Single-cell TCR-sequencing of T cells in crescentic glomerulonephritis
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE223107 | GEO | 2023/03/31
REPOSITORIES: GEO
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Project description:Anti neutrophil cytoplasmic antibody (ANCA) associated vasculitis is the most frequent cause of crescentic glomerulonephritis. Histopathologic features and clinical course of the disease are diverse and judgment of disease activity is often limited due to the lack of reliable activity markers. In order to define potentially new molecular or cellular markers in the kidney which may predict clinical outcome, we performed microarray analyses of renal biopsies from patients with ANCA-associated crescentic glomerulonephritis. We correlated expression profiles with clinical data from our prospective study of patients with renal ANCA disease. The CC chemokine ligand 18 (CCL18) was one of the most up-regulated proteins in kidneys of patients with ANCA-associated crescentic glomerulonephritis. CCL18 producing cells in the kidneys were identified as CD68 and CD209 positive myeloid dendritic cells. The density of CCL18 positive cells correlated with the severity of acute tubular injury and with the impairment of renal function. CCL18 protein levels were elevated in serum samples of patients with renal ANCA disease when compared with patients with non- ANCA-associated crescentic glomerulonephritis. Persistence of high CCL18 serum levels correlated with impairment of renal function and the risk of relapsing disease. Therefore, CCL18 might serve as a marker for persistent disease activity and renal relapses in ANCA-associated vasculitis.
2015-09-03 | E-MTAB-1944 | biostudies-arrayexpress
Project description:Single-cell RNA-seq of renal T cells from steroid treated or not treated crescentic glomerulonephritis mouse model and steroid treated ANCA-GN patients.
2022-11-11 | GSE217508 | GEO
Project description:The glucocorticoid-inducible protein annexin A1 has been shown to function as key-regulator of the resolution phase of inflammation but its role in immune-mediated crescentic glomerulonephritis has not been studied so far. Acute crescentic glomerulonephritis was induced in annexin A1 deficient and wildtype mice using a sheep serum against rat glomerular basement membrane constituents. Alterations in gene expression were determined by RNA-Seq and gene ontology analysis. Intrinsic annexin A1 has a protective effect in reducing pro-inflammatory signals and infiltration of neutrophil granulocytes during crescentic GN. The annexin A1 signaling cascade may therefore provide novel targets for the treatment of inflammatory kidney disease.
2022-10-04 | GSE204873 | GEO
Project description:The Wistar-Kyoto (WKY) rat shows marked susceptibility to crescentic glomerulonephritis, while Lewis rats are resistant. Glomerular injury and crescent formation are macrophage-dependent. The aim of this study is to use gene expression profiling to identify genetic factors that determine macrophage activation and render WKY rats susceptibile to glomerulonephritis.
2011-03-17 | E-MEXP-2624 | biostudies-arrayexpress
Project description:We previously showed that the rupture of Bowman’s capsule (BC) promotes the progression of crescent glomerulonephritis by enhancing CD8+ T cell entry into the glomeruli. In the present study, we utilized digital spatial profiling to simultaneously profile the altered mRNA transcript and protein abundances in the glomerular and periglomerular areas of biopsy samples of ANCA-associated glomerulonephritis. The paraffin-embedded biopsy samples were stained with Collagen IV, CD45, and Syto13 to distinguish the glomeruli with crescent formation but intact BC, with focal BC rupture, and with extensive rupture of BC and glomeruli without crescent formation and leukocytes infiltration in ANCA-GN. By assessing multiple discrete glomerular areas, we found that the transcript expression level of secreted phosphoprotein 1and its receptor CD44 were upregulated significantly in the glomeruli with more severe ruptures of BC, and their expression levels correlated positively with the fibrotic markers. We also found that 1) both alternative and classic complement pathways were activated in the glomeruli from patients with ANCA-GN; 2) M1 macrophages involved mostly in the early stage of BC rupture while M2 macrophages were involved in the late stage and may contribute to the fibrosis process of the crescents, and 3) apoptosis is likely the mechanism mediating the loss of glomerular cells in ANCA-GN. Our results demonstrate that digital spatial profiling allows the comparative analysis of mRNA and protein profiles in the individual glomeruli affected differently by the disease processes and to identify potential novel mechanisms in patients with ANCA-GN.
2022-02-01 | GSE192995 | GEO
Project description:We previously showed that the rupture of Bowman’s capsule (BC) promotes the progression of crescent glomerulonephritis by enhancing CD8+ T cell entry into the glomeruli. In the present study, we utilized digital spatial profiling to simultaneously profile the altered mRNA transcript and protein abundances in the glomerular and periglomerular areas of biopsy samples of ANCA-associated glomerulonephritis. The paraffin-embedded biopsy samples were stained with Collagen IV, CD45, and Syto13 to distinguish the glomeruli with crescent formation but intact BC, with focal BC rupture, and with extensive rupture of BC and glomeruli without crescent formation and leukocytes infiltration in ANCA-GN. By assessing multiple discrete glomerular areas, we found that the transcript expression level of secreted phosphoprotein 1and its receptor CD44 were upregulated significantly in the glomeruli with more severe ruptures of BC, and their expression levels correlated positively with the fibrotic markers. We also found that 1) both alternative and classic complement pathways were activated in the glomeruli from patients with ANCA-GN; 2) M1 macrophages involved mostly in the early stage of BC rupture while M2 macrophages were involved in the late stage and may contribute to the fibrosis process of the crescents, and 3) apoptosis is likely the mechanism mediating the loss of glomerular cells in ANCA-GN. Our results demonstrate that digital spatial profiling allows the comparative analysis of mRNA and protein profiles in the individual glomeruli affected differently by the disease processes and to identify potential novel mechanisms in patients with ANCA-GN.
2022-02-01 | GSE192994 | GEO
Project description:We analyzed the impact of the genetic background during experimental passive non-accelerated anti-glomerular basement membrane glomerulonephritis (anti-GBM-GN) (an equivalent to nephrotoxic nephritis) in two different mouse genetic backgrounds (C57BL6/J vs 129S2svPAS/crl). Glomerular extracts have been made at an early time point (e.g day 4 of the induction of the glomerulonephritis). RNA have been extracted following standard procedures.
2014-07-14 | GSE56236 | GEO
Project description:DNA methylation is one of the key epigenetic modifications involved in gene regulation. While whole-genome bisulfite sequencing (WGBS) allows the genome-wide quantification of DNA methylation at the single-base pair resolution, the contribution of DNA methylation in disease susceptibility remains to be fully understood. Here, we present a novel Bayesian smoothing approach (called ABBA) to accurately detect differentially methylated regions (DMRs) from WGBS data, and employ ABBA to map DNA methylation changes in disease. ABBA enables the genome-wide modeling of single-base resolution DNA methylation data, automatically adapting to different correlation structures in CpG methylation across the genome without requiring user-defined parameters and accounts for covariates and non-genetic confounding factors. First, we demonstrate the approach by an extensive simulation study and benchmarked ABBA against recently proposed alternative methods. We show the better performance of ABBA across a range of relevant parameters, including sequencing depth, number of replicates and noise level originating from incomplete bisulfite conversion. Second, we generated WGBS data from primary macrophages derived from an experimental rat model of glomerulonephritis and control rats, and employed ABBA to identify DMRs (>1,000 at 5% FDR) genome-wide that were associated with disease susceptibility. Investigation of the DMRs revealed differential DNA methylation localized to the promoter of the Ifitm3 gene and comparisons with existing DMR detection methods shows the enhanced interpretability of the results provided by ABBA. Additional ChIP-seq and RNA-seq analyses in the same experimental system showed differential transcription factor binding at the Ifitm3 promoter by JunD (an established determinant of glomerulonephritis) and consistent differential expression of Ifitm3. Taken together, these data suggest a role for DNA methylation alteration of the Ifitm3 gene in the pathogenesis of glomerulonephritis, and provide a proof of concept of using ABBA for differential methylation analysis of WGBS data.
2017-02-23 | GSE84719 | GEO
Project description:We investigated a glomerulonephritis (GN) model in rats induced by nephrotoxic serum (NTS) which contains antibodies against the glomerular basement membrane (GBM). The anti-GBM GN model in rats is widely used since its biochemical and histopathological characteristics are similar to crescentic nephritis and Goodpasture's disease in humans. Male Wistar Kyoto (WKY) and Sprague Dawley (SD) rats were dosed once with 1, 2.5 and 5 ml/kg nephrotoxic serum (NTS) or 1.5 and 5 ml/kg NTS, respectively. GN and tubular damage were observed histopathologically in all treated rats after 14 days. To obtain insight into molecular processes during GN pathogenesis, mRNA expression was investigated in WKY and SD kidneys. The immunopathological processes during GN are still not fully understood and likely involve both innate and adaptive immunity. In the present study, several hundred mRNAs were found deregulated, which functionally were mostly associated with inflammation and regeneration. The ?-chain of the major histocompatibility complex class II RT1.B (Rt1-Bb) and complement component 6 (C6) were identified as two mRNAs differentially expressed between WKY and SD rat strains which could be related to known different susceptibilities to NTS of different rat strains; both were increased in WKY and decreased in SD rats. Increased Rt1-Bb expression in WKY rats could indicate a stronger and more persistent cellular reaction of the adaptive immune system in this strain, in line with findings indicating adaptive immune reactions during GN. The complement cascade is also known to be essential for GN development, especially terminal cascade products like C6. Two different rat strains (WKY and SD) were dosed with different doses of NTS and after 14 days rats were euthanized and kidneys were removed for RNA extraction and hybridization on Affymetrix microarrays. We sought to analyze the deregulation of gene expression during NTS-induced glomerulonephritis and to compare the effect in the two rat strains.
2015-07-06 | E-GEOD-64265 | biostudies-arrayexpress
Project description:Analysis of glomeruli isolated from kidneys of 4 month male BXSB/MpJ-Yaa. The BXSB/MpJ-Yaa mouse strain is a lupus-prone model. Results provide insight into the pathogenic mechanisms linked to glomerulonephritis in BXSB/MpJ-Yaa mice. The glomeruli were isolated from 6 BXSB/MpJ-Yaa (glomerulonephritis model) and BXSB/MpJ-Yaa+ (control). 6 glomerular populations of each strain were devided into 3 groups (1 group / 2 populations). 3 glomerulonephritis models versus 3 controls analysis was performed. BXSB/MpJ-Yaa is a recombinant inbred strain developed originally from a C57BL/6 female mouse and a SB/Le male mouse. Yaa (Y-linked autoimmune accelerator locus) localizing on the Y chromosome of BXSB/MpJ-Yaa male mice is the result of a duplication of an about 4 Mbp telomeric segment near the pseudoautosomal region of the X chromosome onto the Y chromosome. BXSB/MpJ-Yaa+ (control) male mice carry the wild-type Y chromosome in place of the mutant Yaa-containing Y chromosome of BXSB/MpJ-Yaa male mice.
2014-01-01 | E-GEOD-51230 | biostudies-arrayexpress