C29-18 Transcriptomic Profiling of Bronchoalveolar Lavage Cells Reveals Clinical Phenotype-Associated Gene Signatures in Sarcoidosis

Abstract Background Sarcoidosis is a systemic granulomatous disease of unknown etiology that affects multiple organs, including the lungs, eyes, skin, and heart, and presents with highly heterogeneous clinical courses. The mechanisms underlying the diversity of clinical manifestations remain unclear. This study aimed to identify gene expression patterns associated with distinct clinical phenotypes of sarcoidosis through transcriptomic profiling of bronchoalveolar lavage fluid (BALF) cells. Methods BALF samples were obtained from 41 sarcoidosis patients with lung involvement, 20 sarcoidosis patients without lung involvement as controls, and 8 patients with idiopathic pulmonary fibrosis (IPF) as references. Total RNA was extracted from BALF cells, and mRNA sequencing was performed using the Illumina NovaSeq 6000 platform. Gene expression data were processed and normalized, and differentially expressed genes (DEGs) were identified using the DESeq2 package (adjusted p value 0.05 and |log2FC| 1). Genes showing significant expression differences between sarcoidosis patients with and without radiological lung lesions were further analyzed by weighted gene co-expression network analysis (WGCNA) and pathway enrichment analysis. Results Differential expression analysis revealed 78 upregulated and 6 downregulated genes in sarcoidosis patients with pulmonary involvement compared with those without. Comparison between sarcoidosis and IPF identified 32 upregulated and 20 downregulated genes, with eight overlapping genes, including CCL18, CXCL13, MMP7, and SFTPD, suggesting shared mechanisms of fibrotic remodeling. WGCNA identified distinct co-expression modules associated with clinical parameters. A module correlated with multi-organ involvement and BALF lymphocytosis was enriched in pathways related to killing of cells of another organism and inflammatory response, whereas another module associated with younger age, higher total BALF cell count, and a lower CD4/CD8 ratio was enriched in pathways involved in cytoplasmic translation, cellular respiration and ribosome. These findings indicate that immune- and fibrosis-related transcriptional programs coexist in sarcoidosis lungs, potentially driving the variable disease courses observed in clinical practice. Conclusion Transcriptomic profiling of BALF identified sarcoidosis-specific molecular signatures that correlate with clinical and serological phenotypes. The shared upregulation of fibrosis-related genes suggests overlapping molecular pathways with IPF, while immune-related clusters highlight the role of inflammatory responses in multiorgan sarcoidosis. These findings provide new insight into the molecular heterogeneity of sarcoidosis and may guide the discovery of biomarkers for disease activity and progression. This abstract is funded by: JSPS Grants-in-Aid for Scientific Research