Sputum gene expression profiling in asthmatics
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Donavan Cheng
PROVIDER: E-GEOD-41863 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Molecular profiling studies in asthma cohorts have identified a Th2-driven asthma subtype, characterized by elevated lower airway expression of POSTN, CLCA1 and SERPINB2. To assess upper airway gene expression as a potential biomarker for lower airway Th2 inflammation, we assayed upper airway (nasal) and lower airway (bronchial) epithelial gene expression, serum total IgE, blood eosinophils and serum periostin in a cohort of 54 allergic asthmatics and 30 matched healthy controls. 23 of 51 asthmatics in our cohort were classified as âTh2 highâ based on lower airway Th2 gene signature expression. Consistent with this classification, âTh2 highâ subjects displayed elevated total IgE and blood eosinophil levels relative to âTh2 lowâ subjects. Upper airway Th2 signature expression was significantly correlated with lower airway Th2 signature expression (r=0.44), with similar strength of association as serum total IgE and blood eosinophils, known biomarkers of Th2 inflammation. In an unbiased genome-wide scan, we identified 8 upper airway genes more strongly correlated with lower airway Th2 gene signature expression (r=0.58), including Eotaxin-3 (CCL26), Galectin-10 (CLC) and Cathepsin-C (CTSC). Asthmatics classified as âTh2 highâ using this 8-gene signature show similar serum total IgE and blood eosinophil levels as âTh2 highâ asthmatics classified using lower airway Th2 gene signature expression. We have identified an 8-gene upper airway signature correlated with lower airway Th2 inflammation, which may be used as a diagnostic biomarker for Th2-driven asthma. Upper airway (nasal) and lower airway (bronchial) epithelial brushings obtained from a cohort of 54 allergic asthmatics and 30 matched healthy controls were profiled by gene expression by microarray. Subjects were assayed for gene expression, serum total IgE, blood eosinophils and serum periostin.
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2012-01-23 | E-GEOD-28492 | biostudies-arrayexpress
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2013-01-31 | E-GEOD-43210 | biostudies-arrayexpress
Project description:TSLP pathway blockade is a potential strategy for asthma treatment, as TSLP modulates cytokine production by mast cells and regulates the activation of dendritic cells (DCs), which prime the differentiation of naM-CM-/ve T cells into inflammatory Th2 cells. To assess the effect of TSLPR blockade on the development of allergic inflammation and bronchoconstriction in Cynomolgus monkeys after Ascaris suum allergen challenge. Antibodies against human TSLPR were generated and confirmed to be cross-reactive to cynomolgus. Animals were dosed weekly with either vehicle (n=8) or TSLPR HuMAb (n=8) for 6 weeks and their responses to A.Suum challenge at baseline, week 2 and week 6 were assessed. Antibody-treated animals showed reduced bronchoalveolar lavage (BAL) eosinophil counts (p=0.04), reduced lung resistance (RL) area under the curve (p=0.04), and reduced IL-13 cytokine levels in BAL fluid (p=0.03) in response to challenge at 6 weeks compared to vehicle-treated animals. To understand the molecular changes underlying these differences, BAL fluid samples pre- and post-challenge were profiled using microarrays. Genes up-regulated by allergen challenge overlapped strongly with 11 genes up-regulated in DCs when stimulated by TSLP (TSLP-DC signature). The number of genes differentially expressed in response to challenge was reduced in aTSLPR-treated animals after 6 weeks relative to vehicle-treated animals. Expression of the TSLP-DC gene signature was also significantly reduced in aTSLPR-treated animals (p = 0.05). These results demonstrate promising efficacy for TSLPR blockade in an allergen challenge model where TSLP activation of DCs may play a key role. Animals were dosed weekly with either vehicle (n=8) or TSLPR HuMAb (n=8) for 6 weeks and their responses to A.Suum challenge at baseline, week 2 and week 6 were assessed. One monkey in the aTSLPR-treated group expired during the study for reasons not linked to drug safety and tolerability. BAL fluid samples for all animals were subject to gene expression profiling for pre-challenge, 8h and 24h post-challenge timepoints, at baseline, week 2 and week 6. This amounted to a total of 135 microarrays. Data from 8 animals were excluded as outliers, determined by PCA.
2013-10-22 | E-GEOD-41329 | biostudies-arrayexpress
Project description:Blood consists of different cell populations with distinct functions and correspondingly, distinct gene expression profiles. In this study, global miRNA expression profiling was performed across a panel of nine human immune cell subsets (neutrophils, eosinophils, monocytes, B cells, NK cells, CD4 T cells, CD8 T cells, mDCs and pDCs) to identify cell-type specific miRNAs. mRNA expression profiling was performed on the same samples, to determine if miRNAs specific to certain cell types down-regulated expression levels of their target genes. Six cell-type specific miRNAs (miR-143; neutrophil specific, miR-125; T cells and neutrophil specific, miR-500; monocytes and pDC specific, miR-150; lymphoid cells specific, miR-652 and miR-223; both myeloid cells specific) were negatively correlated with expression of their predicted target genes. These results were further validated using an independent cohort where similar immune cell subsets were isolated and profiled for both miRNA and mRNA expression. miRNAs negatively correlated with target gene expression in both cohorts were identified as candidates for miRNA-mRNA regulatory pairs and were used to construct a cell-type specific regulatory network. miRNA-mRNA pairs formed two distinct clusters in the network corresponding to myeloid (nine miRNAs) and lymphoid lineages (two miRNAs). Several myeloid specific miRNAs targeted common genes including ABL2, EIF4A2, EPC1 and INO80D; these common targets were enriched for genes involved in the regulation of gene expression (p < 9.0E-7). Those miRNA might therefore have significant further effect on gene expression by repressing the expression of genes involved in transcriptional regulation. The miRNA and mRNA expression profiles reported in this study form a comprehensive transcriptome database of various human blood cells and serve as a valuable resource for elucidating the role of miRNA mediated regulation in the establishment of immune cell identity. Nine cell subsets (CD16+CD66b+ Neutrophils, CD16-CD66b+ Eosinophils, CD14+ Monocytes, CD4+ T cells, CD8+ T cells, CD56+ NK cells, CD19+ B cells, CD123+ pDCs and CD11c+ mDCs) were isolated from healthy human blood and assessed for cell type purity by flow cytometry. Cell types were isolated from 5 pools of 5 healthy donors each, with the exception for monocytes, where 10 pools were used. RNA obtained from these purified populations were subsequently used for miRNA and mRNA expression profiling by Affymetrix GeneChip miRNA and HG-U133Plus2.0 microarrays.
2012-01-31 | E-GEOD-28491 | biostudies-arrayexpress
Project description:Blood consists of different cell populations with distinct functions and correspondingly, distinct gene expression profiles. In this study, global miRNA expression profiling was performed across a panel of nine human immune cell subsets (neutrophils, eosinophils, monocytes, B cells, NK cells, CD4 T cells, CD8 T cells, mDCs and pDCs) to identify cell-type specific miRNAs. mRNA expression profiling was performed on the same samples, to determine if miRNAs specific to certain cell types down-regulated expression levels of their target genes. Six cell-type specific miRNAs (miR-143; neutrophil specific, miR-125; T cells and neutrophil specific, miR-500; monocytes and pDC specific, miR-150; lymphoid cells specific, miR-652 and miR-223; both myeloid cells specific) were negatively correlated with expression of their predicted target genes. These results were further validated using an independent cohort where similar immune cell subsets were isolated and profiled for both miRNA and mRNA expression. miRNAs negatively correlated with target gene expression in both cohorts were identified as candidates for miRNA-mRNA regulatory pairs and were used to construct a cell-type specific regulatory network. miRNA-mRNA pairs formed two distinct clusters in the network corresponding to myeloid (nine miRNAs) and lymphoid lineages (two miRNAs). Several myeloid specific miRNAs targeted common genes including ABL2, EIF4A2, EPC1 and INO80D; these common targets were enriched for genes involved in the regulation of gene expression (p < 9.0E-7). Those miRNA might therefore have significant further effect on gene expression by repressing the expression of genes involved in transcriptional regulation. The miRNA and mRNA expression profiles reported in this study form a comprehensive transcriptome database of various human blood cells and serve as a valuable resource for elucidating the role of miRNA mediated regulation in the establishment of immune cell identity. Nine cell subsets (CD16+CD66b+ Neutrophils, CD16-CD66b+ Eosinophils, CD14+ Monocytes, CD4+ T cells, CD8+ T cells, CD56+ NK cells, CD19+ B cells, CD123+ pDCs and CD11c+ mDCs) were isolated from healthy human blood and assessed for cell type purity by flow cytometry. Cell types were isolated from 5 pools of 5 healthy donors each, with the exception for monocytes, where 10 pools were used. RNA obtained from these purified populations were subsequently used for miRNA and mRNA expression profiling by Affymetrix GeneChip miRNA and HG-U133Plus2.0 microarrays.
2012-01-31 | E-GEOD-28490 | biostudies-arrayexpress
Project description:Gene expression profiling was performed on sputum samples obtained from asthmatics and matched healthy controls, to identify markers associated with various asthma subtypes.
2015-10-23 | GSE41863 | GEO
Project description:Background: A subset of asthmatics does not respond to steroid therapy and therefore is at risk for escalation of disease severity. The cause of corticosteroid resistant (CR) asthma is unknown. Gene microarray technologies have the potential to substantiate new hypotheses regarding the etiology of corticosteroid resistance. Methods: Gene microarray analysis was performed with bronchoalveolar lavage (BAL) cells of CR and corticosteroid sensitive (CS) asthmatics. Increased gene expression was verified with real time PCR and at the protein level by ELISA. Findings: Microarray analyses demonstrated significantly higher levels (over two-fold increase, p<0.05) of TNF-alpha, IL-1alpha, IL-1beta, IL-6, CXCL1, CXCL2, CXCL3, CXCL8 (IL-8), CCL3, CCL4, CCL20 gene expression in BAL cells of CR than CS asthmatics. These findings, confirmed by RT-PCR in additional BAL samples, were consistent with classical macrophage activation by bacterial products. In contrast, markers of alternatively-activated macrophages, Arginase I and CCL24, were decreased in CR asthmatics. Genes associated with activation of the LPS signaling pathway (EGR1, DUSP2, MAIL, TNFAIP3) were significantly elevated in CR BAL samples (p<0.05). CR asthmatics had significantly higher amounts (1444.0±457.3 pg per mg of total protein) of LPS in BAL fluid than CS asthmatics (270.5±216.0 pg; p<0.05). Prolonged exposure to LPS induced functional steroid resistance to dexamethasone (DEX) in normal monocytes, demonstrated by persistently elevated IL-6 levels in the presence of DEX. Interpretation: Classical macrophage activation and induction of LPS signaling pathways along with high endotoxin levels detected in BAL fluid from CR asthmatics suggest that LPS exposure may contribute to CR asthma. Experiment Overall Design: Patients with a diagnosis of asthma according to American Thoracic Society criteria were selected for evaluation. Asthmatics had a baseline FEV1% predicted of 55% to 85% of predicted, a beta2-adrenergic response of â¥12% of baseline FEV1% predicted and/or a methacholine PC20 value of â¤8 mg/ml. Asthma patients were further subdivided in CR and CS groups, based on their response to steroids. The definition was based on change in FEV1 % predicted over a one-week course of 40 mg/day of oral prednisone. Asthmatic patients were defined as CS if they had an increase in FEV1% predicted of greater than 15% after a one-week course of prednisone, and as CR if less than 12% change in FEV1% predicted was observed. None of the asthmatic subjects recruited for this study had evidence for other types of lung diseases. None of the subjects had received systemic corticosteroid therapy for at least one month prior to bronchoscopy. All subjects provided written informed consent to participate in the study. The study was approved by the Institutional Review Board at National Jewish Medical and Research Center, Denver, CO. Gene array studies of BAL macrophages were performed in 3 CR and 3 CS asthmatics.
2009-07-01 | E-GEOD-7368 | biostudies-arrayexpress