Multiple sclerosis treatment effects on plasma cytokine receptor levels

Bedri, Sahl Khalid; Fink, Katharina; Manouchehrinia, Ali; Lundström, Wangko; Kockum, Ingrid; Olsson, Tomas; Hillert, Jan; Glaser, Anna

doi:10.1016/j.clim.2017.08.023

Cited by 7 publications

(6 citation statements)

References 53 publications

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“…Intrinsically, findings from our study and the study by Bedri et al. ( 58 ) are compatible with the trans-signaling model of higher protection against MS risk through increased sgp130-mediated downregulation of IL-6/sIL6R-dependent pro-inflammatory activities and highlight these MS risk SNPs as potential determinants of circulating sgp130. However, this pattern is incongruent with the rs7731626 genotype effect on sgp130 mRNA levels in CD4 + T lymphocytes ( Supplementary Figure S3 ), which shows a pattern in homozygotes that is opposed to that of serum sgp130 levels ( Figure 8D ).…”

Section: Discussionsupporting

confidence: 92%

“…In CD4 + T cells of HC, MS risk alleles when compared to protective alleles are associated with higher sgp130 isoform mRNA levels, while in moDC, they are associated with lower levels. Serum levels of sgp130 were higher in MS patients, homozygote of the protective allele of MS risk SNPs, reaching significance for rs7731626 ( Figure 8D ), and this is concordant with a recent publication showing significantly increased serum sgp130 levels in MS carriers of the protective allele of the correlated MS risk SNP rs71624119 ( 58 ; Figure 1 ). In the latter study, during fingolimod treatment, serum levels of sgp130 increased in all patients but to a higher degree in patients who are homozygous for the risk allele ( 58 ).…”

Section: Discussionsupporting

confidence: 90%

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Genomic Multiple Sclerosis Risk Variants Modulate the Expression of the ANKRD55–IL6ST Gene Region in Immature Dendritic Cells

et al. 2022

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Intronic single-nucleotide polymorphisms (SNPs) in the ANKRD55 gene are associated with the risk for multiple sclerosis (MS) and rheumatoid arthritis by genome-wide association studies (GWAS). The risk alleles have been linked to higher expression levels of ANKRD55 and the neighboring IL6ST (gp130) gene in CD4+ T lymphocytes of healthy controls. The biological function of ANKRD55, its role in the immune system, and cellular sources of expression other than lymphocytes remain uncharacterized. Here, we show that monocytes gain capacity to express ANKRD55 during differentiation in immature monocyte-derived dendritic cells (moDCs) in the presence of interleukin (IL)-4/granulocyte-macrophage colony-stimulating factor (GM-CSF). ANKRD55 expression levels are further enhanced by retinoic acid agonist AM580 but downregulated following maturation with interferon (IFN)-γ and lipopolysaccharide (LPS). ANKRD55 was detected in the nucleus of moDC in nuclear speckles. We also analyzed the adjacent IL6ST, IL31RA, and SLC38A9 genes. Of note, in healthy controls, MS risk SNP genotype influenced ANKRD55 and IL6ST expression in immature moDC in opposite directions to that in CD4+ T cells. This effect was stronger for a partially correlated SNP, rs13186299, that is located, similar to the main MS risk SNPs, in an ANKRD55 intron. Upon analysis in MS patients, the main GWAS MS risk SNP rs7731626 was associated with ANKRD55 expression levels in CD4+ T cells. MoDC-specific ANKRD55 and IL6ST mRNA levels showed significant differences according to the clinical form of the disease, but, in contrast to healthy controls, were not influenced by genotype. We also measured serum sgp130 levels, which were found to be higher in homozygotes of the protective allele of rs7731626. Our study characterizes ANKRD55 expression in moDC and indicates monocyte-to-dendritic cell (Mo–DC) differentiation as a process potentially influenced by MS risk SNPs.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 90%

Genomic Multiple Sclerosis Risk Variants Modulate the Expression of the ANKRD55–IL6ST Gene Region in Immature Dendritic Cells

et al. 2022

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“…The interleukin-2 receptor α-subunit (IL-2RA) has generated great interest since polymorphisms of this gene have been associated with the risk of developing MS ( 65 ) and due to the recent approval of daclizumab, a humanized IgG1 monoclonal antibody directed against the alpha subunit of the high-affinity IL-2 receptor, which has demonstrated high efficacy in the control of MS activity ( 66 ). Fingolimod treatment decreases soluble IL-2RA plasma levels ( 67 ). In accordance with those results, we detected a decrease in IL-2-producing cells and a downregulation of the IL-2RA gene in PBMCs of treated MS patients.…”

Section: Discussionmentioning

confidence: 99%

Immunophenotype and Transcriptome Profile of Patients With Multiple Sclerosis Treated With Fingolimod: Setting Up a Model for Prediction of Response in a 2-Year Translational Study

Torres

Garcı́a²,

Marconi

et al. 2018

Front. Immunol.

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BackgroundFingolimod is a functional sphingosine-1-phosphate antagonist approved for the treatment of multiple sclerosis (MS). Fingolimod affects lymphocyte subpopulations and regulates gene expression in the lymphocyte transcriptome. Translational studies are necessary to identify cellular and molecular biomarkers that might be used to predict the clinical response to the drug. In MS patients, we aimed to clarify the differential effects of fingolimod on T, B, and natural killer (NK) cell subsets and to identify differentially expressed genes in responders and non-responders (NRs) to treatment.Materials and methodsSamples were obtained from relapsing–remitting multiple sclerosis patients before and 6 months after starting fingolimod. Forty-eight lymphocyte subpopulations were measured by flow cytometry based on surface and intracellular marker analysis. Transcriptome sequencing by next-generation technologies was used to define the gene expression profiling in lymphocytes at the same time points. NEDA-3 (no evidence of disease activity) and NEDA-4 scores were measured for all patients at 1 and 2 years after beginning fingolimod treatment to investigate an association with cellular and molecular characteristics.ResultsFingolimod affects practically all lymphocyte subpopulations and exerts a strong effect on genetic transcription switching toward an anti-inflammatory and antioxidant response. Fingolimod induces a differential effect in lymphocyte subpopulations after 6 months of treatment in responder and NR patients. Patients who achieved a good response to the drug compared to NR patients exhibited higher percentages of NK bright cells and plasmablasts, higher levels of FOXP3, glucose phosphate isomerase, lower levels of FCRL1, and lower Expanded Disability Status Scale at baseline. The combination of these possible markers enabled us to build a probabilistic linear model to predict the clinical response to fingolimod.ConclusionMS patients responsive to fingolimod exhibit a recognizable distribution of lymphocyte subpopulations and a different pretreatment gene expression signature that might be useful as a biomarker.

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“…The group also reported that different treatments have been shown to impact sCD127 levels differently, thus, sCD127 levels might be exploited as a possible biomarker of treatment outcome, as they propose. 153 In individuals with SLE, the use of sCD127 serum levels has also been proposed to be used as a biomarker. This is the result of two studies that demonstrated sCD127 levels to be correlated to SLEDAI score, a marker of kidney disease activity in SLE, especially in patients with lupus nephritis.- 147,148 Interestingly, Chi and collaborators also observed a correlation between sCD127 plasma levels and anti-C1q antibodies in SLE patients.…”

Section: Scd127 As a Potential Biomarker And Therapeutic Agentmentioning

confidence: 99%

Soluble IL-7Rα/sCD127 in Health, Disease, and Its Potential Role as a Therapeutic Agent

Barros¹,

Berthoud²,

Aloufi³

et al. 2021

ITT

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Soluble cytokine receptors can influence immune responses by modulating the biological functions of their respective ligands. These effects can be either agonistic or antagonistic and a number of soluble cytokine receptors have been shown to play critical roles in both maintenance of health and disease pathogenesis. Soluble IL-7Ra (sCD127) is one such example. With its impact on the IL-7/CD127 pathway, which is fundamental for the development and homeostasis of T cells, the role of sCD127 in health and disease has been extensively studied in recent years. Within this review, the role of sCD127 in maintaining host immune function is presented. Next, by addressing genetic factors affecting sCD127 expression and the associated levels of sCD127 production, the roles of sCD127 in autoimmune disease, infections and cancer are described. Finally, advances in the field of soluble cytokine therapy and the potential for sCD127 as a biomarker and therapeutic agent are discussed.

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Multiple sclerosis treatment effects on plasma cytokine receptor levels

Cited by 7 publications

References 53 publications

Genomic Multiple Sclerosis Risk Variants Modulate the Expression of the ANKRD55–IL6ST Gene Region in Immature Dendritic Cells

Genomic Multiple Sclerosis Risk Variants Modulate the Expression of the ANKRD55–IL6ST Gene Region in Immature Dendritic Cells

Immunophenotype and Transcriptome Profile of Patients With Multiple Sclerosis Treated With Fingolimod: Setting Up a Model for Prediction of Response in a 2-Year Translational Study

Soluble IL-7Rα/sCD127 in Health, Disease, and Its Potential Role as a Therapeutic Agent

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