-cytokine receptor interaction. In particular, P4 significantly affected genes of relevance to diseases known to be modulated during pregnancy, where genes associated to MS were most significantly affected, supporting a role for P4 in the pregnancy-induced immunomodulation. By using another approach, the role of thymus in T cell regulation during pregnancy was assessed. Two established measures of thymic output, CD31

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Section: Response To Tcr-mediated Stimulation In Patients With Msmentioning

confidence: 71%

Effects of Pregnancy and Hormones on T cell Immune Regulation in Multiple Sclerosis

Hellberg

2019

Linköping University Medical Dissertations

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“…The Agilent-039494 SurePrint G3 Human GE v2 8 × 60K Microarray platform was used and data preprocessing was performed by the Feature Extraction software version 10.7.3.1 (Agilent Technologies, Santa Clara, California, United States), using default parameters (protocol GE1-107_Sep09) [60]. Gene expression profiles of PBMCs of MS patients in stable and relapsing disease were obtained from the publicly available microarray dataset, GSE19224 [61]. The dataset included 14 patients with RR-MS [61].…”

Section: In Silico Analysis: Microarray Selectionmentioning

confidence: 99%

“…Gene expression profiles of PBMCs of MS patients in stable and relapsing disease were obtained from the publicly available microarray dataset, GSE19224 [61]. The dataset included 14 patients with RR-MS [61]. The relapse samples were obtained within the first week of clinical exacerbation and before initiation of corticosteroid treatment.…”

Section: In Silico Analysis: Microarray Selectionmentioning

confidence: 99%

“…The female/male ratio was 9:5. Six patients were on IFN-β treatment at both sampling times, two patients were on no disease-modifying treatment, four patients were receiving glatiramer acetate at both sampling times, and two patients were untreated at the time of relapse and on glatiramer when the stable samples were obtained [61]. The dataset was generated using Illumina HumanRef-8 v3.0 expression beadchip [61].…”

Section: In Silico Analysis: Microarray Selectionmentioning

confidence: 99%

“…Six patients were on IFN-β treatment at both sampling times, two patients were on no disease-modifying treatment, four patients were receiving glatiramer acetate at both sampling times, and two patients were untreated at the time of relapse and on glatiramer when the stable samples were obtained [61]. The dataset was generated using Illumina HumanRef-8 v3.0 expression beadchip [61]. To determine the expression levels of the genes of interest in peripheral CD4+ and C8+ T cells from monozygotic twins discordant for MS, we interrogated the GSE16461 dataset, originally published by [62].…”

Section: In Silico Analysis: Microarray Selectionmentioning

confidence: 99%

See 2 more Smart Citations

In Silico and In Vivo Analysis of IL37 in Multiple Sclerosis Reveals Its Probable Homeostatic Role on the Clinical Activity, Disability, and Treatment with Fingolimod

et al. 2019

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We evaluated the in silico expression and circulating levels of interleukin (IL)37 in patients with different forms of multiple sclerosis (MS) and also upon treatment with different disease-modifying drugs. The combined interpretation of the resulting data strengthens and extends the current emerging concept that endogenous IL37 plays an important role in determining onset and progression of MS. The in silico analysis revealed that production of IL37 from cluster of differentiation (CD)4+ T cells from MS patients was reduced in vitro as compared to healthy controls. The analysis of the datasets also demonstrated that "higher" levels of IL37 production from PBMC entailed significant protection from MS relapses. In addition, the in vivo part of the study showed that IL37 was selectively augmented in the sera of MS patients during a relapse and that treatment with the high potency disease-modifying drug fingolimod significantly increased the frequency of patients with circulating blood levels of IL37 (6/9, 66%) as compared to patients receiving no treatment (n = 48) or platform therapy (n = 59) who had levels of IL37 below the limit of the sensitivity of the assay. This finding therefore anticipates that fingolimod may at least partially exert its beneficial effects in MS by upregulating the production of IL37.

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Redox regulation of cellular stress response in multiple sclerosis

Pennisi

Cornelius

Cavallaro

et al. 2011

Biochemical Pharmacology

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Multiple sclerosis (MS) is an autoimmune-mediated neurodegenerative disease with characteristic foci of inflammatory demyelination in the brain, spinal cord, and optic nerves. Recent studies have demonstrated not only that axonal damage and neuronal loss are significant pathologic components of MS, but that this neuronal damage is thought to cause the permanent neurologic disability often seen in MS patients. Emerging finding suggests that altered redox homeostasis and increased oxidative stress, primarily implicated in the pathogenesis of MS, are a trigger for activation of a brain stress response. Relevant to maintenance of redox homeostasis, integrated mechanisms controlled by vitagenes operate in brain in preserving neuronal survival during stressful conditions. Vitagenes encode for heat shock proteins (Hsp) Hsp32, Hsp70, the thioredoxin and the sirtuin protein systems. In the present study we assess stress response mechanisms in the CSF, plasma and lymphocytes of control patients compared to MS patients. We found that the levels of vitagenes Hsp72, Hsc70, HO-1, as well as oxidative stress markers carbonyls and hydroxynonenals were significantly higher in the blood and CSF of MS patients than in control patients. In addition, an increased expression of Trx and sirtuin 1, together with a decrease in the expression of TrxR were observed. Our data strongly support a pivotal role for redox homeostasis disruption in the pathogenesis of MS and, consistently with the notion that new therapies that prevent neurodegeneration through nonimmunomodulatory mechanisms can have a tremendous potential to work synergistically with current MS therapies, unravel important targets for new cytoprotective strategies

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Gene Expression Changes in Multiple Sclerosis Relapse Suggest Activation of T and Non-T Cells

Cited by 14 publications

References 32 publications

Effects of Pregnancy and Hormones on T cell Immune Regulation in Multiple Sclerosis

Effects of Pregnancy and Hormones on T cell Immune Regulation in Multiple Sclerosis

In Silico and In Vivo Analysis of IL37 in Multiple Sclerosis Reveals Its Probable Homeostatic Role on the Clinical Activity, Disability, and Treatment with Fingolimod

Redox regulation of cellular stress response in multiple sclerosis

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