Differential transcriptomics in sarcoidosis lung and lymph node granulomas with comparisons to pathogen-specific granulomas

Abstract

Rationale Despite the availability of multi-“omics” strategies, insights into the etiology and pathogenesis of sarcoidosis have been elusive. This is partly due to the lack of reliable preclinical models and a paucity of validated biomarkers. As granulomas are a key feature of sarcoidosis, we speculate that direct genomic interrogation of sarcoid tissues, may lead to identification of dysregulated gene pathways or biomarker signatures. Objective To facilitate the development sarcoidosis genomic biomarkers by gene expression profiling of sarcoidosis granulomas in lung and lymph node tissues (most commonly affected organs) and comparison to infectious granulomas (coccidiodomycosis and tuberculosis). Methods Transcriptomic profiles of immune-related gene from micro-dissected sarcoidosis granulomas within lung and mediastinal lymph node tissues and compared to infectious granulomas from paraffin-embedded blocks. Differentially-expressed genes (DEGs) were profiled, compared among the three granulomatous diseases and analyzed for functional enrichment pathways. Results Despite histologic similarities, DEGs and pathway enrichment markedly differed in sarcoidosis granulomas from lymph nodes and lung. Lymph nodes showed a clear immunological response, whereas a structural regenerative response was observed in lung. Sarcoidosis granuloma gene expression data corroborated previously reported genomic biomarkers (STAB1, HBEGF, and NOTCH4), excluded others and identified new genomic markers present in lung and lymph nodes, ADAMTS1, NPR1 and CXCL2. Comparisons between sarcoidosis and pathogen granulomas identified pathway divergences and commonalities at gene expression level. Conclusion These findings suggest the importance of tissue and disease-specificity evaluation when exploring sarcoidosis genomic markers. This relevant translational information in sarcoidosis and other two histopathological similar infections provides meaningful specific genomic-derived biomarkers for sarcoidosis diagnosis and prognosis.

Biochemical and genomic identification of novel biomarkers in progressive sarcoidosis: HBEGF, eNAMPT, and ANG-2

“…We next interrogated the expression of genes encoding the six plasma biomarkers ( HBEGF, IL-1RA, NAMPT, IL6 , ANG2 , and IL8 ) using our previously reported publicly available gene expression dataset (GSE157671) generated by NextGen sequencing of micro-dissected sarcoidosis granulomas within lung tissues ( 6 ) and mediastinal lymph nodes ( 11 , 32 ). Comparisons of biomarker panel gene expression failed to identify significant differential expression of the targeted genes between sarcoidosis lymph node granulomas and healthy lymph node tissues.…”

“…Enrichment analysis of the DEGs and protein–protein interaction analysis using String database ( 33 , 34 ) demonstrated an association of HBEGF and NAMPT together with proteins involved in inflammatory and lung fibrosis pathways ( Figure 5 ). These included MMP9, a matrix metalloproteinase strongly associated with lung injury and fibrosis ( 35 ), and NOTCH4, an important regulator of inflammation and lung remodeling previously implicated in sarcoidosis ( 4 , 32 , 36 ) ( Figure 5 ). A total of 33 KEGG pathways were identified with the top significant dysregulated pathways ( q -value < 0.03) comprised of cytokine-cytokine receptor interaction, MAPK signaling, IL-17, Jak-STAT signaling, chemokine signaling, NF-kappa B, and TNF signaling pathways ( Figure 5 ).…”

“…Transcripts with a fold change (FC) > 2 and a q -value < 0.01 were deemed as differentially expressed. Detailed methods and analysis have been previously reported ( 32 ).…”

Exome Sequencing Reveals Genetic Variability and Identifies Chronic Prognostic Loci in Chinese Sarcoidosis Patients

“…Most of the genes were related to T-cell regulation and T-cell activation during antigen presentation by APCs (antigen-presenting cells) (5). Other genes associated with immune regulation of sarcoidosis, including NOTCH4, TNFa, NOD2, and ANXA11, were also detected by GWAS analysis in different races (28)(29)(30)(31). Multiple factors, including genetic composition and the context of antigen presentation, could impact the inflammatory immune response, resulting in a selflimiting or a chronic relapse type of sarcoidosis prognosis.…”

Pathological and Tissue-Based Molecular Investigation of Granulomas in Cichlids Reared as Ornamental Fish

“…Sarcoidosis is an enigmatic, multi-systemic human disease of unknown origin: insights into the etiology and pathogenesis have been elusive [ 41 ]. It is postulated to be a multifactorial disease caused by chronic antigenic stimulation [ 42 ].…”