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Next generation sequencing facilitates quantitative analysis of tissue-specific molecular signatures in lupus mice

ABSTRACT: Purpose: Next-generation sequencing (NGS) technology was used to map expression profiles of effector (spleen) and key target tissues (kidney and brain) in mouse model of Systemic Lupus Erythematosus (SLE). Methods: Total RNA was extracted from total brain, total kidney and total spleen using Trizol and mRNA libraries were generated using the Illumina TruSeq Sample Preparation kit v2. Paired-end 37-bp mRNA sequencing was performed on Illumina HiSeq2000 platform. Quality of sequencing was assessed using FastQC software. Raw reads in fastq format were collected and aligned to the mouse genome (mm10 version) using STAR 2.6 algorithm. Gene quantification was performed using HTSeq and differential expression analysis was performed using edgeR package. Results: We defined kidney-specific molecular signatures of the murine lupus transcriptome that mirrors nephritis-specific transcriptome alterations in human SLE. Conclusions: By the use of the mouse kidney-specific transcriptome and through training of a large whole-blood RNA-sequencing dataset of SLE patients, we developed and validated an algorithm that predicts patients with active LN from SLE patients without LN and suggest vigilance in the monitoring of these patients and potential enrollment in LN prevention studies.

ORGANISM(S): Mus musculus

PROVIDER: GSE186367 | GEO | 2022/10/01

REPOSITORIES: GEO

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Kidney tertiary lymphoid structures in Lupus Nephritis develop into large interconnected networks and resembles lymph nodes in gene signature.

Project description:Immune aggregates organized as tertiary lymphoid structures (TLS) are observed within kidneys of systemic lupus erythematosus (SLE) patients with lupus nephritis (LN). We characterized renal TLS in lupus-prone (NZBxNZW) F1 mice with respect to cell composition and vessel formation. Ribonucleic acid (RNA) sequencing was performed on transcriptomes isolated from Lymph nodes (LyN), macro-dissected TLS from kidneys, and total kidneys of mice at different disease stages by using Ion Torrent Personal Genome Machine (Ion PGM) and RNAseq from Illumina. Formation of TLS was found in anti-dsDNA antibody positive mice and the structures were organized as interconnected large networks with distinct T and B cell zones with adjacent dendritic cells, macrophages, plasma cells, high endothelial venules, supporting follicular dendritic cells network, and functional germinal centers. Comparison of gene profiles of whole kidney, renal TLS and LyN revealed a similar gene signature of TLS and LyN. The upregulated genes within the kidneys of lupus-prone mice during the development of LN reflected the TLS formation, while the downregulated genes were involved in metabolic processes of the kidney cells. A comparison with human LN gene expression revealed similar upregulated genes as observed during the development of murine LN and TLS. We conclude that kidney TLS have a similar cell composition, structure and gene signature as LyN, and therefore may function as a kidney specific type of LyN.

2020-07-30 | GSE155405 | GEO

An integrated analysis of lncRNAs and mRNAs expression profiles in the kidney of mice with lupus nephritis

Project description:Long non-coding RNAs (lncRNAs) are pervasively expressed and have been reported as potential biomarkers and therapeutic targets in various diseases, including systemic lupus erythematosus (SLE). However, there was limited information about lncRNAs expression in kidney tissue with lupus nephritis (LN), a serious complication of SLE. To explore the underlying molecular and cellular mechanisms of lncRNAs during pathogenesis of LN, RNA sequencing (RNA_seq) was performed to determine the lncRNAs and mRNAs expression of kidney tissues from LN (MRL/lpr) and control mouse. We identified 12, 979 novel lncRNAs in mouse. The expression profiles of both mRNA and lncRNA were significant different between LN and control mouse. In particular, both upregulated lncRNAs and mRNAs were more than downregulated ones in kidney tissue of LN mouse. However, GO analysis showed that more downregulated genes were enriched in immune and inflammatory response associated pathway. KEGG analysis showed that both downregulated and upregulated genes were enriched in pathway including SLE pathway, about half of these SLE-assocaited genes were inflammatory factors. Moreover, we found that 2, 181 DElncRNAs potential targeted and regulated expresison of 778 mRNA in kidney tissues of LN. The results showed that 11 DE-LncRNAs targeted and co-expressed with six immune and SLE-assocaited genes. qPCR confirmed that lncRNA Gm20513 would positively regualte the expression of SLE-associated gene H2-Aa. In conclusion, our study demonstrates that lncRNA will influence the progression of LN and will provide some cues for further study of lncRNAs in LN. LncRNA-mRNA regulation network may have important value in LN diagnosis and therapy.

2020-12-30 | GSE153547 | GEO

LncRNA expression profiling for 9 human plasma samples from systemic lupus erythematosus patients and healthy controls

Project description:To screen the differentially expressed lncRNAs, we performed lncRNA profiling using ArrayStar Human LncRNA Microarray in 24 new-onset systemic lupus erythematosus (SLE) patients and 12 age- and sex-matched healthy controls (HCs). For the lncRNA microarray screening, total RNA from plasma was isolated from 12 SLE without nephritis, 12 lupus nephritis (LN) and 12 HCs. Four RNA samples were mixed togther as a pool of sample for microarray analysis. Accordingly, there were each three pooled RNA samples from 12 SLE without nephritis, 12 LN and 12 HCs for microarray analysis. Hierarchical clustering showed the plasma levels of lncRNAs and mRNAs differed significantly between 24 new-onset SLE patients and 12 control subjects. With a fold change ≥ 2 and P ≤ 0.05, we identified 1315 significantly differentially expressed lncRNAs (743 lncRNAs up-regulated and 572 lncRNAs down-regulated) and 1363 differentially expressed mRNAs (745 mRNAs up-regulated and 618 mRNAs down-regulated) in plasma of SLE patients compared with control samples.

2017-08-12 | GSE102547 | GEO

Genome-wide peripheral blood transcriptome analysis of Arab female Lupus and Lupus nephritis

Project description:Genome-wide alternative splice analysis of RNA from lupus and its severe form lupus nephritis We aimed to explore the genome-wide peripheral blood transcriptome of lupus (SLE) and its severe form lupus nephritis (LN) cases compared to healthy subjects (HC) using high density Affymetrix Human Exon1.0.ST arrays. Analysis revealed 15 splice variants that are differentially expressed between SLE/HC and 99 variants between LN/HC (pâ¤0.05,SI>orâ¤0.5,Benjamin Hochberg-False discovery rate correction). Comparison between LN/SLE revealed 7 variants that are differentially expressed with pâ¤0.05,SI>0.5,Benjamin Hochberg-FDR correction. Pathway analysis of differentially spliced genes revealed 11 significant pathways in SLE and 12 in LN (p<0.05). Analysis of peripheral blood transcriptome revealed signature causative genes that are alternatively spliced, signifying their clinical relevance in the pathophysiology of disease. The extent of differential splicing was found to be higher in LN than in SLE, signifying the need for further in-depth research in the same domain. Present study is the first to reveal the significance of alternative variants in susceptibility to SLE and LN. We analyzed blood from 11 female subjects (5 lupus, 3 lupus nephritis and 3 healthy control) using the Affymetrix Human Exon 1.0 ST platform. Array data was processed by Alt Analyze and Genespring software. No techinical replicates were performed. One of the outiler sample (HC2) was excluded from further analysis.

2016-01-06 | E-GEOD-62764 | biostudies-arrayexpress

Extramedullary hematopoiesis and immune training drive systemic inflammation and associated organ damage in Systemic Lupus Erythematosus (RRBS)

Project description:Extramedullary hematopoiesis (EMH) is an emerging player in peripheral tissue injury in autoimmune disorders. Here, we use the NZBW/F1 lupus mouse model to explore the contribution of EMH to disease pathogenesis of SLE. We demonstrate that EMH takes place in the spleen of F1-L mice and show it is correlated with the activity of lupus nephritis (LN). Transcriptomic analysis demonstrated that splenic hematopoietic stem and progenitor cells (HSPC) carry a higher inflammatory potential than their bone marrow counterparts. Administration of β-glucan, an inducer of innate immunity, exacerbated splenic EMH, increased neutrophil production and worsened LN. Transcriptomic signatures of HSPCs in SLE patients with high disease activity show changes similar to the ones observed in the lupus-prone mouse model. Overall, EMH and trained immunity are ubiquitous in SLE, contributing to disease pathogenesis by sustaining and amplifying the inflammatory response and increasing the risk for flare of the disease.

2024-03-20 | GSE218779 | GEO

Extramedullary hematopoiesis and immune training drive systemic inflammation and associated organ damage in Systemic Lupus Erythematosus (RNA-seq)

2024-03-20 | GSE218778 | GEO

Lupus Nephritis is characterized by defective removal of Neutrophil Extracellular Traps that are modified in protein composition and contain specific auto-antigens.

Project description:Neutrophyl Extracellular Traps (NETs) accumulated in serum of patients with Lupus Nephritis for defective removal by DNAse. Among a complex protein panel (overall 802) two clusters of 16 and 13 proteins were more expressed by LN and SLE NETs respectively; oxidized aenolase and annexin A1 were main components of the first series in LN. NETs may represent a source of modified intracellular antigens for autoimmunity in LN.

2019-11-12 | PXD007754 | Pride

Genome-wide peripheral blood transcriptome analysis of Arab female Lupus and Lupus nephritis

Project description:Genome-wide alternative splice analysis of RNA from lupus and its severe form lupus nephritis We aimed to explore the genome-wide peripheral blood transcriptome of lupus (SLE) and its severe form lupus nephritis (LN) cases compared to healthy subjects (HC) using high density Affymetrix Human Exon1.0.ST arrays. Analysis revealed 15 splice variants that are differentially expressed between SLE/HC and 99 variants between LN/HC (p≤0.05,SI>or≤0.5,Benjamin Hochberg-False discovery rate correction). Comparison between LN/SLE revealed 7 variants that are differentially expressed with p≤0.05,SI>0.5,Benjamin Hochberg-FDR correction. Pathway analysis of differentially spliced genes revealed 11 significant pathways in SLE and 12 in LN (p<0.05). Analysis of peripheral blood transcriptome revealed signature causative genes that are alternatively spliced, signifying their clinical relevance in the pathophysiology of disease. The extent of differential splicing was found to be higher in LN than in SLE, signifying the need for further in-depth research in the same domain. Present study is the first to reveal the significance of alternative variants in susceptibility to SLE and LN.

2016-01-06 | GSE62764 | GEO

Expression data from human with lupus nephritis (LN)

Project description:Nephritis (LN) is a serious manifestation of SLE. Therapeutic studies in mouse LN models do not always predict outcomes of human therapeutic trials, raising concerns about the human relevance of these models. In this study we used an unbiased transcriptional network approach to define similarities and differences between three lupus models and human LN. Affymetrix-based expression profiles were analyzed using Genomatix Bibliosphere software and transcriptional networks were compared using the Tool for Approximate LargE graph matching (TALE). The 20 network hubs (nodes) shared between all three models and human LN reflect key pathologic processes, namely immune cell infiltration/activation, macrophage/dendritic cell activation, endothelial cell activation/injury and tissue remodeling/fibrosis. Each model also shares unique features with human LN. Pathway analysis of the TALE nodes highlighted macrophage/DC activation as a cross-species shared feature. To distinguish which genes and activation pathways might derive from mononuclear phagocytes in the human kidneys the gene expression profile of isolated NZB/W renal mononuclear cells was compared with human LN kidney profiles. Network analysis of the shared signature highlighted NFkappaB1 and PPARgamma as major hubs in the tubulointerstitial and glomerular networks respectively. Key nodes in the renal macrophage inflammatory response form the basis for further mechanistic and therapeutic studies. We used microarrays to analyze the transcriptome of microdissected renal biopsies from patients with lupus nephritis (LN) RNA from glomeruli and tubulointerstitial compartments was extracted and processed for hybridization on Affymetrix microarrays.

2012-06-27 | E-GEOD-32591 | biostudies-arrayexpress

Expression data from lupus NZB/W, NZM2410, NZW/BXSB mouse kidneys prenephritic and nephritic.

Project description:Nephritis (LN) is a serious manifestation of SLE. Therapeutic studies in mouse LN models do not always predict outcomes of human therapeutic trials, raising concerns about the human relevance of these models. In this study we used an unbiased transcriptional network approach to define similarities and differences between three lupus models and human LN. Affymetrix-based expression profiles were analyzed using Genomatix Bibliosphere software and transcriptional networks were compared using the Tool for Approximate LargE graph matching (TALE). The 20 network hubs (nodes) shared between all three models and human LN reflect key pathologic processes, namely immune cell infiltration/activation, macrophage/dendritic cell activation, endothelial cell activation/injury and tissue remodeling/fibrosis. Each model also shares unique features with human LN. Pathway analysis of the TALE nodes highlighted macrophage/DC activation as a cross-species shared feature. To distinguish which genes and activation pathways might derive from mononuclear phagocytes in the human kidneys the gene expression profile of isolated NZB/W renal mononuclear cells was compared with human LN kidney profiles. Network analysis of the shared signature highlighted NFkappaB1 and PPARgamma as major hubs in the tubulointerstitial and glomerular networks respectively. Key nodes in the renal macrophage inflammatory response form the basis for further mechanistic and therapeutic studies. We used microarrays to analyze the renal transcriptome of three different lupus mouse models, at early stage of lupus and during lupus nephritis. RNA from whole kidneys was extracted and processed for hybridization on Affymetrix microarrays.

2012-08-01 | E-GEOD-32583 | biostudies-arrayexpress

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