Differential transcriptomics in sarcoidosis lung and lymph node granulomas with comparisons to pathogen-specific granulomas
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ABSTRACT:
PROVIDER: PRJNA662362 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12610759.fastq.gz | Fastqsanger.gz | |||
| SRR12610760.fastq.gz | Fastqsanger.gz | |||
| SRR12610761.fastq.gz | Fastqsanger.gz | |||
| SRR12610762.fastq.gz | Fastqsanger.gz | |||
| SRR12610763.fastq.gz | Fastqsanger.gz |
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Project description:Rationale: Despite the availability of multi-“omics” strategies, insights into the etiology and pathogenesis of sarcoidosis have been elusive. This is partly due to the lack of reliable preclinical models and a paucity of validated biomarkers. As granulomas are a key feature of sarcoidosis, we speculate that direct genomic interrogation of sarcoid tissues, may lead to identification of dysregulated gene pathways or biomarker signatures. Objective: To facilitate the development sarcoidosis genomic biomarkers by gene expression profiling of sarcoidosis granulomas in lung and lymph node tissues (most commonly affected organs) and comparison to infectious granulomas (coccidiodomycosis and tuberculosis).
2020-12-09 | GSE157671 | GEO
Project description:RationaleDespite the availability of multi-"omics" strategies, insights into the etiology and pathogenesis of sarcoidosis have been elusive. This is partly due to the lack of reliable preclinical models and a paucity of validated biomarkers. As granulomas are a key feature of sarcoidosis, we speculate that direct genomic interrogation of sarcoid tissues, may lead to identification of dysregulated gene pathways or biomarker signatures.ObjectiveTo facilitate the development sarcoidosis genomic biomarkers by gene expression profiling of sarcoidosis granulomas in lung and lymph node tissues (most commonly affected organs) and comparison to infectious granulomas (coccidiodomycosis and tuberculosis).MethodsTranscriptomic profiles of immune-related gene from micro-dissected sarcoidosis granulomas within lung and mediastinal lymph node tissues and compared to infectious granulomas from paraffin-embedded blocks. Differentially-expressed genes (DEGs) were profiled, compared among the three granulomatous diseases and analyzed for functional enrichment pathways.ResultsDespite histologic similarities, DEGs and pathway enrichment markedly differed in sarcoidosis granulomas from lymph nodes and lung. Lymph nodes showed a clear immunological response, whereas a structural regenerative response was observed in lung. Sarcoidosis granuloma gene expression data corroborated previously reported genomic biomarkers (STAB1, HBEGF, and NOTCH4), excluded others and identified new genomic markers present in lung and lymph nodes, ADAMTS1, NPR1 and CXCL2. Comparisons between sarcoidosis and pathogen granulomas identified pathway divergences and commonalities at gene expression level.ConclusionThese findings suggest the importance of tissue and disease-specificity evaluation when exploring sarcoidosis genomic markers. This relevant translational information in sarcoidosis and other two histopathological similar infections provides meaningful specific genomic-derived biomarkers for sarcoidosis diagnosis and prognosis.
| S-EPMC7716494 | biostudies-literature
Project description:Endobronchial ultrasound (EBUS) guided biopsy is becoming the mainstay for investigation of mediastinal lymphadenopathy to aid laboratory diagnosis of malignancy, sarcoidosis or tuberculosis. However, diagnostic uncertainty is still common in the distinction between culture negative tuberculosis and sarcoidosis or malignancy and reactive lymphadenitis. We sought to evaluate the role of genome-wide transcriptional profiling of EBUS guided lymph node samples to aid diagnostic processes in this setting.
2016-01-06 | E-MTAB-2547 | biostudies-arrayexpress
Project description:Purpose: Granulomas are lumps of immune cells that can form in various organs, causing chronic inflammation and tissue destruction. While most granulomas appear histologically heterogeneous and unstructured, they have a certain resemblance of lymphoid organ formation. We thus pursued the hypothesis that granuloma formation is a highly orchestrated process that mixes and repurposes various regulatory mechanisms of normal development Methods: We performed single-cell sequencing and spatial transcriptomics on granulomas from patients diagnosed with cutaneous sarcoidosis, and we bioinformatically reconstructed their gene-regulatory networks and cell-cell interactions Results: We observed regulatory processes underlying granuloma formation that were highly conserved across individuals and followed characteristic spatial patterns. We identified metabolically reprogrammed macrophages, various T cells subsets and structural cells including fibroblasts and endothelial cells as key players in granulomas. Specifically, exhausted interferon-gamma-producing Th17.1 cells with cytotoxic potential and inflammatory fibroblasts were identified as drivers of granuloma formation by attracting various immune cell types. Summary: we found that granuloma formation in sarcoidosis is a molecular and cellular process that adopts specific aspects of normal lymphoid organ development in aberrant combinations. Our study frames human granuloma formation as a developmental pathology and raises the future perspective of therapeutic targeting of granuloma-specific regulatory programs.
2023-02-07 | GSE192460 | GEO
Project description:Purpose: Granulomas are lumps of immune cells that can form in various organs, causing chronic inflammation and tissue destruction. While most granulomas appear histologically heterogeneous and unstructured, they have a certain resemblance of lymphoid organ formation. We thus pursued the hypothesis that granuloma formation is a highly orchestrated process that mixes and repurposes various regulatory mechanisms of normal development Methods: We performed single-cell sequencing and spatial transcriptomics on granulomas from patients diagnosed with cutaneous sarcoidosis, and we bioinformatically reconstructed their gene-regulatory networks and cell-cell interactions Results: We observed regulatory processes underlying granuloma formation that were highly conserved across individuals and followed characteristic spatial patterns. We identified metabolically reprogrammed macrophages, various T cells subsets and structural cells including fibroblasts and endothelial cells as key players in granulomas. Specifically, exhausted interferon-gamma-producing Th17.1 cells with cytotoxic potential and inflammatory fibroblasts were identified as drivers of granuloma formation by attracting various immune cell types. Summary: we found that granuloma formation in sarcoidosis is a molecular and cellular process that adopts specific aspects of normal lymphoid organ development in aberrant combinations. Our study frames human granuloma formation as a developmental pathology and raises the future perspective of therapeutic targeting of granuloma-specific regulatory programs.
2023-02-07 | GSE192456 | GEO
Project description:Sarcoidosis is a granulomatous disease of unknown cause. We performed single-cell RNA sequencing to identify the macrophages that comprise sarcoidosis granulomas.
2023-09-25 | GSE234901 | GEO
Project description:Rationale: Chronic sarcoidosis is a complex granulomatous disease with limited treatment options that can progress over time. Understanding the molecular pathways contributing to disease would aid in new therapeutic development. Objectives: To understand if macrophages from non-resolving chronic sarcoidosis patients are predisposed to macrophage aggregation and granuloma formation, and if modulation of the underlying molecular pathways influence sarcoidosis granuloma formation. Methods: Macrophages were cultivated in vitro from isolated peripheral blood CD14+ monocytes and evaluated for spontaneous aggregation. Transcriptomics analyses, phenotypic and drug inhibitory experiments were performed on these monocyte-derived macrophages. Human skin biopsies from sarcoidosis patients and a myeloid Tsc2-specific sarcoidosis mouse model were analyzed for validatory experiments. Measurements and Main Results: Monocyte-derived macrophages from chronic sarcoidosis patients spontaneously formed extensive granulomas in vitro compared to healthy controls. Transcriptomic analyses separated healthy and sarcoidosis macrophages and identified an enrichment in lipid metabolic processes. In vitro patient granulomas, sarcoidosis mouse model granulomas, and those directly analyzed from lesional patient skin expressed an aberrant lipid metabolism profile and contained increased neutral lipids. Conversely, a combination of statins and cholesterol-reducing agents reduced granuloma formation both in vitro and in vivo in a sarcoidosis mouse model. Conclusions: Together, our findings show that altered lipid metabolism in sarcoidosis macrophages is associated with its predisposition to granuloma formation and suggest cholesterol-reducing therapies as a treatment option in patients.
2024-12-31 | GSE251802 | GEO
Project description:Sarcoidosis is a multiorgan inflammatory disease that is characterized by tissue granulomas and remains so challenging for clinicians to diagnose that it has been called “the great imitator”. Here, by performing single-cell sequencing and spatial transcriptomics on skin granulomas from sarcoid and non-sarcoid patients, we discovered increased recruitment of innate lymphoid cells in granulomas. Sarcoid-associated cells exhibited increased cell migration compared to healthy individuals. Importantly, granuloma formation was attenuated in mice genetically lacking these cells or treated with a pharmacologic inhibitor.
2024-09-13 | GSE227041 | GEO
Project description:We hypothesised that whole transcriptome analysis of human TB granulomas isolated by laser capture microdissection could identify therapeutic targets, and that comparison with a non-infectious granulomatous disease, sarcoidosis, would identify disease-specific pathological mechanisms. Bioinformatic analysis of RNAseq data identified numerous shared pathways between TB and sarcoidosis lymph nodes, and also specific clusters demonstrating TB results from a dysregulated inflammatory immune response. To translate these insights, we compared three primary human cell culture models at the whole transcriptome level, and demonstrated that the 3D collagen granuloma model most closely reflected human TB disease. We investigated shared signaling pathways with human disease and identified twelve intracellular enzymes as potential therapeutic targets. Sphingosine kinase 1 inhibition controlled Mtb growth, concurrently reducing intracellular pH in infected monocytes and suppressing inflammatory mediator secretion. Immunohistochemical staining confirmed that sphingosine kinase 1 is expressed in human lung TB granulomas, and therefore represents a host therapeutic target to improve TB outcomes.
2021-05-15 | GSE174443 | GEO
Project description:Many chronic cutaneous diseases associated with microbial antigens demonstrate clinical progression due to T cell hyporesponsiveness. Appropriate antimicrobial therapy restores T cell function, leading to clinical resolution. Due to the association of sarcoidosis with mycobacterial antigens, we compared the efficacy of antimycobacterial therapy with placebo in chronic cutaneous sarcoidosis. We conducted a randomized, placebo-controlled, single-blind trial on chronic cutaneous sarcoidosis subjects. Participants received the oral CLEAR regimen: Levofloxacin 750 mg on day 1, then 500 mg daily, Ethambutol 1200 mg daily, Azithromycin 500 mg on day 1, then 250 mg daily, and Rifampin 300 mg daily, or a comparative placebo regimen, for a total of 8 weeks, with a 180 day follow-up. Participants were monitored for absolute change in lesion diameter and decrease in granulomas burden upon completion of therapy.
2013-07-23 | E-GEOD-39606 | biostudies-arrayexpress