Single cell transcriptome signatures and cell-cell interactions associated with sarcoidosis in lung immune cell populations

Background Sarcoidosis is a complex, multi-system granulomatous disease characterized by immune dysregulation and chronic inflammation, primarily affecting the lungs. To identify cell specific molecular changes associated with sarcoidosis development and progression, we aimed to characterize cellular composition, gene expression patterns, and cell-cell interactions in bronchoalveolar lavage (BAL) cells from patients with pulmonary sarcoidosis and healthy controls. Methods Single cell RNA-seq on 16 sarcoidosis cases (8 progressive and 8 non-progressive) and 14 controls were analyzed to identify differences in cell proportions by disease group using F-tests and differential gene expression (DE) using pseudobulk analysis. Enriched pathways and upstream regulators were identified using Ingenuity Pathway Analysis (IPA). Cell-to-cell communication and ligand-receptor interaction analyses were performed using CellChat. Results We identified significant DE of genes and pathways associated with sarcoidosis in resident macrophages (upregulation of IL1R1 , PSTPIP2 , TAPBP) , recruited macrophages (downregulation of AKT1 , ACKR3 , AZU1) , and proliferating macrophages (upregulation of CCL4 ). We also observed a limited number of DE transcripts associated with disease progression in resident and recruited macrophages. In non-macrophages cells, we observed a significant reduction in the number of B cells in sarcoidosis. Among T cell populations, we identified specific transcriptional alterations at gene and pathway levels. Most changes in upstream regulators were observed in CD4+ T cells, including activation of TNF, IFNG, and IL1B . We observed distinct differences in cell-to-cell interactions of macrophages and T cells between sarcoidosis patients and controls. While overall cell interactions were reduced in sarcoidosis, there was a relative increase in CD4+ T cell interactions, indicating a potential shift in immune dynamics. Key disruptions observed included downregulation of LGALS9-CD45 signaling. Conclusions These findings underscore the complexity of immune cell involvement in pulmonary sarcoidosis and highlight potential cellular and molecular targets for further investigation.