Abstract
RationaleDespite 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.ObjectiveTo 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).MethodsTranscriptomic 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.ResultsDespite 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.ConclusionThese 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.
Highlights
Sarcoidosis is a multisystemic disease of unknown etiology characterized by the formation of granulomatous lesions, especially in lung tissues and thoracic lymphCasanova et al Respir Res (2020) 21:321 nodes [1, 2]
Despite histologic similarities, Differ‐ entially-expressed genes (DEGs) and pathway enrichment markedly differed in sarcoidosis granulomas from lymph nodes and lung
Sarcoidosis granulomas exhibited 138 dysregulated transcripts in both lung (Fig. 2a) and lymph node (Fig. 2b), 87 transcripts were exclusive present in sarcoidosis, notoriously, 30% of the DEGs in lung granulomas were unique to sarcoidosis, and the overlapping transcripts dysregulated in both sarcoidosis tissues was only 4%
Summary
Sarcoidosis is a multisystemic disease of unknown etiology characterized by the formation of granulomatous lesions, especially in lung tissues and thoracic lymphCasanova et al Respir Res (2020) 21:321 nodes [1, 2]. The clinical heterogeneity and unpredictable disease course in sarcoidosis represents a challenge in early diagnosis and prediction of progression. Validated sarcoidosis biomarkers are desperately needed to distinguish patients who will spontaneously recover from patients who will worsen and develop severe manifestations of the disease. While there has been progress in identifying genetic variants that contribute to complicated sarcoidosis [5, 6], and we have previously utilized genomic expression profiling of peripheral mononuclear cells (PBMCs) to subphenotype patients with a variety of inflammatory disorders [7,8,9] including sarcoidosis [10], there remains an important and unmet need for molecular and specific genome-based biomarkers for diagnosis and prediction of disease severity in sarcoidosis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
