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Blood transcriptome indicates different disease etiology in pediatric ANCA-associated vasculitis subtypes.

ABSTRACT: Blood transcriptome indicates different disease etiology in pediatric ANCA-associated vasculitis subtypes.

PROVIDER: PRJNA532630 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11743900.fastq.gz	Fastqsanger.gz
	SRR11743901.fastq.gz	Fastqsanger.gz
	SRR11743902.fastq.gz	Fastqsanger.gz
	SRR11743859.fastq.gz	Fastqsanger.gz
	SRR11743860.fastq.gz	Fastqsanger.gz

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Blood transcriptome indicates different disease etiology in pediatric ANCA-associated vasculitis subtypes.

Project description:Purpose: The goal of this study was to compare gene expression profiles from whole blood RNA-Seq data from pediatric ANCA-associated vasculitis patients to identify mechanistic endotypes. Methods: Whole blood mRNA profiles were generated from pediatric and adult vasculitis patients using Illumina GAIIx or Hi Seq 2500 RNA-Seq. Fastq files were alinged to human genome version GRC38.91 using STAR v2.6 and count data was generated with HTSEQ v0.61p1. Counts that passed quality and minimum expression filteres were anlayzed by hierarchical clustering based on Euclidean distance, and then for differential expression with DESeq2. Results: Our workflow identified 14,156 transcripts consistently expressed in vasculitis patients. Distance hierarchcial clustering identified three groups within these pediatric samples, and two groups plus one outlier in the adult samples. The two largest pediatric clusters were used as groups for differential expression analysis with the DESeq2 package for R. DE analysis identified 3,809 differentially expressed genes between clusters. Between the two adult groups, 1,682 genes were differentially expressed. DE genes were anlayzed for enrichment using ReatomePA as the reference database. This analysis revealed that genes involved in T-cell mediated immunity are more highly expressed in pediatric patients that fell into one endotype and those involved in neutrophil and Toll-like receptor mediated inflammation are more highly expressed in pediatric patients that fell into the other endotype group. Similar results were also seen in adults. Conclusions: This study utilizes RNA-Seq data to investigate the etiologies of ANCA-associated vasculitis. Using this approach we have identified T-cell mediated immunity and Toll-like receptor mediated inflammation as potentially differing inflammatory mechanisms in both pediatric and adult vasculitis patients that do not fall along normal diagnostic criteria.

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The effect of anti-MPO and anti-PR3 IgG from patients with ANCA vasculitis on human monocytes.

Project description:These data are part of a body of work exploring the effect of IgG from patients with ANCA vasculitis on human monocytes in vitro. Please see the relevant publication for a full description.

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Immune profiling-based targeting of pathogenic T cells with ustekinumab in ANCA-associated glomerulonephritis

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.

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CC chemokine ligand 18 (CCL18) is associated with disease activity and relapse in ANCA-associated crescentic glomerulonephritis

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.

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