Defining molecular and cellular landscape behind non-response to Lupus Nephritis drugs
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PROVIDER: PRJNA932236 | ENA |
REPOSITORIES: ENA
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Project description:Lupus nephritis (LN) is one of the more severe systemic lupus erythematosus manifestations with the potential of developing into end stage kidney disease. Mycophenolate mofetil (MMF) and Azathioprine (AZA) are widely used for both induction and maintenance therapy for LN, but the one year complete renal response ranges from 30-40% in most trials. Reasons for non-response are still unknown. Thus, anticipating lack of drug efficacy in a patient could lead to early introduction of advanced therapies. A longitudinal cohort comprising gene-expression and clinical data of responder and non-responder samples to MMF, AZA and standar of care drugs (hidroxicloroquine (HC) and HC + glococorticoids (GC) (SOC)) was retrospectively analyzed. Response to drugs was defined over time using SRI-4 scores. Differential gene expression and functional analysis were performed. Response rate was measured based on blood cell proportions. Single-cell RNA sequencing data was analyzed to identify the cell subtypes influencing non-response and their contributing genes. SLE: Systemic Lupus Erythematosus; MMF: Mycophenolate mofetil; AZA: Azathioprine; HC: Hydroxychloroquine; PHC: Prednisone (Glucocorticoid (GC)) + HC; SOC: Standard Of Care drugs (HC and HC + PHC)
2023-05-01 | GSE224705 | GEO
Project description:Membranous lupus nephritis is a frequent cause of nephrotic syndrome in patients with systemic lupus erythematosus. Unlike phospholipase A2 receptor or thrombospondin type 1 domain containing 7A-associated membranous nephropathy, where known antibodies can be detected within sera by indirect immunofluorescence and/or enzyme-linked immunosorbent assay, it is not possible to monitor disease activity in membranous lupus nephritis where the target autoantigens are mostly unknown. Determination of the target autoantigen has diagnostic significance, informs prognosis, and allows for non-invasive monitoring of disease activity in serum. We utilized mass spectrometry for antigen discovery of laser capture microdissected glomeruli from formalin-fixed paraffin embedded tissue and tissue IgG immunoprecipitation studies from frozen kidney biopsy tissue. We identified neural cell adhesion molecule 1 (NCAM1) to be a target antigen in membranous lupus nephritis and within rare cases of primary membranous nephropathy. The prevalence of NCAM1-associated membranous neuropathy was 5.7% of cases of membranous lupus nephritis. NCAM1 co-localizes with IgG within glomerular immune deposits. Additionally, serum from NCAM1 patients showed reactivity to NCAM1 recombinant protein. The presence of anti-NCAM1 antibodies in sera could allow for non-invasive monitoring of the disease. We propose that NCAM1 is a target autoantigen in a subset of patients with membranous lupus nephritis. Future studies are needed to determine whether anti-NCAM1 antibody levels correlate with disease activity or response to therapy.
2020-10-19 | PXD021123 | Pride
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
Project description:MicroRNAs (miRNA) have emerged as an important new class of modulators of gene expression. In this sudy we investigated miRNA that are differentially expressed in lupus nephritis. Microarray technology was used to investigate differentially expressed miRNA in PBMCs and EBV-transformed cell lines obtained from lupus nephritis patients and controls. TaqMan-based stem-loop real-time PCR was used for validation. Microarray analysis of miRNA expressed in African Americans (AA) derived lupus nephritis samples revealed 29 differentially expressed miRNA, of 850 tested. Microarray analysis of miRNA expressed in European American (EA) derived lupus nephritis samples revealed 50 differentially expressed miRNA, of 850 tested.
2011-12-30 | GSE21384 | GEO
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
2008-11-21 | GSE12024 | GEO
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:Lupus nephritis is a serious complication of systemic lupus erythematosus, mediated by IgG immune complex (IC) deposition in kidneys, with limited treatment options. Kidney macrophages are critical tissue sentinels that express IgG-binding Fcγ receptors (FcγRs), with previous studies identifying prenatally seeded resident macrophages as major IC responders. Using single-cell transcriptomic and spatial analyses in murine and human lupus nephritis, we sought to understand macrophage heterogeneity and subset-specific contributions in disease. In lupus nephritis, the cell fate trajectories of tissue-resident (TrMac) and monocyte-derived (MoMac) kidney macrophages were perturbed, with disease-associated transcriptional states indicating distinct pathogenic roles for TrMac and MoMac subsets. Lupus nephritis–associated MoMac subsets showed marked induction of FcγR response genes, avidly internalized circulating ICs, and presented IC-opsonized antigen. In contrast, lupus nephritis-associated TrMac subsets demonstrated limited IC uptake, but expressed monocyte chemoattractants, and their depletion attenuated monocyte recruitment to the kidney. TrMacs also produced B cell tissue niche factors, suggesting a role in supporting autoantibody-producing lymphoid aggregates. Extensive similarities were observed with human kidney macrophages, revealing cross-species transcriptional disruption in lupus nephritis. Overall, our study suggests a division of labor in the kidney macrophage response in lupus nephritis, with treatment implications — TrMacs orchestrate leukocyte recruitment while MoMacs take up and present IC antigen.
2022-10-14 | GSE215272 | GEO
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
Project description:GeneSet variation analysis was performed on microarrays to study the transcriptome of microdissected renal biopsies from lupus nephritis patients.
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Project description:Microarray gene expression analyses were performed on human skin samples from cutaneous lupus subtypes (SCLE and CCLE) and normal patients along with human kidney samples from lupus nephritis and normal patients
2021-04-22 | GSE112943 | GEO