Unknown,Transcriptomics,Genomics,Proteomics

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Gene and microRNA expression in pulmonary tuberculosis and sarcoidosis

ABSTRACT: Common gene and microRNA expression patterns in TB and sarcoidosis Gene and microRNA expression analysis of whole blood RNA from tuberculosis and sarcoidosis patients and healthy controls

ORGANISM(S): Homo sapiens

SUBMITTER: Jeroen Maertzdorf

PROVIDER: E-GEOD-34608 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Common patterns and disease-related signatures in tuberculosis and sarcoidosis.

Maertzdorf Jeroen J Weiner January J Mollenkopf Hans-Joachim HJ Bauer Torsten T Prasse Antje A Müller-Quernheim Joachim J Kaufmann Stefan H E SH

Proceedings of the National Academy of Sciences of the United States of America 20120430 20

In light of the marked global health impact of tuberculosis (TB), strong focus has been on identifying biosignatures. Gene expression profiles in blood cells identified so far are indicative of a persistent activation of the immune system and chronic inflammatory pathology in active TB. Definition of a biosignature with unique specificity for TB demands that identified profiles can differentiate diseases with similar pathology, like sarcoidosis (SARC). Here, we present a detailed comparison betw ...[more]

PMID: 22547807

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Project description:Tuberculosis (TB) is an ancient infectious disease that remains one of the major health threats in humans worldwide. Biosignatures can play a significant role in the development of novel intervention measures against TB and blood transcriptional profiling is increasingly exploited for their rational design. We have compared whole blood gene expression in TB patients, as well as in healthy infected and uninfected individuals in a cohort in The Gambia, West Africa and validated previously identified signatures showing high similarities of expression profiles among different cohorts. In this study, we applied a unique combination of classical gene expression analysis with pathway and functional association analysis integrated with intra-individual expression correlations. These gene signature analyses were employed for pathognomonic associations, identifying a network of Fc gamma receptor 1 signaling with correlating transcriptional activity as hallmark of gene expression in TB. Remarkable similarities to characteristic signatures in the autoimmune disease systemic lupus erythematosus (SLE) were observed, and functional gene clusters of immunoregulatory interactions provide detailed insights into the dysregulation of critical immune processes in TB. Transcriptomics thus (i) provides a robust system for identification and validation of biosignatures for TB diagnosis and (ii) application of integrated analysis tools yields novel insights into functional networks underlying TB pathogenesis. A total of 46 sputum smear and chest x-ray positive TB patients (TB), 25 latently infected healthy donors (LTBI, TB case contacts with Mantoux test induration >= 10mm) and 37 uninfected donors (NID, Mantoux test induration = 0mm) were included from a cohort in The Gambia. All subjects were HIV– and samples from TB patients were taken prior to chemotherapy. Whole blood RNA was extracted using the PAXgene Blood RNA Kit (PreAnalytix) and labeled with Agilents Fluorescent Linear Amplification Kit. Quantity and labeling efficiency were verified before hybridization of the samples to whole-genome 4×44k human expression arrays and scanned at 5 μm using an Agilent scanner.

Project description:We hypothesized that patients with sarcoidosis have characteristic mRNA profiles. Microarray analysis of gene expression was done on peripheral blood. Comparing peripheral blood from patients with sarcoidosis to controls, 872 transcripts were upregulated and 1039 were downregulated at >1.5-fold change and a significant q value. Several transcripts associated with interferon and STAT1 were upregulated. Lung and lymph node analyses also showed dramatic increases in STAT1 and STAT1-regulated chemokines. Granulomas in lymph nodes of patients with sarcoidosis expressed abundant STAT1 and phosphorylated STAT1. STAT1 might play an important role in sarcoidosis. This novel hypothesis unites seemingly disparate observations with regard to sarcoidosis including implication of a casual role for interferons, a suspected infectious trigger, TH1 predominating lymphocytes in bronchoalveolar lavage, and the association with hypercalcemia. This study tested the hypothesis that SpA is characterized by a distinct pattern of gene expression in peripheral blood of affected individuals compared with healthy controls. High-density, human GeneChip probe arrays were used to profile mRNA of peripheral blood cells from 18 subjects with SpA and 25 normal individuals. Samples were processed as two separate sets at different times. Blood samples were taken at a time when patients were not receiving systemic immunomodulatory therapy. Differential expression was defined as a 1.5-fold change with a q value <5%. Gene ontology and pathway information were also studied. Signals from 134 probe sets (representing 95 known and 12 unknown gene transcripts) were consistently different from controls in both Sets 1 and 2. Included among these were transcripts for a group of 20 genes, such as interleukin-1 receptors 1 and 2, NLRP2, SLPI, SPARC, and TREM-1 that are clearly related to the immune or inflammatory response and a group of 4 transcripts that have a strong role in bone remodeling. Our observations are the first to implicate SPARC, SLPI, and NLRP2, a component of the innate immune system, in the pathogenesis of SpA. Our results also indicate a possible role for interleukin-1 and its receptors in SpA. In accord with the bone pathology component of SpA, we also found that expression levels of transcripts reflecting bone remodeling factors are also distinguishable in peripheral blood from patients with SpA versus controls. These results confirm some previously identified biomarkers implicated in the pathogenesis of SpA and also point to novel mediators in this disease. Peripheral blood was collected from diseased and control subjects. The sarcoidosis portion of the study included 12 patients and 12 control subjects. The spondyloarthropathy study was done in two independent sets. The first set included 11 patients and the same 12 control subjects used for the sarcoidosis study. The second set included 7 patients and 13 control subjects. For each sample, total RNA was isolated and analyzed by hybridization on Affymetrix arrays.

Dataset Information

Gene and microRNA expression in pulmonary tuberculosis and sarcoidosis

Publications

Common patterns and disease-related signatures in tuberculosis and sarcoidosis.

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