Neutralizing the IL-7Ra limits injury in ANCA-associated glomerulonephritis
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ABSTRACT:
PROVIDER: PRJNA1078820 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28034177.fastq.gz | Fastqsanger.gz | |||
| SRR28034178.fastq.gz | Fastqsanger.gz | |||
| SRR28034179.fastq.gz | Fastqsanger.gz | |||
| SRR28034180.fastq.gz | Fastqsanger.gz | |||
| SRR28034181.fastq.gz | Fastqsanger.gz |
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Project description:Increased T cell IL-7Rα (CD127) signaling is associated with poor prognosis in ANCA-associated vasculitis patients, whereas genes linked to T cell exhaustion such as PD-1 correlate with fewer relapses and better patient outcomes. This study characterised intrarenal CD127 and PD-1 expressing CD4+ and CD8+ T cells in mice with anti-MPO glomerulonephritis by RNA sequencing and examined the functional role of IL-7Rα in experimental glomerulonephritis mediated by anti-MPO T cell autoimmunity. There were 3,738 and 2,726 genes differentially expressed between intrarenal CD127-PD-1+ and CD127+PD-1- CD8+ and CD4+ T cells, respectively, with a substantial overlap of differentially expressed genes between CD8+ and CD4+ T cells. Both CD127-PD-1+ CD8+ and CD4+ T cells were enriched for previously described T cell exhaustion signatures that predict prognosis in autoimmune disease. As effector memory T cells drive inflammation, we blocked CD127 after the induction of anti-MPO autoimmunity. Compared with control IgG, anti-IL-7Rα antibodies limited histological injury, reduced albuminuria and reduced numbers of glomerular and interstitial leukocytes, with reduced intrarenal chemokine and pro-inflammatory cytokine expression. Intrarenal effector memory and exhausted CD4+ and CD8+ T cells are present in experimental anti-MPO glomerulonephritis. Neutralising effector memory T cells via the IL-7Rα after the induction of autoimmunity limits intrarenal inflammation and disease. IL-7Rα may be a therapeutic target in ANCA-associated vasculitis.
2025-02-01 | GSE256267 | GEO
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:ANCA Glomerulonephritis: From Molecules to Man
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Project description:Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis is a life-threatening systemic autoimmune disease that frequently presents as crescentic glomerulonephritis (GN) leading to kidney failure1. Despite recent advances2, treatment for most patients with ANCA-associated GN relies on unspecific immunosuppressive agents that are hazardous and only partially efficacious. To develop an anti-T-cell cytokine treatment strategy based on the immunopathogenesis of the individual patient, we established the combination of rapid single-cell immune profiling with standard histopathological analyses of renal biopsies. We report two patients with biopsy-proven ANCA-associated GN who presented with renal failure and active urinary sediment despite immunosuppressive therapy. Our data suggest that the integration of single-cell immune profiling with clinical and histopathological information facilitates personalized anti-cytokine therapies, such as ustekinumab in ANCA-GN, and warrants further investigation.
2025-10-01 | GSE207438 | GEO
Project description:Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis is a life-threatening autoimmune disease that often results in kidney failure caused by crescentic glomerulonephritis (ANCA-GN). To date, treatment of most patients with ANCA-GN relies on unspecific immunosuppressive agents that harbor serious adverse effects and limited efficiency. Using spatial and single-cell transcriptome analysis we characterized inflammatory niches in the kidneys of 34 patients with ANCA-GN and idenjpgied proinflammatory cytokine producing CD4+ and CD8+ T cells as a key pathogenic tissue signature. By employing digital pharmacology we then idenjpgied ustekinumab, a monoclonal antibody targeting IL-12 and IL-23 in these T cells, as promising therapeutic avenue. Based on these findings, four patients with relapsing ANCA-GN were treated with ustekinumab in combination with low-dose cyclophosphamide. Ustekinumab was given subcutaneously (90 mg) at weeks 0, 4, 12, and 24 and clinical and renal response were evaluated at week 26. Treatment induced substantial clinical response in all ANCA-GN patients, with improvements in kidney function, and Birmingham Vasculitis Activity Score, and was well tolerated. Our findings suggest that the pathogenesis-based treatment of ANCA-GN patients with ustekinumab is efficacious and warrants further investigation in clinical trials.
2024-06-28 | GSE250138 | GEO
Project description:Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis is a life-threatening autoimmune disease that often results in kidney failure caused by crescentic glomerulonephritis (ANCA-GN). To date, treatment of most patients with ANCA-GN relies on unspecific immunosuppressive agents that harbor serious adverse effects and limited efficiency. By performing spatial and single-cell transcriptome analysis, we characterized inflammatory niches in the kidneys of 34 patients with ANCA-GN and identified pro-inflammatory, cytokine producing CD4+ (TH1 and TH17 subsets) and CD8+ T cells (TC1 and TC17-like subsets) as a key pathogenic signature. Digital pharmacology identified ustekinumab, a monoclonal antibody targeting IL-12 and IL-23 in these T cells, as the most promising therapeutic drug to target. Based on these findings, four patients with relapsing ANCA-GN were treated with ustekinumab in combination with low-dose cyclophosphamide. Ustekinumab was given subcutaneously (90 mg) at weeks 0, 4, 12, and 24 and clinical and renal responses were evaluated at week 26. This treatment was well-tolerated and induced clinical response in all ANCA-GN patients, including an improved kidney function and Birmingham Vasculitis Activity Score. Our findings suggest that the pathogenesis-based treatment of ANCA-GN patients with ustekinumab is efficacious and warrants further investigation in clinical trials.
2024-07-01 | GSE253633 | 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 | GSE192995 | GEO
Project description:Single-cell TCR sequencing of T cells from ANCA-associated glomerulonephritis patients and experimental crescentic glomerulonephritis mouse model.
2023-03-31 | GSE223107 | 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:Immune Profiling-Based Treatment for ANCA-Associated Glomerulonephritis with Ustekinumab
| PRJNA855491 | ENA