Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of human peripheral blood cells from sarcoidosis patients vs. healthy controls

ABSTRACT: Sarcoidosis + Follow-up 6 month after

ORGANISM(S): Homo sapiens

SUBMITTER: Florent Baty

PROVIDER: E-GEOD-1907 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Functional genomics and prognosis in sarcoidosis--the critical role of antigen presentation.

Rutherford Robert M RM Staedtler Frank F Kehren Jeanne J Chibout Salah-Dine SD Joos Ladina L Tamm Michel M Gilmartin John J JJ Brutsche Martin H MH

Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG 20040301 1

<h4>Background</h4>Sarcoidosis is a systemic disorder of unknown cause, highly variable phenotype and unpredictable outcome. Antigen processing, inflammatory response and immunomodulation appear critical to development and prognosis of the disease.<h4>Methods</h4>We performed a comprehensive genomic analysis, applying high-density human GeneChip probe arrays (HUG95A, Affymetrix Inc.) for gene expression profiling from peripheral blood of patients with acute pulmonary sarcoidosis (n = 12) and mat ...[more]

PMID: 15127969

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Project description:Introduction: In sarcoidosis, peripheral lymphopenia and anergy have been associated with increased inflammation and maladaptive immune activity, likely promoting development of chronic and progressive disease. However, the molecular mechanisms that lead to reduced lymphocyte proportions, particularly CD4+ T-cells, have not been fully elucidated. We posit that paradoxical peripheral lymphopenia is characterized by a dysregulated transcriptomic network associated with cell function and fate that results from altered transcription factor targeting activity. Methods: Messenger RNA-sequencing (mRNA-seq) was performed on peripheral blood mononuclear cells (PBMCs) from ACCESS study subjects with sarcoidosis and matched controls and findings validated on a sarcoidosis case-control cohort and a sarcoidosis case series. Preserved PBMC transcriptomic networks between case-control cohorts were assessed to establish cellular associations with gene modules and define regulatory targeting involved in sarcoidosis immune dysregulation utilizing weighted gene co-expression network analysis and differential transcription factor involvement analysis. Network centrality measures identified master transcriptional regulators of subnetworks related to cell proliferation and death. Predictive models of differential PBMC proportions constructed from ACCESS target gene expression corroborated the relationship between aberrant transcription factor regulatory activity and imputed and clinical PBMC populations in the validation cohorts. Results: We identified two unique and preserved gene modules significantly associated with sarcoidosis immune dysregulation. Strikingly, increased expression of a monocyte-driven, and not a lymphocyte-driven, gene module related to innate immunity and cell death was the best predictor of peripheral CD4+ T-cell proportions. Within the gene network of this monocyte-driven module, TLE3 and CBX8 were determined to be master regulators of the cell death subnetwork. A core gene signature of differentially over-expressed target genes of TLE3 and CBX8 involved in cellular communication and immune response regulation accurately predicted imputed and clinical monocyte expansion and CD4+ T-cell depletion. Conclusions: Altered transcriptional regulation associated with aberrant gene expression of a monocyte-driven transcriptional network likely influences lymphocyte function and survival. Although further investigation is warranted, this indicates that crosstalk between hyperactive monocytes and lymphocytes may instigate peripheral lymphopenia and underlie sarcoidosis immune dysregulation and pathogenesis. Future therapies selectively targeting master regulators, or their targets, may mitigate dysregulated immune processes in sarcoidosis and disease progression.

Dataset Information

Transcription profiling of human peripheral blood cells from sarcoidosis patients vs. healthy controls

Publications

Functional genomics and prognosis in sarcoidosis--the critical role of antigen presentation.

Similar Datasets

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