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Differential Transcriptome Features of Peripheral Blood Mononuclear Cells in Pulmonary Sarcoidosis with and without Extrapulmonary Lesions

ABSTRACT: Sarcoidosis is a systemic granulomatous disease of unknown etiology. Pulmonary sarcoidosis with extrapulmonary lesions (EPL), especially in cardiac sarcoidosis, is associated with poor prognosis. The transcriptome features of peripheral blood mononuclear cells (PBMCs) could be crucial in sarcoidosis pathogenesis. However, the gene expression characteristics associated with EPL development in pulmonary sarcoidosis remain unknown. Therefore, we investigated gene expression patterns associated with the development of EPL in pulmonary sarcoidosis. First, we conducted trascriptome analysis between patients with pulmonary sarcoidosis and healthy controls. Principal component analysis (PCA) revealed a clear distinction between them, with 227 differentially expressed genes detected. Enrichment analysis revealed upregulated immunological pathways related to granuloma formation in pulmonary sarcoidosis PBMCs, including T helper 17 and tumor necrosis factor-alpha signaling pathways, inflammatory cytokine production, and response to external stimuli. Furtheremore, PCA differentiated patients with pulmonary sarcoidosis with and without EPL, and 206 differentially expressed genes identified, including interferon-gamma (IFNG) and interferon lambda receptor 1 (IFNLR1). Gene ontology (GO) analysis revealed that interleukin 6 (IL-6) and IL-23 production were upregulated in patients with pulmonary sarcoidosis and EPL. In cardiac sarcoidosis, nitric oxide synthases (NOS), including NOS1 and NOS2, were upregulated in PBMCs. The current study strengthens our understanding of the mechanisms underlying granuloma formation in sarcoidosis and demonstrates the differential transcriptome features of PBMCs in patients with pulmonary sarcoidosis with and without EPL, highlighting IFNG and IFNLR1 upregulation. The upregulation of these genes may be related to EPL development and could serve as potential therapeutic targets for sarcoidosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE302854 | GEO | 2025/12/05

REPOSITORIES: GEO

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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.

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Differential Transcriptome Features of Peripheral Blood Mononuclear Cells in Pulmonary Sarcoidosis with and without Extrapulmonary Lesions

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