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Peripheral blood B lymphocytes derived from patients with idiopathic pulmonary arterial hypertension express a different RNA pattern compared with healthy controls: a cross sectional study.

ABSTRACT: BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is a progressive and still incurable disease. Research of IPAH-pathogenesis is complicated by the lack of a direct access to the involved tissue, the human pulmonary vasculature. Various auto-antibodies have been described in the blood of patients with IPAH. The purpose of the present work was therefore to comparatively analyze peripheral blood B lymphocyte RNA expression characteristics in IPAH and healthy controls. METHODS: Patients were diagnosed having IPAH according to WHO (mean pulmonary arterial pressure > or = 25 mmHg, pulmonary capillary occlusion pressure < or = 15 mmHg, absence of another explaining disease). Peripheral blood B-lymphocytes of patients and controls were immediately separated by density gradient centrifugation and magnetic beads for CD19. RNA was thereafter extracted and analyzed by the use of a high sensitivity gene chip (Affymetrix HG-U133-Plus2) able to analyze 47000 transcripts and variants of human genes. The array data were analyzed by two different softwares, and up-and down-regulations were defined as at least 1.3 fold with standard deviations smaller than fold-changes. RESULTS: Highly purified B-cells of 5 patients with IPAH (mean pulmonary artery pressure 51 +/- 13 mmHg) and 5 controls were analyzed. Using the two different analyzing methods we found 225 respectively 128 transcripts which were up-regulated (1.3-30.7 fold) in IPAH compared with healthy controls. Combining both methods, there were 33 overlapping up-regulated transcripts and no down-regulated B-cell transcripts. CONCLUSION: Patients with IPAH have a distinct RNA expression profile of their peripheral blood B-lymphocytes compared to healthy controls with some clearly up-regulated genes. Our finding suggests that in IPAH patients B cells are activated.

SUBMITTER: Ulrich S

PROVIDER: S-EPMC2262076 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Peripheral blood B lymphocytes derived from patients with idiopathic pulmonary arterial hypertension express a different RNA pattern compared with healthy controls: a cross sectional study.

Ulrich Silvia S Taraseviciene-Stewart Laima L Huber Lars C LC Speich Rudolf R Voelkel Norbert N

Respiratory research 20080212

<h4>Background</h4>Idiopathic pulmonary arterial hypertension (IPAH) is a progressive and still incurable disease. Research of IPAH-pathogenesis is complicated by the lack of a direct access to the involved tissue, the human pulmonary vasculature. Various auto-antibodies have been described in the blood of patients with IPAH. The purpose of the present work was therefore to comparatively analyze peripheral blood B lymphocyte RNA expression characteristics in IPAH and healthy controls.<h4>Methods ...[more]

PMID: 18269757

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Project description:Pulmonary vascular arterial remodeling is an integral and well-understood component of pulmonary hypertension (PH). In contrast, morphological alterations of pulmonary veins in PH are scarcely described. Explanted lungs (n = 101) from transplant recipients with advanced chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary arterial hypertension (IPAH) were analyzed for venous vascular involvement according to a pre-specified, semi-quantitative grading scheme, which categorizes the intensity of venous remodeling in three groups of incremental severity: venous hypertensive (VH) grade 0 = characterized by an absence of venous vascular remodeling; VH grade 1 = defined by a dominance of either arterialization or intimal fibrosis; and VH grade 2 = a substantial composite of arterialization and intimal fibrosis. Patients were grouped according to clinical and hemodynamic characteristics in three groups: COPD non-PH, COPD-PH, and IPAH, respectively. Histological specimens were examined by a cardiovascular pathologist blinded to clinical and hemodynamic data. Pathological alterations of pulmonary veins were present in all hemodynamic groups, with the following incidences of VH grade 0/1/2: 34/66/0% in COPD non-PH; 19/71/10% in COPD-PH; and 11/61/28% in IPAH. In COPD, explorative correlation analysis of venous remodeling suggested a modest positive correlation with systolic and mean pulmonary artery pressure ( P = 0.032, respectively) and an inverse modest correlation with diffusion capacity for carbon monoxide ( P = 0.027). In addition, venous remodeling correlated positively with the degree of arterial remodeling ( P = 0.014). In COPD-PH and IPAH, advanced forms of pulmonary venous remodeling are present, emphasizing that the disease is not exclusively restricted to arterial lesions. In addition, venous remodeling may be related to the hemodynamic severity, but more rigorous analysis is required to clearly define potential relationships.

Project description:Despite recent improvements in management of idiopathic pulmonary arterial hypertension, mortality remains high. Understanding the alterations in the transcriptome–phenotype of the key lung cells involved could provide insight into the drivers of pathogenesis. In this study, we examined differential gene expression of cell types implicated in idiopathic pulmonary arterial hypertension from lung explants of patients with idiopathic pulmonary arterial hypertension compared to control lungs. After tissue digestion, we analyzed all cells from three idiopathic pulmonary arterial hypertension and six control lungs using droplet-based single cell RNA-sequencing. After dimensional reduction by t-stochastic neighbor embedding, we compared the transcriptomes of endothelial cells, pericyte/smooth muscle cells, fibroblasts, and macrophage clusters, examining differential gene expression and pathways implicated by analysis of Gene Ontology Enrichment. We found that endothelial cells and pericyte/smooth muscle cells had the most differentially expressed gene profile compared to other cell types. Top differentially upregulated genes in endothelial cells included novel genes: ROBO4, APCDD1, NDST1, MMRN2, NOTCH4, and DOCK6, as well as previously reported genes: ENG, ORAI2, TFDP1, KDR, AMOTL2, PDGFB, FGFR1, EDN1, and NOTCH1. Several transcription factors were also found to be upregulated in idiopathic pulmonary arterial hypertension endothelial cells including SOX18, STRA13, LYL1, and ELK, which have known roles in regulating endothelial cell phenotype. In particular, SOX18 was implicated through bioinformatics analyses in regulating the idiopathic pulmonary arterial hypertension endothelial cell transcriptome. Furthermore, idiopathic pulmonary arterial hypertension endothelial cells upregulated expression of FAM60A and HDAC7, potentially affecting epigenetic changes in idiopathic pulmonary arterial hypertension endothelial cells. Pericyte/smooth muscle cells expressed genes implicated in regulation of cellular apoptosis and extracellular matrix organization, and several ligands for genes showing increased expression in endothelial cells. In conclusion, our study represents the first detailed look at the transcriptomic landscape across idiopathic pulmonary arterial hypertension lung cells and provides robust insight into alterations that occur in vivo in idiopathic pulmonary arterial hypertension lungs.

Project description:BackgroundIn comparison with the general population, adolescents with juvenile idiopathic arthritis (JIA) are at higher risk for morbidity and mortality. However, limited evidence is available about this condition's underlying metabolic profile in adolescents with JIA relative to healthy controls. In this untargeted, cross-sectional metabolomics study, we explore the plasma metabolites in this population.MethodsA sample of 20 adolescents with JIA and 20 controls aged 13-17 years were recruited to complete surveys, provide medical histories and biospecimens, and undergo assessments. Fasting morning plasma samples were processed with liquid chromatography-mass spectrometry. Data were centered, scaled, and analyzed using generalized linear models accounting for age, sex, and medications (p-values adjusted for multiple comparisons using the Holm method). Spearman's correlations were used to evaluate relationships among metabolites, time since diagnosis, and disease severity.ResultsOf 72 metabolites identified in the samples, 55 were common to both groups. After adjustments, 6 metabolites remained significantly different between groups. Alpha-glucose, alpha-ketoglutarate, serine, and N-acetylaspartate were significantly lower in the JIA group than in controls; glycine and cystine were higher. Seven additional metabolites were detected only in the JIA group; 10 additional metabolites were detected only in the control group. Metabolites were unrelated to disease severity or time since diagnosis.ConclusionsThe metabolic signature of adolescents with JIA relative to controls reflects a disruption in oxidative stress; neurological health; and amino acid, caffeine, and energy metabolism pathways. Serine and N-acetylaspartate were promising potential biomarkers, and their metabolic pathways are linked to both JIA and cardiovascular disease risk. The pathways may be a source of new diagnostic, treatment, or prevention options. This study's findings contribute new knowledge for systems biology and precision health approaches to JIA research. Further research is warranted to confirm these findings in a larger sample.

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Peripheral blood B lymphocytes derived from patients with idiopathic pulmonary arterial hypertension express a different RNA pattern compared with healthy controls: a cross sectional study.

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Peripheral blood B lymphocytes derived from patients with idiopathic pulmonary arterial hypertension express a different RNA pattern compared with healthy controls: a cross sectional study.

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