MiR-410 Down-Regulates the Expression of Interleukin-10 by Targeting STAT3 in the Pathogenesis of Systemic Lupus Erythematosus

Background/Aims: Systemic lupus erythematosus (SLE) is a heterogeneous chronic inflammatory autoimmune disorder, in the pathogenesis of which miRNAs play a versatile function. The purpose of this study was to investigate the effect of miRNA-410 on the pathogenesis of SLE in T cells of SLE patients. Methods: Real-time PCR was used to test the mRNA levels of miRNA-410 in SLE patients and healthy controls. ELISA analysis was performed to examine the production levels of IL-10. Luciferase Assay was used to confirm the targeting effect of miRNA-410 on 3'UTR of STAT3 mRNA. Results: We found that the expression level of miR-410 in T cells of SLE patients was decreased comparing to that in healthy controls, whereas overexpression of miR-410 significantly reduced the expression levels of IL-10. Furthermore, miR-410 suppresses the transcription activity of STAT3 by binding directly to the 3 'UTR of STAT3 mRNA. Moreover, silence of STAT3 down regulated IL-10 expression in CD3+ T cells. Conclusion: Our results demonstrate that miR-410 is the key regulatory factor in the pathogenesis of SLE by regulating the expression of IL-10 through targeting STAT3. These data suggest a novel function of miR-410 and bring new insight into understanding the complex mechanisms involved in SLE.

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Elevated levels of IL-24 in systemic lupus erythematosus patients

Lupus ◽

10.1177/0961203319845476 ◽

2019 ◽

Vol 28 (6) ◽

pp. 748-754 ◽

Cited By ~ 1

Author(s):

R C Li ◽

J Guo ◽

L C Su ◽

A F Huang

Keyword(s):

Systemic Lupus Erythematosus ◽

Disease Activity ◽

Lupus Erythematosus ◽

Inflammatory Cytokine ◽

Activity Index ◽

Clinical Manifestations ◽

Mrna Levels ◽

Healthy Controls ◽

Systemic Lupus ◽

Good Ability

Objective This study aimed to assess IL-24 levels and their association with clinical manifestations in patients with systemic lupus erythematosus (SLE). Methods There were 75 patients with SLE and 58 healthy controls recruited in this study. Serum levels of IL-24 were measured by enzyme-linked immunosorbent assays, and mRNA levels of IL-24 were tested by quantitative real-time polymerase chain reaction . The area under the curve of the receiver operating characteristic (ROC) curve was used for diagnostic ability of the inflammatory cytokine. Results Serum IL-24 levels were significantly higher in SLE patients than that in healthy controls. SLE patients with nephritis had higher IL-24 levels than those without nephritis. Active SLE patients showed higher expression of IL-24 as compared to less active disease patients. The mRNA levels of IL-24 were much higher in SLE patients. Correlation analysis showed significant correlation between serum IL-24 levels and SLE disease activity index. In addition, ROC analysis may suggest good ability of serum IL-24 in differentiating SLE. Conclusion The inflammatory cytokine correlated with SLE disease activity, and may be involved in this disease pathogenesis.

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mRNA expression analysis confirms CD44 splicing impairment in systemic lupus erythematosus patients

Lupus ◽

10.1177/09612033211004725 ◽

2021 ◽

pp. 096120332110047

Author(s):

Andrea Latini ◽

Lucia Novelli ◽

Fulvia Ceccarelli ◽

Cristiana Barbati ◽

Carlo Perricone ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

Mrna Expression ◽

Lupus Erythematosus ◽

Mononuclear Cells ◽

Direct Sequencing ◽

Healthy Controls ◽

Systemic Lupus ◽

Peripheral Tissues ◽

Variant Isoforms

Background Systemic Lupus Erythematosus (SLE) is a complex chronic autoimmune disease characterized by several immunological alterations. T cells have a peculiar role in SLE pathogenesis, moving from the bloodstream to the peripheral tissues, causing organ damage. This process is possible for their increased adherence and migration capacity mediated by adhesion molecules, such as CD44. Ten different variant isoforms of this molecule have been described, and two of them, CD44v3 and CD44v6 have been found to be increased on SLE T cells compared to healthy controls, being proposed as biomarkers of disease and disease activity. The process of alternative splicing of CD44 transcripts is not fully understood. We investigated the mRNA expression of CD44v3 and CD44v6 and also analyzed possible CD44 splicing regulators (ESRP1 molecule and rs9666607 CD44 polymorphism) in a cohort of SLE patients compared to healthy controls. Methods This study involved 18 SLE patients and 18 healthy controls. Total RNA and DNA were extracted by peripheral blood mononuclear cells. The expression study was conducted by quantitative RT-polymerase chain reaction, using SYBR Green protocol. Genotyping of rs9666607 SNP was performed by direct sequencing. Results CD44v6 mRNA expression was higher in SLE patients compared to healthy controls (p = 0.028). CD44v3/v6 mRNA ratio in healthy controls was strongly unbalanced towards isoform v3 compared to SLE patients (p = 0.002) and decreased progressively from healthy controls to the SLE patients in remission and those with active disease (p = 0.015). The expression levels of CD44v3 and CD44v6 mRNA correlated with the disease duration (p = 0.038, Pearson r = 0.493 and p = 0.038, Pearson r = 0.495, respectively). Splicing regulator ESRP1 expression positively correlated with CD44v6 expression in healthy controls (p = 0.02, Pearson r = 0.532) but not in SLE patients. The variant A allele of rs9666607 of CD44 was associated with higher level of global CD44 mRNA (p = 0.04) but not with the variant isoforms. Conclusions In SLE patients, the increase in CD44v6 protein correlates with a higher transcript level of this isoform, confirming an impairment of CD44 splicing in the disease, whose regulatory mechanisms require further investigation.

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Dysregulated T Cell Activation and Aberrant Cytokine Expression Profile in Systemic Lupus Erythematosus

Mediators of Inflammation ◽

10.1155/2019/8450947 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 4

Author(s):

Haiyan Zhou ◽

Bojiang Li ◽

Jing Li ◽

Tongqian Wu ◽

Xiaoqian Jin ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

T Cell ◽

Lupus Erythematosus ◽

Critical Role ◽

Cytokine Expression ◽

Healthy Controls ◽

Systemic Lupus ◽

Hla Dr ◽

Dsdna Antibody

Accumulating evidence indicates a critical role for T cells and relevant cytokines in the pathogenesis of systemic lupus erythematosus (SLE). However, the specific contribution of T cells together with the related circulating cytokines in disease pathogenesis and organ involvement is still not clear. In the current study, we investigated relevant molecule expressions and cytokine levels in blood samples from 49 SLE patients and 22 healthy control subjects. The expression of HLA-DR and costimulatory molecules on T cells was evaluated by flow cytometry. Concentrations of serum C-reactive protein, erythrocyte sedimentation rate, anti-double-stranded DNA (anti-dsDNA) antibody, total lgG, complement 3, and complement 4 were measured. Serum cytokines and chemokines were measured by a cytometric bead array assay. Elevated frequencies of HLA-DR+ T cells and ICOS+ T cells were observed in SLE patients with positive anti-dsDNA antibodies compared with those in healthy controls (P<0.001). The expression of HLA-DR+ T cells was positively correlated with SLEDAI (r=0.15, P<0.01). Furthermore, levels of serum IL-6, MCP-1, TNFRI, IL-10, IL-12, and CCL20 were higher in SLE patients compared with healthy controls. In addition, patients with hematologic manifestations displayed elevated frequencies of HLA-DR+ T cells and ICOS+ T cells. Patients with renal manifestations had a decreased frequency of TIGIT+ T cells. These results suggested a dysregulated T cell activity and cytokine expression profiles in SLE subjects. We also developed a chemokine and cytokine profiling strategy to predict the activity of SLE, which has clinical implication for better monitoring the flares and remission during the course of SLE and for assessing therapeutic interventions.

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CD3+CD4+gp130+ T Cells Are Associated With Worse Disease Activity in Systemic Lupus Erythematosus Patients

Frontiers in Immunology ◽

10.3389/fimmu.2021.675250 ◽

2021 ◽

Vol 12 ◽

Author(s):

Nur Diyana Mohd Shukri ◽

Aziz Farah Izati ◽

Wan Syamimee Wan Ghazali ◽

Che Maraina Che Hussin ◽

Kah Keng Wong

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

T Cell ◽

Disease Activity ◽

Lupus Erythematosus ◽

Lymphocyte Subpopulations ◽

Gene Set Enrichment Analysis ◽

T Cell Subsets ◽

Healthy Controls ◽

Systemic Lupus

The receptors for IL-35, IL-12Rβ2 and gp130, have been implicated in the inflammatory pathophysiology of autoimmune diseases. In this study, we set out to investigate the serum IL-35 levels and the surface levels of IL-12Rβ2 and gp130 in CD3+CD4+, CD3+CD4─ and CD3─CD4─ lymphocyte subpopulations in systemic lupus erythematosus (SLE) patients (n=50) versus healthy controls (n=50). The potential T cell subsets associated with gp130 transcript (i.e. IL6ST) expression in CD4+ T cells of SLE patients was also examined in publicly-available gene expression profiling (GEP) datasets. Here, we report that serum IL-35 levels were significantly higher in SLE patients than healthy controls (p=0.038) but it was not associated with SLEDAI-2K scores. The proportions of IL-12Rβ2+ and gp130+ cells in SLE patients did not differ significantly with those of healthy controls in all lymphocyte subpopulations investigated. Essentially, higher SLEDAI-2K scores were positively correlated with increased proportion of gp130+ cells, but not IL-12Rβ2+ cells, on CD3+CD4+ T cells (r=0.425, p=0.002, q=0.016). Gene Set Enrichment Analysis (GSEA) of a GEP dataset of CD4+ T cells isolated from SLE patients (n=8; GSE4588) showed that IL6ST expression was positively associated with genes upregulated in CD4+ T cells vs myeloid or B cells (q<0.001). In an independent GEP dataset of CD4+ T cells isolated from SLE patients (n=9; GSE1057), IL6ST expression was induced upon anti-CD3 stimulation, and that Treg, TCM and CCR7+ T cells gene sets were significantly enriched (q<0.05) by genes highly correlated with IL6ST expression (n=92 genes; r>0.75 with IL6ST expression) upon anti-CD3 stimulation in these SLE patients. In conclusion, gp130 signaling in CD3+CD4+ T cell subsets may contribute to increased disease activity in SLE patients, and it represents a promising therapeutic target for inhibition in the disease.

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Impaired Differentiation of Highly Proliferative ICOS+-Tregs Is Involved in the Transition from Low to High Disease Activity in Systemic Lupus Erythematosus (SLE) Patients

International Journal of Molecular Sciences ◽

10.3390/ijms22179501 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9501

Author(s):

Florian Kälble ◽

Lisa Wu ◽

Hanns-Martin Lorenz ◽

Martin Zeier ◽

Matthias Schaier ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

Lupus Erythematosus ◽

Costimulatory Molecule ◽

Flow Cytometric Analysis ◽

Significant Shift ◽

Healthy Controls ◽

Systemic Lupus ◽

Color Flow ◽

Active Disease

Dysregulations in the differentiation of CD4+-regulatory-T-cells (Tregs) and CD4+-responder-T-cells (Tresps) are involved in the development of active systemic lupus erythematosus (SLE). Three differentiation pathways of highly proliferative inducible costimulatory molecule (ICOS)+- and less proliferative ICOS−-CD45RA+CD31+-recent-thymic-emigrant (RTE)-Tregs/Tresps via CD45RA−CD31+-memory-Tregs/Tresps (CD31+-memory-Tregs/Tresps), their direct proliferation via CD45RA+CD31−-mature naïve (MN)-Tregs/Tresps, and the production and differentiation of resting MN-Tregs/Tresp into CD45RA−CD31−-memory-Tregs/Tresps (CD31−-memory-Tregs/Tresps) were examined in 115 healthy controls, 96 SLE remission patients, and 20 active disease patients using six color flow cytometric analysis. In healthy controls an appropriate sequence of these pathways ensured regular age-dependent differentiation. In SLE patients, an age-independently exaggerated differentiation was observed for all Treg/Tresp subsets, where the increased conversion of resting MN-Tregs/Tresps particularly guaranteed the significantly increased ratios of ICOS+-Tregs/ICOS+-Tresps and ICOS−-Tregs/ICOS−-Tresps during remission. Changes in the differentiation of resting ICOS+-MN-Tresps and ICOS−-MN-Tregs from conversion to proliferation caused a significant shift in the ratio of ICOS+-Tregs/ICOS+-Tresps in favor of ICOS+-Tresps and a further increase in the ratio of ICOS−-Tregs/ICOS−-Tresps with active disease. The differentiation of ICOS+-RTE-Tregs/Tresps seems to be crucial for keeping patients in remission, where their limited production of proliferating resting MN-Tregs may be responsible for the occurrence of active disease flares.

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Relationship between T lymphocyte subsets and cortisol in systemic lupus erythematosus

Kathmandu University Medical Journal ◽

10.3126/kumj.v7i3.2726 ◽

1970 ◽

Vol 7 (3) ◽

pp. 213-219 ◽

Cited By ~ 8

Author(s):

D Shah ◽

R Kiran ◽

A Wanchu ◽

A Bhatnagar

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Lupus Erythematosus ◽

Serum Cortisol ◽

Cd8 T Cell ◽

Healthy Controls ◽

Systemic Lupus ◽

T Lymphocyte Subsets

Background: Systemic Lupus Erythematosus (SLE) is a complex chronic immunological disease characterized by increased B cell activity and altered T cell function. Objective: To investigate relationship between T lymphocyte subsets and cortisol with the disease activity of systemic lupus erythematosus patients in North India. Materials and methods: The percentage of CD4+ and CD8+ T cells in the lymphocyte of SLE patients and healthy controls were determined by flow cytometry. Serum cortisol of SLE patients and healthy controls was determined by enzyme-linked immunosorbent assay (ELISA). Results: A significant decrease in the percentage of CD4+ T cells and increase in the percentage of CD8+ T cells were found in patients with SLE compared to the healthy controls. Decrease in the ratio of CD4+/CD8+ T cell and low level of serum cortisol were found in the patients with SLE. The ratio of CD4+/CD8+ T cell was inversely correlated with systemic lupus erythematosus disease activity index (SLEDAI) score and erythrocyte sedimentation rate (ESR). A positive correlation was observed between CD8+ T cells and SLEDAI score. Furthermore, CD8+ T cells were positively correlated with ESR in the patients with SLE. Conclusion: The results showed that low level of cortisol and high percentage of CD8+ T cells in the lymphocytes could be actively involved in the pathogenesis of SLE. Key words: CD4+/CD8+ T cell ratio; cortisol; systemic lupus erythematosus; T-cell activation DOI: 10.3126/kumj.v7i3.2726 Kathmandu University Medical Journal (2009) Vol.7, No.3 Issue 27, 213-219

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LncRNA XIST alters the balance of peripheral blood immune cells in systemic lupus erythematosus by regulating the miR-17-92, OFLM4 and CEACAM8 axis

10.21203/rs.3.rs-621553/v1 ◽

2021 ◽

Author(s):

Qi Cheng ◽

Jieying Xu ◽

Mo Chen ◽

Xin Chen ◽

Peiyu Zhang ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

Immune Cells ◽

Lupus Erythematosus ◽

Peripheral Blood ◽

Quantitative Polymerase Chain Reaction ◽

Diagnostic Value ◽

Healthy Controls ◽

Systemic Lupus ◽

Bioinformatics Analyses

Abstract BackgroundX-inactive-specific transcript (XIST) has been shown to silence linked genes on the X chromosome that may be related to the pathogenesis of systemic lupus erythematosus (SLE) in female patients. However, the function of XIST in SLE at other levels remains unclear. The present study aimed to clarify the correlations between XIST expression and SLE clinical features and the contribution of XIST to SLE pathogenesis at the transcriptome level.MethodsExpression of XIST in 79 SLE patients and 23 healthy controls was detected by quantitative-polymerase chain reaction. Bioinformatics methods were used to explore the function and regulatory mechanism of XIST.ResultsExpression of XIST was significantly upregulated in SLE patients compared with healthy controls, and had a high diagnostic value for SLE. Importantly, SLE patients with high expression of XIST tended to have elevated levels of total T cells and CD8 + T cells, but reduced levels of Treg cells and NK cells. Bioinformatics analyses suggested that XIST may regulate the expression of OLFM4 and CEACAM8 by acting as a spongy body for miR-20a, miR-92a, miR-106a, and miR-449a. Furthermore, OLFM4 and CEACAM8 are significantly upregulated in SLE patients and had significant positive correlations with expression of XIST.ConclusionsWe propose that XIST may alter the balance of peripheral blood immune cells in SLE by acting as a spongy body for the miR-17-92 cluster and promoting the expression of OLFM4 and CEACAM8, resulting in immune dysregulation and tissue damage in SLE.

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Hypomethylation ofIL10andIL13Promoters in CD4+T Cells of Patients with Systemic Lupus Erythematosus

Journal of Biomedicine and Biotechnology ◽

10.1155/2010/931018 ◽

2010 ◽

Vol 2010 ◽

pp. 1-9 ◽

Cited By ~ 52

Author(s):

Ming Zhao ◽

Jinling Tang ◽

Fei Gao ◽

Xiaoyan Wu ◽

Yunsheng Liang ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

Lupus Erythematosus ◽

Healthy Controls ◽

Dna Hypomethylation ◽

Mrna Transcription ◽

Systemic Lupus ◽

Regulatory Domains ◽

Th2 Cell ◽

Gene Regulatory

Interleukin- (IL-)10 and IL-13 play important roles in Th2 cell differentiation and production of autoantibodies in patients with (SLE). However, the mechanisms leading toIL10andIL13overexpression in SLE patients are not well understood. In this study, we confirm that the levels of bothIL10andIL13mRNA in CD4+T cells and of serumIL10andIL13proteins are increased in SLE patients. We show that the DNA methylation levels withinIL10andIL13gene regulatory domains are reduced in SLE CD4+T cells relative to healthy controls and negatively correlate withIL10andIL13mRNA expression. Moreover, treating healthy CD4+T cells with the demethylating agent 5-azacytidine (5-azaC) increasedIL10andIL13mRNA transcription. Together, our results show that promoter methylation is a determinant ofIL10andIL13expression in CD4+T cells, and we propose that DNA hypomethylation leads toIL10andIL13overexpression in SLE patients.

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CD107a+ (LAMP-1) Cytotoxic CD8+ T-Cells in Lupus Nephritis Patients

Frontiers in Medicine ◽

10.3389/fmed.2021.556776 ◽

2021 ◽

Vol 8 ◽

Author(s):

Anika Wiechmann ◽

Benjamin Wilde ◽

Bartosz Tyczynski ◽

Kerstin Amann ◽

Wayel H. Abdulahad ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

Lupus Nephritis ◽

Cd8 T Cells ◽

Lupus Erythematosus ◽

Inactive Disease ◽

Healthy Controls ◽

Systemic Lupus ◽

Altered Expression

Cytotoxic CD8+ T-cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). The aim of this study was to investigate the role of CD107a (LAMP-1) on cytotoxic CD8+ T-cells in SLE-patients in particular with lupus nephritis. Peripheral blood of SLE-patients (n = 31) and healthy controls (n = 21) was analyzed for the expression of CD314 and CD107a by flow cytometry. Kidney biopsies of lupus nephritis patients were investigated for the presence of CD8+ and C107a+ cells by immunohistochemistry and immunofluorescence staining. The percentages of CD107a+ on CD8+ T-cells were significantly decreased in SLE-patients as compared to healthy controls (40.2 ± 18.5% vs. 47.9 ± 15.0%, p = 0.02). This was even more significant in SLE-patients with inactive disease. There was a significant correlation between the percentages of CD107a+CD8+ T-cells and SLEDAI. The evaluation of lupus nephritis biopsies showed a significant number of CD107a+CD8+ T-cells mainly located in the peritubular infiltrates. The intrarenal expression of CD107a+ was significantly correlated with proteinuria. These results demonstrate that CD8+ T-cells of patients with systemic lupus erythematosus have an altered expression of CD107a which seems to be associated with disease activity. The proof of intrarenal CD107a+CD8+ suggests a role in the pathogenesis of lupus nephritis.

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A Novel Long Noncoding RNA lincRNA00892 Activates CD4+ T Cells in Systemic Lupus Erythematosus by Regulating CD40L

Frontiers in Pharmacology ◽

10.3389/fphar.2021.733902 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiao Liu ◽

Jinran Lin ◽

Hao Wu ◽

Yilun Wang ◽

Lin Xie ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Flow Cytometry ◽

T Cells ◽

T Cell ◽

Lupus Erythematosus ◽

Healthy Controls ◽

Systemic Lupus ◽

Hnrnp K ◽

Qrt Pcr ◽

Potential Target

Objective: The mechanism of CD4+ T-cell dysfunction in systemic lupus erythematosus (SLE) has not been fully understood. Increasing evidence show that long noncoding RNAs (lncRNAs) can regulate immune responses and take part in some autoimmune diseases, while little is known about the lncRNA expression and function in CD4+ T of SLE. Here, we aimed to detect the expression profile of lncRNAs in lupus CD4+ T cells and explore the mechanism that how lincRNA00892 in CD4+ T cells is involved in the pathogenesis of SLE.Methods: The expression profiles of lncRNAs and mRNAs in CD4+ T cells from SLE patients and healthy controls were detected by microarray. LincRNA00892 and CD40L were chosen for validation by quantitative real-time PCR (qRT-PCR). Coexpression network was conducted to predict the potential target genes of lincRNA00892. Then lincRNA00892 was overexpressed in normal CD4+ T cells via lentivirus transfection. The expression of lincRNA00892 was detected by qRT-PCR. The expression of CD40L was detected by qRT-PCR, western blotting, and flow cytometry, respectively. The expression of CD69 and CD23 was measured by flow cytometry. The secretion of IgG was determined by enzyme-linked immunosorbent assay (ELISA). The proteins targeted by lincRNA00892 were measured by RNA pulldown and subsequent mass spectrometry (MS). The interaction between heterogeneous nuclear ribonucleoprotein K (hnRNP K) and lincRNA00892 or CD40L was detected by RNA immunoprecipitation (RIP) assay.Results: A total of 1887 lncRNAs and 3375 mRNAs were found to be aberrantly expressed in CD4+ T cells of SLE patients compared to healthy controls. LincRNA00892 and CD40L were confirmed to be upregulated in CD4+ T cells of SLE patients by qRT-PCR. The lncRNA–mRNA coexpression network analysis indicated that CD40L was a potential target of lincRNA00892. Overexpression of lincRNA00892 enhanced CD40L protein levels while exerting little influence on CD40L mRNA levels in CD4+ T cells. In addition, lincRNA00892 could induce the activation of CD4+ T cells. Furthermore, lincRNA00892 led to the activation of B cells and subsequent secretion of IgG in a CD4+ T-cell–dependent manner. Finally, hnRNP K was found to be among the proteins pulled down by lincRNA00892, and hnRNP K could bind to lincRNA00892 or CD40L directly.Conclusion: Our results showed that the lncRNA expression profile was altered in CD4+ T cells of SLE. LincRNA00892 possibly contributed to the pathogenesis of SLE by targeting hnRNP K and subsequently upregulating CD40L expression to activate CD4+ T and B cells. These provided us a potential target for further mechanistic studies of SLE pathogenesis.

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