Dataset Information

Sarcoidosis blood transcriptome reflects lung inflammation and overlaps with tuberculosis.

ABSTRACT:

Rationale

Sarcoidosis is a granulomatous disease of unknown etiology, although M. tuberculosis may play a role in the pathogenesis. The traditional view holds that inflammation in sarcoidosis is compartmentalized to involved organs.

Objectives

To determine whether whole blood gene expression signatures reflect inflammatory pathways in the lung in sarcoidosis and whether these signatures overlap with tuberculosis.

Methods

We analyzed transcriptomic data from blood and lung biopsies in sarcoidosis and compared these profiles with blood transcriptomic data from tuberculosis and other diseases.

Measurements and main results

Applying machine learning algorithms to blood gene expression data, we built a classifier that distinguished sarcoidosis from health in derivation and validation cohorts (92% sensitivity, 92% specificity). The most discriminative genes were confirmed by quantitative PCR and correlated with disease severity. Transcript profiles significantly induced in blood overlapped with those in lung biopsies and identified shared dominant inflammatory pathways (e.g., Type-I/II interferons). Sarcoidosis and tuberculosis shared more overlap in blood gene expression compared with other diseases using the 86-gene signature reported to be specific for tuberculosis and the sarcoidosis signature presented herein, although reapplication of machine learning algorithms could identify genes specific for sarcoidosis.

Conclusions

These data indicate that blood transcriptome analysis provides a noninvasive method for identifying inflammatory pathways in sarcoidosis, that these pathways may be leveraged to complement more invasive procedures for diagnosis or assessment of disease severity, and that sarcoidosis and tuberculosis share overlap in gene regulation of specific inflammatory pathways.

SUBMITTER: Koth LL

PROVIDER: S-EPMC3262024 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:RationaleNew approaches to define factors underlying the immunopathogenesis of pulmonary diseases including sarcoidosis and tuberculosis are needed to develop new treatments and biomarkers. Comparing the blood transcriptional response of tuberculosis to other similar pulmonary diseases will advance knowledge of disease pathways and help distinguish diseases with similar clinical presentations.ObjectivesTo determine the factors underlying the immunopathogenesis of the granulomatous diseases, sarcoidosis and tuberculosis, by comparing the blood transcriptional responses in these and other pulmonary diseases.MethodsWe compared whole blood genome-wide transcriptional profiles in pulmonary sarcoidosis, pulmonary tuberculosis, to community acquired pneumonia and primary lung cancer and healthy controls, before and after treatment, and in purified leucocyte populations.Measurements and main resultsAn Interferon-inducible neutrophil-driven blood transcriptional signature was present in both sarcoidosis and tuberculosis, with a higher abundance and expression in tuberculosis. Heterogeneity of the sarcoidosis signature correlated significantly with disease activity. Transcriptional profiles in pneumonia and lung cancer revealed an over-abundance of inflammatory transcripts. After successful treatment the transcriptional activity in tuberculosis and pneumonia patients was significantly reduced. However the glucocorticoid-responsive sarcoidosis patients showed a significant increase in transcriptional activity. 144-blood transcripts were able to distinguish tuberculosis from other lung diseases and controls.ConclusionsTuberculosis and sarcoidosis revealed similar blood transcriptional profiles, dominated by interferon-inducible transcripts, while pneumonia and lung cancer showed distinct signatures, dominated by inflammatory genes. There were also significant differences between tuberculosis and sarcoidosis in the degree of their transcriptional activity, the heterogeneity of their profiles and their transcriptional response to treatment.

Project description:Pulmonary tuberculosis (PTB) is characterized by lung granulomas, inflammation and tissue destruction. Here we used within-subject peripheral blood gene expression over time to correlate with the within-subject lung metabolic activity, as measured by positron emission tomography (PET) to identify biological processes and pathways underlying overall resolution of lung inflammation. We used next-generation RNA sequencing and [18F]FDG PET-CT data, collected at diagnosis, week 4, and week 24, from 75 successfully cured PTB patients, with the [18F]FDG activity as a surrogate for lung inflammation. Our linear mixed-effects models required that for each individual the slope of the line of [18F]FDG data in the outcome and the slope of the peripheral blood transcript expression data correlate, i.e., the slopes of the outcome and explanatory variables had to be similar. Of 10,295 genes that changed as a function of time, we identified 639 genes whose expression profiles correlated with decreasing [18F]FDG uptake levels in the lungs. Gene enrichment over-representation analysis revealed that numerous biological processes were significantly enriched in the 639 genes, including several well known in TB transcriptomics such as platelet degranulation and response to interferon gamma, thus validating our novel approach. Others not previously associated with TB pathobiology included smooth muscle contraction, a set of pathways related to mitochondrial function and cell death, as well as a set of pathways connecting transcription, translation and vesicle formation. We observed up-regulation in genes associated with B cells, and down-regulation in genes associated with platelet activation. We found 254 transcription factor binding sites to be enriched among the 639 gene promoters. In conclusion, we demonstrated that of the 10,295 gene expression changes in peripheral blood, only a subset of 639 genes correlated with inflammation in the lungs, and the enriched pathways provide a description of the biology of resolution of lung inflammation as detectable in peripheral blood. Surprisingly, resolution of PTB inflammation is positively correlated with smooth muscle contraction and, extending our previous observation on mitochondrial genes, shows the presence of mitochondrial stress. We focused on pathway analysis which can enable therapeutic target discovery and potential modulation of the host response to TB.