PO20 - Epigenetic and Transcriptomic Profiling of Peripheral Blood Mononuclear Cells in Fibrotic and Non-Fibrotic Pulmonary Sarcoidosis
Lisa A. Maier, MD, MSPH (United States)1 2 3; Brian Vestal, PhD (United States)4; Camille Moore, PhD (Portugal)4; Cheyret Wood MS (United States)5; Jonathan Cardwell, MS (United States)2; Joshua Macaluso (United States)1; Margaret M. Mroz, MS (United States)1; Clara I. Restrepo, MD (United States)1; Ivana Yang, PhD (United States)5; Li Li, MD, PhD (United States)1;
1 - Department of Medicine, National Jewish Health, Denver, CO; 2 - Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO; 3 - Department of Environmental and Occupational Health, University of Colorado Anschutz Medical Campus, Aurora, CO; 4 - Department of Immunology and Genomic Medicine, National Jewish Health, Denver, CO; 5 - Department of Biostatistics & Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO;
Keywords: Sarcoidosis Phenotypes; Epigenetics; genome-wide methylation;
Select the theme: Genetics and Immunopathology: Advances in Contemporary Understanding and Prospects for Future Research
Type: Original Papers
Presentation: Poster Presentation

Introduction: Pulmonary sarcoidosis exhibits heterogeneous clinical manifestations and outcomes, ranging from non-progression to fibrosis, with limited understanding of associated molecular programs.

Objectives: Define epigenetic and transcriptional profiles of fibrotic, progressive and non-progressive pulmonary sarcoidosis.

Materials and 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[PF]) and 30 healthy controls. RNAsequencing and genome-wide DNA methylation profiling (Illumina HumanMethylationEPIC arrays) were performed. Differential expression (DE) and methylation (DM) analyses were conducted, with integrated multi-omic analysis validated in blood CD4⁺ T cells.

Results: RNAseq identified 1,488 genes dysregulated across sarcoidosis subtypes. PF cases exhibited greatest 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 showed enhanced innate immune DE (S100A8, CX3CR1, FCN1). Comparisons between subtypes highlighted oxidative stress (CYBRD1) and complement pathway genes (C3AR1, C1QB) associated with fibrosis(Figure).

DM analysis identified 45 CpGs and 113 DMregions in sarcoidosis versus controls. PF cases demonstrated the highest number of DMregions (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 fibrosis.

Comparison of PBMCs and blood CD4⁺ T-cell transcriptomes demonstrated overlap in DE in interferon-regulated genes (STAT1, CX3CR1, GBP4, OAS1, TAP1). 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 interferon-driven immune signatures, with fibrotics distinguished by enhanced oxidative stress, complement activation, and epigenetically-regulated transcriptional programs. Integrated PBMC and blood CD4⁺ T-cell analyses reveal shared and cell type–specific signatures.

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