Activation of Interferon and Complement Pathways in Thrombotic Microangiopathy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA556908 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9847790.fastq.gz | Fastqsanger.gz | |||
| SRR9847800.fastq.gz | Fastqsanger.gz | |||
| SRR9847791.fastq.gz | Fastqsanger.gz | |||
| SRR9847801.fastq.gz | Fastqsanger.gz | |||
| SRR9847792.fastq.gz | Fastqsanger.gz |
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Project description:Transplant-associated thrombotic microangiopathy (TA-TMA) is a significant cause of mortality after hematopoietic stem cell transplant (HSCT). Complement blockade is an effective therapeutic strategy for TA-TMA, but some patients with severe disease lack a complete response, prompting a search for additional targetable endothelial injury pathways. We performed transcriptome analysis of peripheral blood mononuclear cells collected prior to HSCT and at onset of TA-TMA and observed significant up-regulation of classical and alternative complement pathways during active TA-TMA. At resolution of TA-TMA after eculizumab therapy, essentially all up-regulated genes and pathways returned to baseline expression levels, supporting the clinical practice of successfully discontinuing complement blockade after resolution of TA-TMA. Further analysis of the global transcriptional regulatory network showed a notable interferon signature associated with TA-TMA with increased STAT1 and STAT2 signaling. To confirm our observations, we documented a high incidence of clinically significant TMA in children with hemophagocytic lymphohistiocytosis (HLH), an interferon gamma-driven disease, outside the setting of transplantation. We also confirmed increased interferon signaling in a separate cohort of patients by measuring CXCL9 and CXCL10 in urine. Our data suggest a key relationship between increased interferon signaling, complement activation, and TMA in two distinct clinical settings, HLH and TA-TMA. Combined anti-complement and anti-interferon treatment may facilitate disease control in patients with refractory TA-TMA. These data cast light on the occurrence of TMA in persons receiving therapeutic interferons, and possibility of TMA in other interferon-driven diseases where interferon may be a novel therapeutic target.
2020-03-30 | GSE134979 | GEO
Project description:Complement proteins are deposited in the muscles of patients with myositis. However, the local expression and regulation of complement genes within myositis muscle have not been well characterized. In this study, bulk RNA sequencing (RNAseq) analyses of muscle biopsy specimens revealed that complement genes are locally overexpressed and correlate with markers of myositis disease activity, including the expression of interferon-gamma (IFN )-induced genes. Single cell and single nuclei RNAseq analyses showed that most local expression of complement genes occurs in macrophages, fibroblasts, and satellite cells, with each cell type expressing different sets of complement genes. Biopsies from immune-mediated necrotizing myopathy patients, who have the lowest levels of IFN -induced genes, also had the lowest complement gene expression levels. Furthermore, data from cultured human cells showed that IFN upregulates complement expression in macrophages, fibroblasts, and muscle cells. Taken together, our results suggest that in myositis muscle, IFN coordinates the local overexpression of complement genes that occurs in several cell types.
2023-02-08 | GSE220915 | GEO
Project description:Background and objectives: Atypical hemolytic uremic syndrome is a form of thrombotic microangiopathy caused by dysregulation of the alternative complement pathway. There is evidence showing complement activation in other thrombotic microangiopathies. The aim of this study was to evaluate complement activation in different thrombotic microangiopathies and to monitor treatment response.Design, setting, participants, & measurements: Complement activation was assessed by exposing endothelial cells to sera or activated-patient plasma-citrated plasma mixed with a control sera pool (1:1)-to analyze C5b-9 deposits by immunofluorescence. Patients with atypical hemolytic uremic syndrome (n=34) at different stages of the disease, HELLP syndrome (a pregnancy complication characterized by hemolysis, elevated liver enzymes, and low platelet count) or severe preeclampsia (n=10), and malignant hypertension (n=5) were included.Results: Acute phase atypical hemolytic uremic syndrome-activated plasma induced an increased C5b-9 deposition on endothelial cells. Standard and lower doses of eculizumab inhibited C5b-9 deposition in all patients with atypical hemolytic uremic syndrome, except in two who showed partial remission and clinical relapse. Significant fibrin formation was observed together with C5b-9 deposition. Results obtained using activated-plasma samples were more marked and reproducible than those obtained with sera. C5b-9 deposition was also increased with samples from patients with HELLP (all cases) and preeclampsia (90%) at disease onset. This increase was sustained in those with HELLP after 40 days, and levels normalized in patients with both HELLP and preeclampsia after 6-9 months. Complement activation in those with malignant hypertension was at control levels.Conclusions: The proposed methodology identifies complement overactivation in patients with atypical hemolytic uremic syndrome at acute phase and in other diseases such as HELLP syndrome and preeclampsia. Moreover, it is sensitive enough to individually assess the efficiency of the C5 inhibition treatment.
| S-EPMC6895490 | biostudies-literature
Project description:Transplant-associated thrombotic microangiopathy (TA-TMA) is an important cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The complement inhibitor eculizumab improves TA-TMA, but not all patients respond to therapy, prompting a search for additional targetable pathways of endothelial injury. TA-TMA is relatively common after HSCT and can serve as a model to study mechanisms of tissue injury in other thrombotic microangiopathies. In this work, we performed transcriptome analyses of peripheral blood mononuclear cells collected before HSCT, at onset of TA-TMA, and after resolution of TA-TMA in children with and without TA-TMA after HSCT. We observed significant upregulation of the classical, alternative, and lectin complement pathways during active TA-TMA. Essentially all upregulated genes and pathways returned to baseline expression levels at resolution of TA-TMA after eculizumab therapy, supporting the clinical practice of discontinuing complement blockade after resolution of TA-TMA. Further analysis of the global transcriptional regulatory network showed a notable interferon signature associated with TA-TMA with increased STAT1 and STAT2 signaling that resolved after complement blockade. In summary, we observed activation of multiple complement pathways in TA-TMA, in contrast to atypical hemolytic uremic syndrome (aHUS), where complement activation occurs largely via the alternative pathway. Our data also suggest a key relationship between increased interferon signaling, complement activation, and TA-TMA. We propose a model of an "interferon-complement loop" that can perpetuate endothelial injury and thrombotic microangiopathy. These findings open opportunities to study novel complement blockers and combined anti-complement and anti-interferon therapies in patients with TA-TMA and other microangiopathies like aHUS and lupus-associated TMAs.
| S-EPMC7094010 | biostudies-literature
Project description:Coordinated local overexpression of complement induced by interferon gamma in myositis
| PRJNA911908 | ENA
Project description:Whole blood transcriptome identifies interferon-regulated genes as key drivers in thrombotic primary antiphospholipid syndrome
| PRJNA845785 | ENA
Project description:Microglia repair injury and maintain homeostasis in the brain, but whether aberrant microglial activation can contribute to neurodegeneration remains unclear. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive up-regulation of lysosomal and innate immunity genes, increased complement production, and synaptic pruning activity in microglia. During aging, Grn-/- mice show profound accumulation of microglia and preferential elimination of inhibitory synapses in the ventral thalamus, which contribute to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, blocking complement activation by deleting C1qa gene significantly reduces synaptic pruning by Grn-/- microglia, and mitigates neurodegeneration, behavioral phenotypes and premature mortality in Grn-/- mice. These results uncover a previously unrecognized role of progranulin in suppressing microglia activation during aging, and support the idea that blocking complement activation is a promising therapeutic target for neurodegeneration caused by progranulin deficiency. Gene expression study in multiple brain regions from a mouse model of progranulin deficiency Please note that 9 outlier samples were excluded from data analysis. Therefore, there are 326 raw data columns (i.e. 163 samples) in the non_normalized data matrix while 154 samples are represented here.
2016-03-31 | E-GEOD-75083 | biostudies-arrayexpress
Project description:Epigenetic activation of antiviral sensors and effectors of interferon response pathways during SARS-CoV-2 infection
| PRJNA835413 | ENA
Project description:Cervicovaginal complement activation and microbiota during pregnancy and in parturition
| PRJEB51805 | ENA
Project description:Objective: Pathogenesis of antiphospholipid syndrome (APS) isn't fully elucidated. We aimed to identify gene signatures characterizing thrombotic primary APS (thrPAPS) and subgroups at high risk for worse outcomes. Methods: We performed whole blood next-generation RNA-sequencing in 62 patients with thrPAPS and 29 age-/sex-matched healthy controls (HCs), followed by differential gene expression analysis (DGEA) and enrichment analysis. We trained models on transcriptomics data using machine learning. Results: DGEA of 12.306 genes revealed 34 deregulated genes in thrPAPS versus HCs; 33 were upregulated by at least 2-fold, and 14/33 were type I and II interferon-regulated genes (IRGs) as determined by interferome database. Machine learning applied to deregulated genes returned 79% accuracy to discriminate thrPAPS from HCs, which increased to 82% when only the most informative IRGs were analyzed. Comparison of thrPAPS subgroups versus HCs showed an increased presence of IRGs among upregulated genes in venous thrombosis (21/23, 91%), triple-antiphospholipid antibody (aPL) positive (30/50, 60%), and recurrent thrombosis (19/42, 45%) subgroups. Enrichment analysis of upregulated genes in triple-aPL positive patients revealed terms related to 'type I interferon signaling pathway' and 'innate immune response'. DGEA among thrPAPS subgroups revealed upregulated genes, including IRGs, in patients with venous versus arterial thrombosis (n = 11, 9 IRGs), triple-aPL versus non-triple aPL (n = 10, 9 IRGs), and recurrent versus non-recurrent thrombosis (n = 10, 3 IRGs). Conclusion: Upregulated IRGs may better discriminate thrPAPS from HCs than all deregulated genes in peripheral blood. Taken together with DGEA data, IRGs are highly expressed in thrPAPS and high-risk subgroups of triple-aPL and recurrent thrombosis, with potential treatment implications.
2023-12-15 | GSE205465 | GEO