Differential Transcriptomic Features of Peripheral Blood Mononuclear Cells in Pulmonary Sarcoidosis with and Without Extrapulmonary Lesions in an East Asian Population

<b>Background</b>: Sarcoidosis is a systemic granulomatous disease of unknown etiology. Pulmonary sarcoidosis with extrapulmonary lesions (EPL) confers poor prognoses. The transcriptomic features of peripheral blood mononuclear cells (PBMCs) could be crucial in sarcoidosis pathogenesis. However, the gene expression characteristics associated with EPL development remain unknown. <b>Methods</b>: Bulk PBMCs were collected from 26 healthy controls and 14 patients with pulmonary sarcoidosis stratified into those with (<i>n</i> = 9) or without (<i>n</i> = 5) EPL. None of the participants were receiving immunosuppressive agents. PBMC transcriptomic analysis was conducted using RNA sequencing. <b>Results</b>: Principal component analysis (PCA) revealed a clear distinction between pulmonary sarcoidosis and healthy control groups, with 227 differentially expressed genes (88 upregulated, 139 downregulated), including upregulated (<i>CLEC7A</i>, <i>GBP5</i>, <i>JAK2</i>, <i>IL15</i>, <i>IL1B</i>, <i>CXCL8</i>, and <i>CXCL10</i>) and downregulated (<i>TNFRSF13C</i>, <i>CD40LG</i>, <i>CD28</i>, and <i>ID3</i>) genes in pulmonary sarcoidosis group. 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, IL-1B, IL-6, and IL-17 production, and response to external stimuli. Furthermore, patients with and without EPL showed 206 differentially expressed genes (131 upregulated, 75 downregulated), including upregulated (<i>IFNG</i> and <i>IFNLR1</i>) and downregulated (<i>SOCS3</i>, <i>MMP9</i>, and <i>CXCL10</i>) genes. Gene ontology (GO) analysis revealed that interleukin 6 (IL-6) and IL-23 production were upregulated in patients with EPL. <b>Conclusions</b>: These findings elucidate the mechanisms underlying granuloma formation in sarcoidosis and demonstrate the differential transcriptomic features of PBMCs in patients with and without EPL. The upregulation of <i>IFNG</i> and <i>IFNLR1</i> may be related to EPL development and could serve as potential therapeutic targets for sarcoidosis.