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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE218779 | GEO | 2024/03/20

REPOSITORIES: GEO

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

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 | GSE218778 | 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

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

Gene expression profile of DOCK8+CD4 T cell which causes systemic lupus erythematosus

Project description:Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease of unknown cause. We show here that a novel T follicular helper cell type expressing the guanine nucleotide exchange factor DOCK8 on the cell surface causes SLE. These cells, which we have designated autoantibody-inducing CD4 T (aiCD4 T) cells, are generated after resuscitation from anergy following strong TCR stimulation by antigen. When mice normally not prone to autoimmune disease were repeatedly immunized with an antigen such as OVA, they generated DOCK8+ CD4 T cells. These DOCK8+ CD4 T cells, in vivo and also upon transfer to naïve mice, induced a variety of autoantibodies and lesions characteristic of SLE. TCR repertoire analyses showed that a substantial number of novel TCR repertoires were generated in the DOCK8+ CD4 T cells, which induced novel autoantibodies upon transfer to naïve mice. DOCK8+ CD4 T cells are localized in splenic red pulp, the space immunoreactive against a variety of antigens, and specifically increased in the peripheral blood of SLE patients in association with disease activity. Anti-DOCK8 antibody treatment ameliorated the lesions induced by DOCK8+ CD4 T cells and in lupus model (NZB x W) F1 mice. Thus, when CD4 T cells are overstimulated by an external disturbance, i.e., repeatedly stimulated with antigen, to levels that surpass the system’s self-organized criticality, these cells express DOCK8 on the cell surface and acquire autoreactivity via TCR re-revision at the periphery. These DOCK8+ CD4 T cells subsequently induce a variety of autoantibodies and SLE.

2020-10-09 | GSE159240 | 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

B cell signature during inactive systemic lupus

Project description:Systemic lupus erythematosous (SLE) is an autoimmune disease with an important clinical and biological heterogeneity. B lymphocytes appear central to the development of SLE which is characterized by the production of a large variety of autoantibodies and hypergammaglobulinemia. In mice, immature B cells from spontaneous lupus prone animals are able to produce autoantibodies when transferred into immunodeficient mice, strongly suggesting the existence of intrinsic B cell defects during lupus. In order to approach these defects in humans, we compared the peripheral B cell transcriptomes of quiescent lupus patients to normal B cell transcriptomes. 17 patients with quiescent lupus (patient1-17) versus 9 controls (Control1-6,Control8-10).

2011-06-23 | E-GEOD-30153 | biostudies-arrayexpress

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

RNA-seq of peripheral blood mononuclear cell (PBMC) derived from normal healthy donors and systemic lupus erythematosus (SLE) patients

Project description:Systemic lupus erythematosus (SLE), also known simply as lupus, is an autoimmune disease. There is no cure for SLE. The mechanism involves an immune response by autoantibodies against a person's own tissues. However, the mechanism underlying imbalance of autoantibodies is not clear. In this experiment, peripheral blood was obtained from normal healthy donors and systemic lupus erythematosus (SLE) patients. Peripheral blood mononuclear cells (PBMC) were separated by Ficoll separation solution. Samples of four (total eight) donors were pooled and Samples of four (total eight) SLE patients were pooled. The aim was to characterize the mRNA profile of SLE patients compared to healthy donors and find the new target of diagnosis or treatment for SLE.

2020-08-14 | E-MTAB-7145 | biostudies-arrayexpress

B cell signature during inactive systemic lupus

2011-06-23 | GSE30153 | GEO

Single cell RNA sequencing of femur bone marrow cells from the NZBWF1 systemic lupus erythematosus mouse model and its progenitors.

Project description:Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by failure of self-tolerance mechanisms and the resultant production of autoreactive antibodies. The NZBWF1 mouse spontaneously develops a lupus-like syndrome and is used as model of SLE. The NZBWF1 model represents the F1 generation of a cross between New Zealand Black (NZB) and New Zealand White (NZW) mice. In this study we investigated the model and its progenitors (NZB, NZW) gene expression with single cell RNA sequencing on cells isolated from bone marrow and processed with the 10X Chromium.

2021-05-20 | GSE174728 | GEO

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