Spatial profiling of human immune cells in sarcoidosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE227041 | GEO | 2024/09/13
REPOSITORIES: GEO
Similar Datasets
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 | GSE226896 | GEO
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: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:Cardiac involvement is an important determinant of mortality amongst sarcoidosis patients. While granulomatous inflammation is a hallmark finding in cardiac sarcoidosis, the precise immune cell populations that comprise the granuloma remain unresolved. Furthermore, it is unclear how the cellular and transcriptomic landscape of cardiac sarcoidosis differs from other inflammatory heart diseases. We leveraged spatial transcriptomics (GeoMx DSP) and single nucleus RNA sequencing (snRNAseq) to elucidate the cellular and transcriptional landscape of cardiac sarcoidosis. Using GeoMX DSP technology, we compared the transcriptomal profile of CD68+ rich immune cell infiltrates in human cardiac sarcoidosis, giant cell myocarditis, and lymphocytic myocarditis. We performed snRNAseq of human cardiac sarcoidosis to identify immune cell types and examined their transcriptomic landscape and regulation. Using multi-channel immunofluorescence staining, we validated immune cell populations identified by snRNAseq, determined their spatial relationship, and devised an immunostaining approach to distinguish cardiac sarcoidosis from other inflammatory heart diseases. Despite overlapping histological features, spatial transcriptomics identified transcriptional signatures and associated pathways that robustly differentiated cardiac sarcoidosis from giant cell myocarditis and lymphocytic myocarditis. snRNAseq revealed the presence of diverse populations of myeloid cells in cardiac sarcoidosis with distinct molecular features. We identified GPNMB as a novel marker of multinucleated giant cells and predicted that the MITF family of transcription factors regulated this cell type. We also detected additional macrophage populations in cardiac sarcoidosis including HLA-DR+ macrophages, SYTL3+ macrophages and CD163+ resident macrophages. HLA-DR+ macrophages were found immediately adjacent to GPMMB+ giant cells, a distinct feature compared with other inflammatory cardiac diseases. SYTL3+ macrophages were located scattered throughout the granuloma and CD163+ macrophages, CD1c+ dendritic cells, non-classical monocytes, and T-cells were located at the periphery and outside of the granuloma. Finally, we demonstrate mTOR pathway activation is associated with proliferation and is selectively found in HLA-DR+ and SYLT3+ macrophages. In this study, we identified diverse populations of immune cells with distinct molecular signatures that comprise the sarcoid granuloma. These findings provide new insights into the pathology of cardiac sarcoidosis and highlight opportunities to improve diagnostic testing.
2022-07-01 | GSE205734 | GEO
Project description:Sarcoidosis is a multisystemic disease characterized by non-caseating granuloma infiltrating various organs. The form with symptomatic muscular involvement is called muscular sarcoidosis. The impact of immune cells composing the granuloma on the skeletal muscle is misunderstood. Here, we investigated the granuloma-skeletal muscle interactions through spatial transcriptomics. Five major transcriptomic clusters corresponding to perigranuloma, granuloma, and three successive muscle tissue areas (proximal, intermediate and distal) around the granuloma were identified. Analyses revealed upregulated pathways in the granuloma corresponding to the activation of T-lymphocytes and monocytes/macrophages cytokines and upregulation of extracellular matrix signatures and induction of the TGF-β signaling in the perigranuloma. Comparison between proximal and distal muscles to the granuloma revealed an inverse correlation between distance to the granuloma and upregulation of cellular response to interferon-γ/α, TNF-α, IL-1,4,6, fibroblast proliferation, epithelial to mesenchymal cell transition and downregulation of muscle gene expression. These data shed light on the intercommunications between granulomas and the muscle tissue and provides pathophysiological mechanisms by showing that granuloma immune-cells have a direct impact on proximal muscle tissue by promoting its progressive replacement by fibrosis via the expression of pro-inflammatory and pro-fibrosing signatures. These data could possibly explain the evolution towards a state of disability for some patients.
2023-11-29 | GSE243291 | 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.
2024-05-22 | GSE250508 | GEO
Project description:Granulomas are lumps of immune cells that can form in various organs. Most granulomas appear unstructured, yet they have some resemblance to lymphoid organ formation. To better understand granuloma formation, we performed single-cell sequencing and spatial transcriptomics on granulomas from patients with sarcoidosis and bioinformatically reconstructed the underlying gene-regulatory networks. We discovered an immune stimulatory environment in granulomas that repurposed transcriptional programs associated with lymphoid organ development. Granuloma formation followed characteristic spatial patterns and involved genes linked to immunometabolism, cytokine and chemokine signaling, and extracellular matrix remodeling. Three cell types emerged as key players in granuloma formation: metabolically reprogrammed macrophages, cytokine-producing Th17.1 cells, and fibroblasts with inflammatory and tissue remodeling phenotypes. Pharmacological inhibition of one of the identified processes attenuated granuloma formation in a sarcoidosis mouse model. We show that human granulomas adopt characteristic aspects of normal lymphoid organ development in aberrant combinations, indicating that granulomas constitute aberrant lymphoid organs.
| EGAS00001006970 | EGA
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:Kveim-reagent (Kv) skin testing was a historical method of diagnosing sarcoidosis. Intradermal injection of treated sarcoidosis spleen tissue resulted in a granuloma response at injection site by 4-6 weeks. Previous work indicates proteins as the possible trigger of this reaction. We aimed to identify Kv-specific proteins and characterise the ex vivo response of Peripheral Blood Mononuclear Cells (PBMCs) from sarcoidosis, tuberculosis and healthy control patients when stimulated with both Kv and selected Kv-specific proteins.
2017-01-31 | PXD005150 | Pride