scholarly journals Rheumatoid arthritis, systemic lupus erythematosus and primary Sjögren’s syndrome shared megakaryocyte expansion in peripheral blood

2021 ◽  
pp. annrheumdis-2021-220066
Author(s):  
Yukai Wang ◽  
Xuezhen Xie ◽  
Chengpeng Zhang ◽  
Miaotong Su ◽  
Sini Gao ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Systemic Lupus Erythematosus ◽  
Flow Cytometry ◽  
Lupus Erythematosus ◽  
Peripheral Blood ◽  
Immune Cell ◽  
Primary Sjögren’S Syndrome ◽  
Rna Seq ◽  
Systemic Lupus

ObjectivesRheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (pSS) share many clinical manifestations and serological features. The aim of this study was to identify the common transcriptional profiling and composition of immune cells in peripheral blood in these autoimmune diseases (ADs).MethodsWe analysed bulk RNA-seq data for enrichment of biological processes, transcription factors (TFs) and deconvolution-based immune cell types from peripheral blood mononuclear cells (PBMCs) in 119 treatment-naive patients (41 RA, 38 pSS, 28 SLE and 12 polyautoimmunity) and 20 healthy controls. The single-cell RNA-seq (scRNA-seq) and flow cytometry had been performed to further define the immune cell subsets on PBMCs.ResultsSimilar transcriptional profiles and common gene expression signatures associated with nucleosome assembly and haemostasis were identified across RA, SLE, pSS and polyautoimmunity. Distinct TF ensembles and gene regulatory network were mainly enriched in haematopoiesis. The upregulated cell-lineage-specific TFs PBX1, GATA1, TAL1 and GFI1B demonstrated a strong gene expression signature of megakaryocyte (MK) expansion. Gene expression-based cell type enrichment revealed elevated MK composition, specifically, CD41b+CD42b+ and CD41b+CD61+ MKs were expanded, further confirmed by flow cytometry in these ADs. In scRNA-seq data, MKs were defined by TFs PBX1/GATA1/TAL1 and pre-T-cell antigen receptor gene, PTCRA. Cellular heterogeneity and a distinct immune subpopulation with functional enrichment of antigen presentation were observed in MKs.ConclusionsThe identification of MK expansion provided new insights into the peripheral immune cell atlas across RA, SLE, pSS and polyautoimmunity. Aberrant regulation of the MK expansion might contribute to the pathogenesis of these ADs.

scholarly journals Machine learning applied to whole-blood RNA-sequencing data uncovers distinct subsets of patients with systemic lupus erythematosus

2019 ◽  
Author(s):  
William A Figgett ◽  
Katherine Monaghan ◽  
Milica Ng ◽  
Monther Alhamdoosh ◽  
Eugene Maraskovsky ◽  
...  
Keyword(s):  
Gene Expression ◽  
Machine Learning ◽  
Systemic Lupus Erythematosus ◽  
Clinical Trials ◽  
Lupus Erythematosus ◽  
Whole Blood ◽  
Rna Seq ◽  
Systemic Lupus ◽  
Disease Heterogeneity ◽  
Healthy Donors

ABSTRACTObjectiveSystemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease that is difficult to treat. There is currently no optimal stratification of patients with SLE, and thus responses to available treatments are unpredictable. Here, we developed a new stratification scheme for patients with SLE, based on the whole-blood transcriptomes of patients with SLE.MethodsWe applied machine learning approaches to RNA-sequencing (RNA-seq) datasets to stratify patients with SLE into four distinct clusters based on their gene expression profiles. A meta-analysis on two recently published whole-blood RNA-seq datasets was carried out and an additional similar dataset of 30 patients with SLE and 29 healthy donors was contributed in this research; 141 patients with SLE and 51 healthy donors were analysed in total.ResultsExamination of SLE clusters, as opposed to unstratified SLE patients, revealed underappreciated differences in the pattern of expression of disease-related genes relative to clinical presentation. Moreover, gene signatures correlated to flare activity were successfully identified.ConclusionGiven that disease heterogeneity has confounded research studies and clinical trials, our approach addresses current unmet medical needs and provides a greater understanding of SLE heterogeneity in humans. Stratification of patients based on gene expression signatures may be a valuable strategy to harness disease heterogeneity and identify patient populations that may be at an increased risk of disease symptoms. Further, this approach can be used to understand the variability in responsiveness to therapeutics, thereby improving the design of clinical trials and advancing personalised therapy.

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

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.

scholarly journals Analysis of gene expression from systemic lupus erythematosus synovium reveals myeloid cell-driven pathogenesis of lupus arthritis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Erika L. Hubbard ◽  
Michelle D. Catalina ◽  
Sarah Heuer ◽  
Prathyusha Bachali ◽  
Robert Robl ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Immune Cell ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Myeloid Cell ◽  
Inflammatory Cells ◽  
Systemic Lupus ◽  
Common Manifestation

Abstract Arthritis is a common manifestation of systemic lupus erythematosus (SLE) yet understanding of the underlying pathogenic mechanisms remains incomplete. We, therefore, interrogated gene expression profiles of SLE synovium to gain insight into the nature of lupus arthritis (LA), using osteoarthritis (OA) and rheumatoid arthritis (RA) as comparators. Knee synovia from SLE, OA, and RA patients were analyzed for differentially expressed genes (DEGs) and also by Weighted Gene Co-expression Network Analysis (WGCNA) to identify modules of highly co-expressed genes. Genes upregulated and/or co-expressed in LA revealed numerous immune/inflammatory cells dominated by a myeloid phenotype, in which pathogenic macrophages, myeloid-lineage cells, and their secreted products perpetuate inflammation, whereas OA was characterized by fibroblasts and RA of lymphocytes. Genes governing trafficking of immune cells into the synovium by chemokines were identified, but not in situ generation of germinal centers (GCs). Gene Set Variation Analysis (GSVA) confirmed activation of specific immune cell types in LA. Numerous therapies were predicted to target LA, including TNF, NFκB, MAPK, and CDK inhibitors. Detailed gene expression analysis identified a unique pattern of cellular components and physiologic pathways operative in LA, as well as drugs potentially able to target this common manifestation of SLE.

Gene expression profiles of systemic lupus erythematosus and rheumatoid arthritis

2007 ◽  
Vol 3 (5) ◽  
pp. 797-806 ◽  
Author(s):  
Michael Centola ◽  
Zoltan Szekanecz ◽  
Emese Kiss ◽  
Margit Zeher ◽  
Gyula Szegedi ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Systemic Lupus
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