Immunopathogenesis of renal inflammation during the progression, remission and relapse of renal disease in the NZB/W murine lupus model
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Celine Berthier
PROVIDER: E-GEOD-50038 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below.
2013-08-20 | GSE50038 | GEO
Project description:Renal infiltration with mononuclear cells is associated with poor prognosis in SLE. A renal macrophage/dendritic cell signature is associated with onset of nephritis in NZB/W mice and immune modulating therapies can reverse this signature and the associated renal damage despite ongoing immune complex deposition. Our findings suggest that mononuclear phagocytes with an aberrant activation profile contribute to tissue damage in lupus nephritis by mediating both local inflammation and excessive tissue remodeling. We used microarrays to analyze the gene expression of renal isolated macrophages at early stage of lupus (young) during lupus nephritis (sick) and after induction of remission (Rem) NZB/W F4/80hi mouse cells were isolated using flow cytometry; RNA from cells (young, sick and after complete remission) was extracted and processed for hybridization on Affymetrix microarrays.
2011-12-31 | E-GEOD-27045 | biostudies-arrayexpress
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
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
Project description:ObjectiveA challenging issue in the clinical management of lupus nephritis (LN) is the resistance to immunosuppressive therapy. We postulated that perturbed intrarenal immune cell landscape affected LN onset and remission induction, and shedding light on the characteristics of intrarenal immune cell infiltration could cultivate more efficient treatment regimens.Materials and methodsGenome-wide expression profiles of microarray datasets were downloaded from the Gene Expression Omnibus database. The CIBERSORT algorithm was used to analyze the intrarenal immune cell landscape, followed by Pearson correlation analysis and principal component analysis. The differentially expressed genes were identified and subjected to Gene Ontology (GO) enrichment analyses and protein-protein interaction network establishment, being visualized by Cytoscape and further analyzed by CytoHubba to extract hub genes. Hub genes were also validated in the genomic dataset from kidney biopsy-proven LN patients.ResultsIn addition to memory B cells, monocytes and M1 macrophages were identified as two predominantly increased intrarenal immune cell types in LN-prone NZB/W mice upon nephritis onset. Most interestingly, apart from memory B cells, monocytes and M1 macrophages proportions in kidney tissue were significantly lower in early remission mice compared with late remission mice. Furthermore, GO analysis showed that intrarenal mononuclear phagocytes triggered nephritis onset mainly via the initiation of adaptive immune response and inflammatory reaction, but this functional involvement was mitigated upon remission induction. Hub genes related to LN onset in NZB/W mice were validated in the genomic dataset from kidney biopsy-proven LN patients.ConclusionLN characterizes aberrant mononuclear phagocytes abundance and signature upon disease onset, of which the reversal is associated with early remission induction in LN-prone NZB/W mice. Mononuclear phagocytes might be an adjunctive histology marker for monitoring disease onset and stratifying LN patients in terms of response to remission induction therapy.
| S-EPMC7693546 | biostudies-literature
Project description:To elucidate the molecular mechanisms involved in renal inflammation during the progression, remission, and relapse of nephritis in murine lupus models using transcriptome analysis.Kidneys from (NZB × NZW)F1 (NZB/NZW) and NZM2410 mice were harvested at intervals during the disease course or after remission induction. Genome-wide expression profiles were obtained from microarray analysis of perfused kidneys. Real-time polymerase chain reaction (PCR) analysis for selected genes was used to validate the microarray data. Comparisons between groups using SAM, and unbiased analysis of the entire data set using singular value decomposition and self-organizing maps were performed.Few changes in the renal molecular profile were detected in prenephritic kidneys, but a significant shift in gene expression, reflecting inflammatory cell infiltration and complement activation, occurred at proteinuria onset. Subsequent changes in gene expression predominantly affected mitochondrial dysfunction and metabolic stress pathways. Endothelial cell activation, tissue remodeling, and tubular damage were the major pathways associated with loss of renal function. Remission induction reversed most, but not all, of the inflammatory changes, and progression toward relapse was associated with recurrence of inflammation, mitochondrial dysfunction, and metabolic stress signatures.Immune cell infiltration and activation is associated with proteinuria onset and is reversed by immunosuppressive therapy, but disease progression is associated with renal hypoxia and metabolic stress. Optimal therapy for lupus nephritis may therefore need to target both immune and nonimmune disease mechanisms. In addition, the overlap of a substantial subset of molecular markers with those expressed in the kidneys of lupus patients suggests potential new biomarkers and therapeutic targets.
| S-EPMC4554534 | biostudies-literature
Project description:Renal infiltration with mononuclear cells is associated with poor prognosis in SLE. A renal macrophage/dendritic cell signature is associated with onset of nephritis in NZB/W mice and immune modulating therapies can reverse this signature and the associated renal damage despite ongoing immune complex deposition. Our findings suggest that mononuclear phagocytes with an aberrant activation profile contribute to tissue damage in lupus nephritis by mediating both local inflammation and excessive tissue remodeling. We used microarrays to analyze the gene expression of renal isolated macrophages at early stage of lupus (young) during lupus nephritis (sick) and after induction of remission (Rem)
2011-12-31 | GSE27045 | GEO
Project description:OBJECTIVE:This observational study was a retrospective analysis of prospectively collected Hopkins Lupus Cohort data to compare longterm renal survival in patients with lupus nephritis (LN) who achieved complete (CR), partial (PR), or no remission following standard-of-care LN induction therapy. METHODS:Eligible patients with biopsy-proven LN (revised American College of Rheumatology or Systemic Lupus Collaborating Clinics criteria) were identified and categorized into ordinal (CR, PR, or no remission) or binary (response or no response) renal remission categories at 24 months post-diagnosis [modified Aspreva Lupus Management Study (mALMS) and modified Belimumab International Lupus Nephritis Study (mBLISS-LN) criteria]. The primary endpoint was longterm renal survival [without endstage renal disease (ESRD) or death]. RESULTS:In total, 176 patients met the inclusion criteria. At Month 24 postbiopsy, more patients met mALMS remission criteria (CR = 59.1%, PR = 30.1%) than mBLISS-LN criteria (CR = 40.9%, PR = 16.5%). During subsequent followup, 18 patients developed ESRD or died. Kaplan-Meier plots suggested patients with no remission at Month 24 were more likely than those with PR or CR to develop the outcome using either mALMS (p = 0.0038) and mBLISS-LN (p = 0.0097) criteria for remission. Based on Cox regression models adjusted for key confounders, those in CR according to the mBLISS-LN (HR 0.254, 95% CI 0.082-0.787; p = 0.0176) and mALMS criteria (HR 0.228, 95% CI 0.063-0.828; p = 0.0246) were significantly less likely to experience ESRD/mortality than those not in remission. CONCLUSION:Renal remission status at 24 months following LN diagnosis is a significant predictor of longterm renal survival, and a clinically relevant endpoint.
| S-EPMC5932209 | biostudies-literature
Project description:The CEL files of this study are additional to the GSE32583 and GSE44691; they are microarrays of lupus nephritis NZBW mouse model at 30 wks old, or treated with CTX+CTLAIg+anti-CD154 (early and late after remission) or Ad-TACI-Ig+CTLA4Ig (late after remission) and NZM2410 treated with Ad-BAFF-R-Ig.
2014-12-31 | GSE49898 | GEO
Project description:As a key anti-inflammatory cytokine, IL-10 is crucial in preventing inflammatory and autoimmune diseases. However, in human and murine lupus, its role remains controversial. Our aim was to understand regulation and immunologic effects of IL-10 on different immune functions in the setting of lupus. This was explored in lupus-prone NZB/W F1 mice in vitro and vivo to understand IL-10 effects on individual immune cells as well as in the complex in vivo setting. We found pleiotropic IL-10 expression that largely increased with progressing lupus, while IL-10 receptor (IL-10R) levels remained relatively stable. In vitro experiments revealed pro- and anti-inflammatory IL-10 effects. Particularly, IL-10 decreased pro-inflammatory cytokines and slowed B cell proliferation, thereby triggering plasma cell differentiation. The frequent co-expression of ICOS, IL-21 and cMAF suggests that IL-10-producing CD4 T cells are important B cell helpers in this context. In vitro and in vivo effects of IL-10 were not fully concordant. In vivo IL-10R blockade slightly accelerated clinical lupus manifestations and immune dysregulation. Altogether, our side-by-side in vitro and in vivo comparison of the influence of IL-10 on different aspects of immunity shows that IL-10 has dual effects. Our results further reveal that the overall outcome may depend on the interplay of different factors such as target cell, inflammatory and stimulatory microenvironment, disease model and state. A comprehensive understanding of such influences is important to exploit IL-10 as a therapeutic target.
| S-EPMC7866297 | biostudies-literature