Integrative analysis of Multiple Sclerosis using a systems biology approach

Cervantes-Gracia, Karla; Husi, Holger

doi:10.1038/s41598-018-24032-8

Cited by 31 publications

(20 citation statements)

References 47 publications

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“…Given the association of IL‐3 and IFN levels in the serum, a possible association at the transcriptional level in whole blood cells was explored. An ‘IFN gene signature’ ( EPST11, ISG15, HERC5, IFI44, OAS3, OAS1, LY6E, CMPK2, RSAD2, IFI44L, IFIT1, IFIT3, USP18, SIGLEC1, IFI27, OTOF ) that differentiated most SLE from most healthy donors was determined by hierarchical clustering and pathway analysis of the 500 most variably expressed genes in SLE donors (Figure a), that is those genes that were most differentially expressed in SLE patients compared to healthy donors and were known interferon‐inducible genes per the Interferome database …”

Section: Resultsmentioning

confidence: 99%

A potential association between IL‐3 and type I and III interferons in systemic lupus erythematosus

Oon

Monaghan

et al. 2019

Clin & Trans Imm

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ObjectivesPlasmacytoid dendritic cells (pDCs), through the production of type 1 interferons (IFNs) and other cytokines, are major contributors to systemic lupus erythematosus (SLE) pathogenesis. IL‐3 promotes pDC survival, but its role in SLE is not well characterised. This study investigated serum IL‐3 and IFN levels, and a whole blood ‘IL‐3 gene signature’, in human SLE.MethodsSerum cytokine levels were measured by ELISA in n = 42 SLE patients, and n = 44 healthy donors. IL‐3‐regulated genes were determined by RNASeq of healthy donor whole blood cells (WBCs) stimulated in vitro with IL‐3 for 6 or 24 h. Whole blood cell RNASeq analysis was undertaken in a separate cohort of n = 31 SLE patients, and n = 28 healthy donors.ResultsSerum IL‐3 levels correlated with IFNα (r = 0.612, 95% CI 0.455–0.733, P < 0.001) and type III IFN (r = 0.585, 95% CI 0.406–0.720, P < 0.0001). IL‐3 stimulation of WBC in vitro altered 794 genes (−1 ≥ logFC ≥ 1, FDR < 0.05), of which 35 overlapped with genes differentially expressed between SLE and healthy donors. These 35 genes were expressed in 27/31 SLE donors, revealing the presence of an ‘IL‐3 gene signature’. There was strong correlation between the IL‐3 signature and an IFN signature, as determined by hierarchical clustering of the 500 most variable genes in SLE donors (r = 0.939, 95% CI 0.898–0.964, P < 0.0001).ConclusionA dual IL‐3/IFN gene signature is a feature of SLE. An association between IL‐3 and IFN raises the possibility that dual blockade of IL‐3 and IFN may be especially useful for SLE patients with this dual cytokine gene signature.

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Section: Resultsmentioning

confidence: 99%

A potential association between IL‐3 and type I and III interferons in systemic lupus erythematosus

Oon

Monaghan

et al. 2019

Clin & Trans Imm

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“…In the top-list of genes with increased expression are several proteins that have shown to play a role in activation of the immune response in MS like EPSTI1 and IFI6. 17,18 In the top-list of genes with reduced expression RPS6KA3 is of interest, as this gene has been shown to be downregulated in blood from MS patients in remission. 19 This study has several drawbacks.…”

Section: Discussionmentioning

confidence: 99%

Blood platelet RNA enables the detection of multiple sclerosis

Sol

Leurs

Veld

et al. 2020

Multiple Sclerosis Journal - Experimental, Translational and Cl

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Background In multiple sclerosis (MS), clinical assessment, MRI and cerebrospinal fluid are important in the diagnostic process. However, no blood biomarker has been confirmed as a useful tool in the diagnostic work-up. Objectives Blood platelets contain a rich spliced mRNA repertoire that can alter during megakaryocyte development but also during platelet formation and platelet circulation. In this proof of concept study, we evaluate the diagnostic potential of spliced blood platelet RNA for the detection of MS. Methods We isolated and sequenced platelet RNA of blood samples obtained from 57 MS patients and 66 age- and gender-matched healthy controls (HCs). 60% was used to develop a particle swarm-optimized (PSO) support vector machine classification algorithm. The remaining 40% served as an independent validation series. Results In total, 1249 RNAs with differential spliced junction expression levels were identified between platelets of MS patients as compared to HCs, including EPSTI1, IFI6, and RPS6KA3, in line with reported inflammatory signatures in the blood of MS patients. The RNAs were subsequently used as input for a MS classifier, capable of detecting MS with 80% accuracy in the independent validation series. Conclusions Spliced platelet RNA may enable the blood-based diagnosis of MS, warranting large-scale validation.

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“…A recent study attempted to concatenate all of the GWAS data and has produced two more restricted gene lists for pwMS versus control and pwMS undergoing treatment. This study identified interferon-gamma signalling as the major pathway involved 47 . Importantly, the multiple genes associated with B-cell function/dysfunction and EBV support a role in MS pathology.…”

Section: Identifying the Genes And Proteins Key To Multiple Sclerosismentioning

confidence: 90%

Emerging small-molecule treatments for multiple sclerosis: focus on B cells

et al. 2019

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Multiple sclerosis (MS) is a major cause of disability in young adults. Following an unknown trigger (or triggers), the immune system attacks the myelin sheath surrounding axons, leading to progressive nerve cell death. Antibodies and small-molecule drugs directed against B cells have demonstrated good efficacy in slowing progression of the disease. This review focusses on small-molecule drugs that can affect B-cell biology and may have utility in disease management. The risk genes for MS are examined from the drug target perspective. Existing small-molecule therapies for MS with B-cell actions together with new drugs in development are described. The potential for experimental molecules with B-cell effects is also considered. Small molecules can have diverse actions on B cells and be cytotoxic, anti-inflammatory and anti-viral. The current B cell–directed therapies often kill B-cell subsets, which can be effective but lead to side effects and toxicity. A deeper understanding of B-cell biology and the effect on MS disease should lead to new drugs with better selectivity, efficacy, and an improved safety profile. Small-molecule drugs, once the patent term has expired, provide a uniquely sustainable form of healthcare.

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Integrative analysis of Multiple Sclerosis using a systems biology approach

Cited by 31 publications

References 47 publications

A potential association between IL‐3 and type I and III interferons in systemic lupus erythematosus

A potential association between IL‐3 and type I and III interferons in systemic lupus erythematosus

Blood platelet RNA enables the detection of multiple sclerosis

Emerging small-molecule treatments for multiple sclerosis: focus on B cells

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