A T cell gene expression panel for the diagnosis and monitoring of disease activity in patients with systemic lupus erythematosus

T cell immunoglobulin and mucin domain-containing molecule-3 (Tim-3) has been found to play important roles in systemic lupus erythematosus (SLE), however, whether Tim-3 is involved in apoptosis of NK cells in SLE remains unknown. The proportion of CD3−CD56+ NK cells and the percentage of AnnexinV+ NK cells were analyzed by flow cytometry in SLE patients and healthy controls. Tim-3 expression on NK cells was also evaluated by flow cytometry. We firstly observed a decreased proportion of NK cells and an increased proportion of apoptotic NK cells in SLE patients. The proportion of apoptotic NK cells was positively correlated with anti-dsDNA and SLEDAI. Tim-3 expression on NK cells was up-regulated in SLE patients. Further analysis showed that Tim-3 expression on NK cells was negatively correlated with the proportion of apoptotic NK cells, anti-dsDNA and SLEDAI, while positively correlated with the proportion of NK cells. The present results suggest that Tim-3 might play roles in SLE by regulating the apoptosis of NK cells and Tim-3 might serve as a potential target for the treatment of SLE.

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Polymorphisms of MFGE8 are associated with susceptibility and clinical manifestations through gene expression modulation in Koreans with systemic lupus erythematosus

Scientific Reports ◽

10.1038/s41598-019-55061-6 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Wook-Young Baek ◽

Ji-Min Woo ◽

Hyoun-Ah Kim ◽

Ju-Yang Jung ◽

Chang-Hee Suh

Keyword(s):

Gene Expression ◽

Systemic Lupus Erythematosus ◽

Disease Activity ◽

Lupus Erythematosus ◽

Milk Fat ◽

Clinical Manifestations ◽

Αvβ3 Integrin ◽

Apoptotic Cells ◽

Systemic Lupus ◽

Dsdna Antibody

AbstractSystemic lupus erythematosus (SLE) is characterized by impaired clearance of apoptotic cells. Milk fat globule epidermal growth factor 8 (MFGE8) is a protein that connects αvβ3 integrin on phagocytic macrophages with phosphatidylserine on apoptotic cells. We investigated whether genetic variation of the MFGE8 gene and serum MFGE8 concentration are associated with SLE. Single nucleotide polymorphisms (SNPs) were genotyped and serum concentrations were analyzed. The rs2271715 C allele and rs3743388 G allele showed higher frequency in SLE than in healthy subjects (HSs). Three haplotypes were found among 4 SNPs (rs4945, rs1878327, rs2271715, and rs3743388): AACG, CGCG, and CGTC. CGCG haplotype was significantly more common in SLE than in HSs. rs4945 was associated with the erythrocyte sedimentation rate and rs1878327 was associated with alopecia, C-reactive protein, complement 3, anti-dsDNA antibody, and high disease activity. rs2271715 and rs3743388 were associated with renal disease, cumulative glucocorticoid dose, and cyclophosphamide and mycophenolate mofetil use. Serum MFGE8 concentrations were significantly higher in SLE than in HSs. Furthermore, the levels of MFGE8 were significantly higher in SLE than HSs of the rs2271715 CC genotype. In conclusion, MFGE8 genetic polymorphisms are associated not only with susceptibility to SLE but also with disease activity through modulation of gene expression.

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Associations of site-specific CD4+-T-cell hypomethylation within CD40-ligand promotor and enhancer regions with disease activity of women with systemic lupus erythematosus

Lupus ◽

10.1177/0961203320965690 ◽

2020 ◽

Vol 30 (1) ◽

pp. 45-51

Author(s):

Stefan Vordenbäumen ◽

Anna Rosenbaum ◽

Claudia Gebhard ◽

Johanna Raithel ◽

Alexander Sokolowski ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

T Cell ◽

Disease Activity ◽

Lupus Erythematosus ◽

Activity Index ◽

Disease Activity Index ◽

Cd40 Ligand ◽

Systemic Lupus ◽

Site Specific

Objective To comprehensively assess associations of site-specific CD4+-T-cell hypomethylation of the CD40-Ligand gene ( CD40L) with disease activity of women with systemic lupus erythematosus (SLE). Methods CpG-sites within the DNA of the promotor and two enhancer regions (n = 22) of CD40L were identified and numbered consecutively. The rate of methylated DNA in isolated CD4+-T-cells of women with SLE were quantified for each methylation site by MALDI-TOF. Disease activity was assessed by SLE Disease Activity Index (SLEDAI). Associations of site-specific methylation rates with the SLEDAI scores were assessed by linear regression modelling. P values were adjusted according to Bonferroni-Holm as indicated. Results 60 female SLE patients participated in the study (age 45.7 ± 11.1 years, disease duration 17.0 ± 8.3 years). Significant associations to the SLEDAI were noted for CpG22 hypomethylation of the promotor (β = −40.1, p = 0.017, adjusted p = 0.027), trends were noted for CpG17 hypomethylation of the promotor (β = −30.5, p = 0.032, adjusted p = 0.6), and for CpG11 hypermethylation of the second enhancer (β = 15.0, p = 0.046, adjusted p = 0.8). Conclusion Site-specific hypomethylation of the CD40L promotor in CD4+-T-cells show associations with disease activity in female SLE patients.

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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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Genomic dissection of Systemic Lupus Erythematosus: Distinct Susceptibility, Activity and Severity Signatures

10.1101/255109 ◽

2018 ◽

Author(s):

Nikolaos I. Panousis ◽

George Bertsias ◽

Halit Ongen ◽

Irini Gergianaki ◽

Maria Tektonidou ◽

...

Keyword(s):

Gene Expression ◽

Systemic Lupus Erythematosus ◽

Disease Activity ◽

Lupus Erythematosus ◽

Whole Blood ◽

Personalized Therapy ◽

Flare Activity ◽

Rna Seq ◽

Healthy Individuals ◽

Systemic Lupus

AbstractRecent genetic and genomics approaches have yielded novel insights in the pathogenesis of Systemic Lupus Erythematosus (SLE) but the diagnosis, monitoring and treatment still remain largely empirical1,2. We reasoned that molecular characterization of SLE by whole blood transcriptomics may facilitate early diagnosis and personalized therapy. To this end, we analyzed genotypes and RNA-seq in 142 patients and 58 matched healthy individuals to define the global transcriptional signature of SLE. By controlling for the estimated proportions of circulating immune cell types, we show that the Interferon (IFN) and p53 pathways are robustly expressed. We also report cell-specific, disease-dependent regulation of gene expression and define a core/susceptibility and a flare/activity disease expression signature, with oxidative phosphorylation, ribosome regulation and cell cycle pathways being enriched in lupus flares. Using these data, we define a novel index of disease activity/severity by combining the validated Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)1 with a new variable derived from principal component analysis (PCA) of RNA-seq data. We also delineate unique signatures across disease endo-phenotypes whereby active nephritis exhibits the most extensive changes in transcriptome, including prominent drugable signatures such as granulocyte and plasmablast/plasma cell activation. The substantial differences in gene expression between SLE and healthy individuals enables the classification of disease versus healthy status with median sensitivity and specificity of 83% and 100%, respectively. We explored the genetic regulation of blood transcriptome in SLE and found 3142 cis-expression quantitative trait loci (eQTLs). By integration of SLE genome-wide association study (GWAS) signals and eQTLs from 44 tissues from the Genotype-Tissue Expression (GTEx) consortium, we demonstrate that the genetic causality of SLE arises from multiple tissues with the top causal tissue being the liver, followed by brain basal ganglia, adrenal gland and whole blood. Collectively, our study defines distinct susceptibility and activity/severity signatures in SLE that may facilitate diagnosis, monitoring, and personalized therapy.

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Extensive fragmentation and re-organization of gene co-expression patterns underlie the progression of Systemic Lupus Erythematosus

10.1101/2020.01.28.922559 ◽

2020 ◽

Author(s):

Vasilis F. Ntasis ◽

Nikolaos I. Panousis ◽

Maria G. Tektonidou ◽

Emmanouil T. Dermitzakis ◽

Dimitrios T. Boumpas ◽

...

Keyword(s):

Gene Expression ◽

Systemic Lupus Erythematosus ◽

Disease Activity ◽

Gene Expression Data ◽

Lupus Erythematosus ◽

Genome Organization ◽

Expression Data ◽

Systemic Lupus ◽

Gene Coexpression ◽

Kidney Involvement

AbstractSystemic Lupus Erythematosus (SLE) is the prototype of autoimmune diseases, characterized by extensive gene expression perturbations in peripheral blood immune cells. Circumstantial evidence suggests that these perturbations may be due to altered epigenetic profiles and chromatin accessibility but the relationship between transcriptional deregulation and genome organization remains largely unstudied. We developed a genomic approach that leverages patterns of gene coexpression from genome-wide transcriptome profiles in order to identify statistically robust Domains of Co-ordinated gene Expression (DCEs). By implementing this method on gene expression data from a large SLE patient cohort, we identify significant disease-associated alterations in gene co-regulation patterns, which also correlate with the SLE activity status. Low disease activity patient genomes are characterized by extensive fragmentation leading to DCEs of smaller size. High disease activity genomes display excessive spatial redistribution of co-expression domains with expanded and newly-appearing (emerged) DCEs. Fragmentation and redistribution of gene coexpression patterns correlate with SLE-implicated biological pathways and clinically relevant endophenotypes such as kidney involvement. Notably, genes lying at the boundaries of split DCEs of low activity genomes are enriched in the interferon and other SLE susceptibility signatures, suggesting the implication of DCE fragmentation at early disease stages. Interrogation of promoter-enhancer interactions from various immune cell subtypes shows that a significant percentage of nested connections are disrupted by a DCE split or depletion in SLE genomes. Collectively, our results underlining an important role for genome organization in shaping gene expression in SLE, could provide valuable insights into disease pathogenesis and the mechanisms underlying disease flares.SignificanceAlthough widespread gene expression changes have been reported in Systemic Lupus Erythematosus (SLE), attempts to link gene deregulation with genome structure have been lacking. Through a computational framework for the segmentation of gene expression data, we reveal extensive fragmentation and reorganization of gene co-regulation domains in SLE, that correlates with disease activity states. Gene co-expression domains pertaining to biological functions implicated in SLE such as the interferon pathway, are being disrupted in patients, while others associated to severe manifestations such as nephritis, emerge in previously uncorrelated regions of the genome. Our results support extensive genome re-organization underlying aberrant gene expression in SLE, which could assist in the early detection of disease flares in patients that are in remission.Graphical Abstract

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The effect of vitamin D on disease activity, fatigue and interferon signature gene expression in systemic lupus erythematosus

Mediterranean Journal of Rheumatology ◽

10.31138/mjr.28.3.127 ◽

2017 ◽

Vol 28 (3) ◽

pp. 127-132 ◽

Cited By ~ 1

Author(s):

Rosalie Magro ◽

Andrew A Borg

Keyword(s):

Gene Expression ◽

Systemic Lupus Erythematosus ◽

Vitamin D ◽

Disease Activity ◽

Lupus Erythematosus ◽

Systemic Lupus ◽

Interferon Signature

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BNT162b2 vaccine-induced humoral and cellular responses against SARS-CoV-2 variants in Systemic Lupus Erythematosus

10.1101/2021.07.07.21260124 ◽

2021 ◽

Author(s):

Quentin Moyon ◽

Delphine Sterlin ◽

Makoto Miyara ◽

Francois Anna ◽

Alexis Mathian ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cell ◽

Antibody Response ◽

Disease Activity ◽

B Cell ◽

Lupus Erythematosus ◽

Serum Levels ◽

T Cell Response ◽

Inactive Disease ◽

Systemic Lupus

Objectives: Our aims were to evaluate Systemic Lupus Erythematosus (SLE) disease activity and SARS-CoV-2 specific immune responses after BNT162b2 vaccination. Methods: In this prospective study, disease activity and clinical assessments were recorded from the first dose of vaccine, until day 15 after the second dose in 126 SLE patients. SARS-CoV-2 antibody responses were measured against wild-type spike antigen while serum-neutralizing activity was assessed against the SARS-CoV-2 historical strain and variants of concerns (VOCs). Vaccine-specific T-cell responses were quantified by Interferon (IFN)-gamma; release assay after the second dose. Results: BNT162b2 was well tolerated and no statistically significant variations of BILAG and SLEDAI scores were observed throughout the study in SLE patients with active and inactive disease at baseline. Mycophenolate Mofetil (MMF) and Methotrexate (MTX) treatments were associated with drastically reduced BNT162b2 antibody-response (beta=-78; p=0.007, beta=-122; p<0.001, respectively). Anti-spike antibody response was positively associated with baseline total IgG serum levels, naive B cell frequencies (beta=2; p=0.018, beta=2.5; p=0.003) and SARS-CoV-2-specific T cell response (r=0.462; p=0.003). In responders, serum neutralization activity decreased against VOCs bearing the E484K mutation but remained detectable in a majority of patients. Conclusion: MMF, MTX and poor baseline humoral immune status, particularly: low naive B cell frequencies, are independently associated with impaired BNT162b2 mRNA antibody response, delineating SLE patients who might need adapted vaccine regimens and follow-up.

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Low-density granulocytes activate T cells and demonstrate a non-suppressive role in systemic lupus erythematosus

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2018-214620 ◽

2019 ◽

Vol 78 (7) ◽

pp. 957-966 ◽

Cited By ~ 25

Author(s):

Saifur Rahman ◽

Divya Sagar ◽

Richard N Hanna ◽

Yaima L Lightfoot ◽

Pragnesh Mistry ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

T Cell ◽

Disease Activity ◽

Lupus Erythematosus ◽

Cytokine Production ◽

Low Density ◽

Dependent Manner ◽

Systemic Lupus ◽

Lymphocyte Ratio

ObjectivesThe presence of proinflammatory low-density granulocytes (LDG) has been demonstrated in autoimmune and infectious diseases. Recently, regulatory neutrophilic polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) were identified in systemic lupus erythematosus (SLE). Because LDG and PMN-MDSC share a similar phenotype with contrasting functional effects, we explored these cells in a cohort of patients with SLE.MethodsLDG and normal-density granulocytes (NDG) were isolated from fresh blood of healthy donors (HD) and patients with SLE. Associations between LDG and clinical manifestations were analysed. Multicolor flow cytometry and confocal imaging were performed to immunophenotype the cells. The ability of LDG and NDG to suppress T cell function and induce cytokine production was quantified.ResultsLDG prevalence was elevated in SLE versus HD, associated with the interferon (IFN) 21-gene signature and disease activity. Also, the LDG-to-lymphocyte ratio associated better with SLE disease activity index than neutrophil-to-lymphocyte ratio. SLE LDG exhibited significantly heightened surface expression of various activation markers and also of lectin-like oxidised low-density lipoprotein receptor-1, previously described to be associated with PMN-MDSC. Supernatants from SLE LDG did not restrict HD CD4+ T cell proliferation in an arginase-dependent manner, suggesting LDG are not immunosuppressive. SLE LDG supernatants induced proinflammatory cytokine production (IFN gamma, tumour necrosis factor alpha and lymphotoxin alpha) from CD4+ T cells.ConclusionsBased on our results, SLE LDG display an activated phenotype, exert proinflammatory effects on T cells and do not exhibit MDSC function. These results support the concept that LDG represent a distinct proinflammatory subset in SLE with pathogenic potential, at least in part, through their ability to activate type 1 helper responses.

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