Dataset Information

Neutralizing the IL-7Ra limits injury in ANCA-associated glomerulonephritis

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE256267 | GEO | 2025/02/01

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other
	GSE256267_processed_data.tsv.gz	Tabular

Items per page:

1 - 2 of 2

Similar Datasets

Project description:The etiopathogenesis underlying myeloperoxidase anti-neutrophil cytoplasmic antibody associated glomerulonephritis (MPO-AAGN) remains incompletely understood. Furthermore, there are only limited treatment options and treatment resistance of MPO-AAGN is still a common problem. To identify new targeted treatment options, intrarenal single-cell RNA sequencing (scRNA-seq) was applied to kidney biopsies from MPO-AAGN patients and control health kidney tissues to define the transcriptomic landscape at single-cell resolution. Intrarenal scRNAseq was also applied to a pre-clinical mouse model of MPO-AAGN to show that this model of disease can be used to trial new targeted treatments. NF-κB pathway activation was confirmed in a variety of kidney cells in MPO-AAGN patients. Kidney infiltrating immune cells of MPO-AAGN patients were mainly enriched in inflammatory pathways including TNF signaling, IL-17 signaling and NOD-like receptor signaling. These findings were similar in our pre-clinical mouse model of MPO-AAGN. Furthermore, there was an overexpression of inflammasome related genes (AIM2, IFI16) in MPO-AAGN patients. A dynamic gene expression in glomerular resident cells was observed in MPO-AAGN, including increased expression of several genes, including CD9 and SPARC, which were closely related to parietal epithelial hyperplasia and crescent formation and lesion progression. Importantly, overexpression of HSP90AA1 in non-focal mesangial cells and endothelial cells was found and the expression of several chemokines (CCL20, CXCL3, CXCL8, CXCL1, CCL2) were upregulated in non-focal proximal tubule cells. Moreover, MPO-AAGN patients with treatment resistance had higher proportions of kidney infiltrating classical monocytes and CD8+ T cells. Elevated expression of SPARC and LAMA4 in mesangial cells, IL33 in endothelial cells, and CFL1 in several cell clusters (proximal tubule cells, loop of Helen, macrophages) were observed in MPO-AAGN patients with treatment resistance when compared with patients who achieved remission after induction therapy. These results offer new insight into the pathogenesis of the progression and treatment resistance MPO-AAGN. We have identified new therapeutic targets for MPO-AAGN that can be tested in a pre-clinical model of disease.

Dataset Information

Neutralizing the IL-7Ra limits injury in ANCA-associated glomerulonephritis

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets