C94-07 Epigenetic and Transcriptomic Landscapes of Peripheral Blood Mononuclear Cells in Severe Sarcoidosis

Abstract Rationale Sarcoidosis exhibits heterogeneous clinical outcomes, ranging from non-progressive to progressive fibrotic disease. Defining molecular programs associated with disease activity and progression may help identify biomarkers and therapeutic targets. Methods Peripheral blood mononuclear cells (PBMCs) were isolated from 91 sarcoidosis patients (32 progressive/non-fibrotic P/NF, 31 non-progressive NP, 28 progressive/fibrotic P/F) and 30 healthy controls using standard definitions as per our prior studies. RNA sequencing and genome-wide DNA methylation profiling (Illumina HumanMethylationEPIC arrays) were performed. Differential expression and methylation analyses were conducted, with integrated multi-omic analysis validated in CD4+ T cells. Results Transcriptomic profiling identified a core set of 1,488 genes commonly dysregulated across sarcoidosis subtypes, reflecting shared immune activation. P/F cases displayed the most distinct profile, with upregulation of interferon-stimulated and Th1-associated genes (STAT1, CXCL10, GBP1, IFI44L) and downregulation of metabolic/regulatory genes (ACACB, TFRC). P/NF cases exhibited Th1-biased pro-inflammatory signatures (GBP1, FCGR1A, TAP1, CCR2), whereas NP cases showed enhanced innate immune gene expression (S100A8, CX3CR1, FCN1). Comparisons between subtypes highlighted oxidative stress (CYBRD1) and complement pathway genes (C3AR1, C1QB) as markers of fibrotic progression (Figure). Genome-wide methylation analysis identified 45 CpGs and 113 regions differentially methylated in sarcoidosis versus controls. P/F cases demonstrated the highest number of differentially methylated regions (190 total, 85 significant), including THRB, NFE2L3, and DPP10. Integrated expression–methylation analysis revealed coordinated changes in LBX2-AS1, PSMB9, TAP1, FOXK1, NFE2L3, and CELSR1, suggesting epigenetic regulation of fibrotic progression. Comparison of PBMC and CD4+ T-cell transcriptomes demonstrated substantial overlap in differentially expressed genes, with many interferon-regulated genes (STAT1, CX3CR1, GBP4, OAS1, TAP1) showing concordant upregulation across both compartments. The strong correlation in log2 fold-change (r ≈ 0.85) highlights shared immune activation between PBMCs and CD4+ T cells, while distinct subsets of genes (PIK3R1, IL6ST, ZBTB16) indicate cell type–specific regulatory patterns. Conclusions Sarcoidosis subtypes share a common interferon-driven immune signature, with progressive fibrotic disease distinguished by enhanced oxidative stress, complement activation, and epigenetically regulated transcriptional programs. Integrated PBMC and CD4+ T-cell analyses reveal both shared and cell type–specific molecular signatures, emphasizing the central role of interferon and Th1 pathways in sarcoidosis progression and identifying candidate biomarkers and therapeutic targets for fibrotic disease. This abstract is funded by: R01ES034767, R01ES033678, R21ES03637 and the Anne Theodore Foundation Breakthrough Sarcoidosis Initiative (ATF-BSI)