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

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. Overall design: To investigate the pathogenesis of pulmonary sarcoidosis in PBMCs, we compared patients with pulmonary sarcoidosis (n=14) and healthy controls (n=26) samples by RNA-seq. Then, to investigate the pathogenesis of pulmonary sarcoidosis with extrapulmonary lesions (EPL), we compared samples between pulmonary sarcoidosis with EPL (n=9) and without EPL (n=5), respectively, by RNA-seq.