Sarcoidosis activates diverse transcriptional programs in bronchoalveolar lavage cells

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)
Sina A.,Malur,Anagha,Huizar,Isham,Barna,Barbara P.,Kavu Gharib (Creator)
East Carolina University (ECU )
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Abstract: Background: Sarcoidosis is a multisystem immuno-inflammatory disorder of unknown etiology that mostcommonly involves the lungs. We hypothesized that an unbiased approach to identify pathways activated inbronchoalveolar lavage (BAL) cells can shed light on the pathogenesis of this complex disease.Methods: We recruited 15 patients with various stages of sarcoidosis and 12 healthy controls. All subjectsunderwent bronchoscopy with lavage. For each subject, total RNA was extracted from BAL cells and hybridized toan Affymetrix U133A microarray. Rigorous statistical methods were applied to identify differential gene expressionbetween subjects with sarcoidosis vs. controls. To better elucidate pathways differentially activated between thesegroups, we integrated network and gene set enrichment analyses of BAL cell transcriptional profiles.Results: Sarcoidosis patients were either non-smokers or former smokers, all had lung involvement and only twowere on systemic prednisone. Healthy controls were all non-smokers. Comparison of BAL cell gene expressionbetween sarcoidosis and healthy subjects revealed over 1500 differentially expressed genes. Several previouslydescribed immune mediators, such as interferon gamma, were upregulated in the sarcoidosis subjects. Using anintegrative computational approach we constructed a modular network of over 80 gene sets that were highlyenriched in patients with sarcoidosis. Many of these pathways mapped to inflammatory and immune-relatedprocesses including adaptive immunity, T-cell signaling, graft vs. host disease, interleukin 12, 23 and 17 signaling.Additionally, we uncovered a close association between the proteasome machinery and adaptive immunity,highlighting a potentially important and targetable relationship in the pathobiology of sarcoidosis.Conclusions: BAL cells in sarcoidosis are characterized by enrichment of distinct transcriptional programs involvedin immunity and proteasomal processes. Our findings add to the growing evidence implicating alveolar residentimmune effector cells in the pathogenesis of sarcoidosis and identify specific pathways whose activation maymodulate disease progression

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Language: English
Date: 2016
Sarcoidosis, Microarray, Proteasome, Network analysis

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