Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A recombinant TACI-Fc fusion protein targets IgA plasma cells in a mouse model of systemic lupus erythematosus

ABSTRACT: BAFF and APRIL play an important role in driving systemic lupus erythematosus (SLE) immunopathogenesis and kidney damage in lupus nephritis (LN); however, the underlying immune mechanisms contributing to disease pathology and the factors that increase risk of end organ damage are poorly understood. To investigate molecular profiles during the progression of LN, we carried out gene expression analysis on kidneys and spleens from lupus-prone NZM2328 mice treated for four weeks from the time of disease onset. We focused on female mice treated with BAFF and BAFF/APRIL inhibitors alongside cyclophosphamide as a standard therapy to identify mechanisms associated with improved renal outcomes. Inhibition of BAFF alone had a limited impact on gene expression profiles of diseased mice, decreasing myeloid cell and increasing metabolic gene signatures. However, targeting both BAFF and APRIL through competitive inhibition with a TACI-Fc fusion protein significantly altered immune populations in the spleen and depleted IgA plasma cells and also decreased pro-inflammatory immune cells and cytokines in the kidneys of diseased mice. All therapies had a broad impact on kidney pathology through reduction of proteinuria. Targeting both BAFF and APRIL is necessary to reduce autoreactive plasma cell generation and kidney inflammation effectively and especially to decrease IgA secreting plasma cells. The impact of targeting both members of the BAFF family of cytokines in lupus-prone NZM2328 mice provides support for its application in the treatment of human LN.

ORGANISM(S): Mus musculus

PROVIDER: GSE299922 | GEO | 2026/05/14

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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

iRhom2 Promotes Lupus Nephritis through ADAM17-Dependent TNF-α and EGFR Signaling

Project description:Lupus nephritis (LN) often results in progressive renal dysfunction. The inactive Rhomboid 2 (iRhom2) is a newly identified key regulator of A disintegrin and metalloprotease 17 (ADAM17), whose substrates, such as TNF-α and heparin-binding EGF (HB-EGF), have been implicated in the pathogenesis of chronic kidney disease. Here we demonstrate that deficiency of iRhom2 protects the lupus-prone Fcgr2b-/- mice from developing severe kidney damage without altering anti-double stranded (ds) DNA Ab production, by simultaneously blocking the HB-EGF/EGFR and the TNF-α signaling in the kidney tissues. Unbiased transcriptome profiling of kidneys and kidney macrophages revealed that TNF-α and HB-EGF/EGFR signaling pathways are highly upregulated in Fcgr2b-/- mice; alterations that were diminished in the absence of iRhom2. Pharmacological blockade of either TNF-α or EGFR signaling protected Fcgr2b-/- mice from severe renal damage. Finally, kidneys from LN patients showed increased iRhom2 and HB-EGF expression, with interstitial HB-EGF expression significantly associated with chronicity indices. Our data suggest that activation of iRhom2/ADAM17-dependent TNF-α and EGFR signaling plays a crucial role in mediating irreversible kidney damage in LN, thereby uncovering a novel target for selective and simultaneous dual inhibition of two major pathological pathways in the effector arm of the disease.

2019-01-01 | GSE107705 | GEO

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

Investigate the effect of MSCs treatment on the glomeruli of mice with lupus nephritis by RNA sequencing

Project description:Human umbilical cord mesenchymal stem cells (hUC-MSCs) have shown potential as a therapeutic option for lupus nephritis (LN), particularly in patients refractory to conventional treatments. Despite extensive translational research on MSCs, the precise mechanisms by which MSCs migrate to the kidney and restore renal function remain incompletely understood. Here, we aim to clarify the spatiotemporal characteristics of hUC-MSC migration into LN kidneys and their interactions with host cells in microenvironment. This study provides valuable insights into the significant involvement of CXCL10-CXCR3 axis in hUC-MSC migration to the LN kidneys and the subsequent remodeling of renal immune microenvironment.

2024-11-27 | GSE279823 | GEO

Microarray for B cells of TACI-IgG-treated MRL/lpr mice compared to control mice

Project description:Both multiple myeloma (MM) and systemic lupus erythematosus (SLE) are characterized with abnormal production of plasma cells. In both diseases, the process of B cells differentiate into plasmablast/plasma cell is disordered. Despite the continuous research on the development of prognostic factors and introduction of new agents, dysregulation of plasmablast/plasma cells in MM and SLE is still uncontrolled. Thus, it is necessary to explore the novel therapeutic target to plasmablast/plasma cells. We and other researchers have shown that BAFF inhibitor atacicept (TACI-IgG), leads to some degree of B cell depletion. BAFF-specific targeted therapy specifically affects early-stage B cells in the periphery without affecting late-stage compartments such as plasma cells. Specifically depletion of plasma cells could hold great potential for the treatment of autoimmune diseases. To explore the novel therapeutic target to plasma cells, we determined the gene expression profile in B cells (mainly plasma cells) from atacicept (TACI-IgG)-treated lupus-prone MRL/lpr mice by affymetrix microarrays.

2019-07-30 | E-MTAB-7106 | biostudies-arrayexpress

BAFF and APRIL counterregulate susceptibility to inflammation-induced preterm birth

Project description:Emerging clinical evidence points to a function for B cell activating factor (BAFF) in pregnancy. However, a direct role for BAFF-axis members including BAFF, the closely related a proliferation-inducing ligand (APRIL), and their respective receptors in pregnancy has not been examined. This study demonstrates that loss of BAFF results in decreased inflammatory responsiveness and decreased susceptibility to inflammation-induced preterm birth (PTB). In contrast, loss of APRIL increases inflammatory responsiveness and susceptibility to PTB. Consistent with overlapping receptor utilization by BAFF and APRIL, deletion of BAFF-axis receptors is not sufficient to modify susceptibility to PTB. Critically, therapeutic administration of BAFF/APRIL monoclonal antibodies or recombinant proteins is sufficient to manipulate susceptibility to inflammation-induced PTB. Further, macrophages are identified as the principle BAFF producing immune cells at the maternal-fetal interface and BAFF and APRIL divergently manipulate macrophage gene expression and inflammatory function. Genes linked to labor initiation are upregulated in WT and APRIL deficient macrophages while downregulated in BAFF deficient macrophages and correlate with myeloid gene expression in human placental samples during labor. Thus, BAFF and APRIL play important, but divergent, counterregulatory inflammatory roles in pregnancy and provide new therapeutic targets for mitigating the risk of PTB.

2023-08-03 | GSE202811 | GEO

Effect of Sirolimus treatment on lupus nephritis in NZB/W F1 female mice

Project description:NZB/WF1 female mice spontaneously develop autoimmune lupus nephritis. Expression profiling of kidney tissue from (a) 12 week NZB/W F1 female mice defined as asymptomatic for lupus nephritis, (b) 36 and 42 week NZB/W F1 female mice defined as diseased/symptomatic for lupus nephritis and (c) 36 and 42 week NZB/W F1 female mice that are diseased/symptomatic for lupus nephritis and treated with Sirolimus was carried out. The goal of the study was to identify genes associated with lupus nephritis and modulated by Sirolimus, an inhibitor of mTOR. In addition, lupus nephritis genes resistant to Sirolimus therapy were also identfied This series of samples comprises of kidney tissue from (a) 12 week old NZB/W F1 female mice defined as asymptomatic for lupus nephritis (N=4), (b) 36 (N=3) and 42 week (N=3) old NZB/W F1 female mice defined as diseased/symptomatic for lupus nephritis and (c) 36 (N=3)and 42 (N=3) week old NZB/W F1 female mice that are asymptomatic for lupus nephritis on treatment with Sirolimus

2008-11-20 | E-GEOD-12024 | biostudies-arrayexpress

Human and mouse lupus nephritis cross-species transcriptional analysis

Project description:This SuperSeries is composed of the following subset Series: GSE32583: Expression data from lupus NZB/W, NZM2410, NZW/BXSB mouse kidneys prenephritic and nephritic. GSE32591: Expression data from human with lupus nephritis (LN) Refer to individual Series

2012-08-01 | E-GEOD-32592 | biostudies-arrayexpress

Effect of Sirolimus treatment on lupus nephritis in NZB/W F1 female mice

2008-11-21 | GSE12024 | GEO

Kidney gene expression profiles from a lupus nephritis mouse model: SNF1 (SWR X NZB F1) mice treated with pristane

Project description:We characterized the longitudinal gene expression profiles of kidneys from a novel lupus model nephritis: SNF1 (SWR X NZB F1) mice treated with pristane. Genes from biological processes such as IFN response, complement, Fc gamma receptors, immune recruitment, innate immune pattern recognition, antibody response and fibrosis,were upregulated in diseased kidneys.

2016-09-06 | GSE86425 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data