Altered Immune Phenotype in Peripheral Blood Cells of Patients with Scleroderma‐Associated Pulmonary Hypertension

Risbano, Michael G.; Meadows, Christina A.; Coldren, Christopher D.; Jenkins, Tiffany J.; Edwards, Michael G.; Collier, David H.; Huber, W.; Mack, Douglas G.; Fontenot, Andrew P.; Geraci, Mark W.; Bull, Todd

doi:10.1111/j.1752-8062.2010.00218.x

Cited by 51 publications

(46 citation statements)

References 43 publications

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“…Overwhelmingly, we detected a MØ signature associated with severe disease. In the module overlap network, we find that PAH-associated modules from PBMCs [19, 20] have significant overlap with SSc inflammatory subset-associated modules from skin and esophagus (Fig. 2).…”

Section: Discussionmentioning

confidence: 99%

“…Many patients in the skin cohorts provided lesional (forearm) and non-lesional (back) skin biopsies; a subset of patients in the Northwestern skin cohort provided biopsies longitudinally over time as part of a clinical trial for mycophenolate mofetil. Peripheral blood mononuclear cells (PBMC) samples from patients with and without SSc-associated PAH (SSc-PAH), patients with idiopathic PAH (IPAH), and healthy controls were included from a Boston University cohort [19] and a University of Colorado PAH cohort [20]. Lung data contained a cohort of late or end-stage patients that underwent lung transplant at the University of Pittsburgh [15] and a second cohort of open lung biopsies from early SSc-associated PF (SSc-PF) obtained in Brazil [14].…”

Section: Methodsmentioning

confidence: 99%

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A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis

et al. 2017

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BackgroundSystemic sclerosis (SSc) is a multi-organ autoimmune disease characterized by skin fibrosis. Internal organ involvement is heterogeneous. It is unknown whether disease mechanisms are common across all involved affected tissues or if each manifestation has a distinct underlying pathology.MethodsWe used consensus clustering to compare gene expression profiles of biopsies from four SSc-affected tissues (skin, lung, esophagus, and peripheral blood) from patients with SSc, and the related conditions pulmonary fibrosis (PF) and pulmonary arterial hypertension, and derived a consensus disease-associate signature across all tissues. We used this signature to query tissue-specific functional genomic networks. We performed novel network analyses to contrast the skin and lung microenvironments and to assess the functional role of the inflammatory and fibrotic genes in each organ. Lastly, we tested the expression of macrophage activation state-associated gene sets for enrichment in skin and lung using a Wilcoxon rank sum test.ResultsWe identified a common pathogenic gene expression signature—an immune–fibrotic axis—indicative of pro-fibrotic macrophages (MØs) in multiple tissues (skin, lung, esophagus, and peripheral blood mononuclear cells) affected by SSc. While the co-expression of these genes is common to all tissues, the functional consequences of this upregulation differ by organ. We used this disease-associated signature to query tissue-specific functional genomic networks to identify common and tissue-specific pathologies of SSc and related conditions. In contrast to skin, in the lung-specific functional network we identify a distinct lung-resident MØ signature associated with lipid stimulation and alternative activation. In keeping with our network results, we find distinct MØ alternative activation transcriptional programs in SSc-associated PF lung and in the skin of patients with an “inflammatory” SSc gene expression signature.ConclusionsOur results suggest that the innate immune system is central to SSc disease processes but that subtle distinctions exist between tissues. Our approach provides a framework for examining molecular signatures of disease in fibrosis and autoimmune diseases and for leveraging publicly available data to understand common and tissue-specific disease processes in complex human diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0417-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis

et al. 2017

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“…One of these gene sets, erythrocyte maturation, was enriched specifically in PAH and correlated with haemodynamic measures of increasing disease severity in patients with IPAH. R isbano et al [46] compared gene expression profiles of PBMCs from SSc patients with and without coexisting PAH, and identified IL-7 receptor ( IL7R ) to be significantly decreased in samples from PAH patients. C hesné et al .…”

Section: Microarray Studies On Human Lung Tissuementioning

confidence: 99%

Microarray analysis in pulmonary hypertension

et al. 2016

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Microarrays are a powerful and effective tool that allows the detection of genome-wide gene expression differences between controls and disease conditions. They have been broadly applied to investigate the pathobiology of diverse forms of pulmonary hypertension, namely group 1, including patients with idiopathic pulmonary arterial hypertension, and group 3, including pulmonary hypertension associated with chronic lung diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. To date, numerous human microarray studies have been conducted to analyse global (lung homogenate samples), compartment-specific (laser capture microdissection), cell type-specific (isolated primary cells) and circulating cell (peripheral blood) expression profiles. Combined, they provide important information on development, progression and the end-stage disease. In the future, system biology approaches, expression of noncoding RNAs that regulate coding RNAs, and direct comparison between animal models and human disease might be of importance.

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“…Recently, a difference in the peripheral blood transcriptome was shown between IPF patients and healthy controls (13, 14); however, the ability of the transcriptome to predict outcome was not assessed. Given the evidence that peripheral blood mononuclear cell (PBMC) gene expression is informative of disease presence and outcomes in other clinical entities, such as multiple sclerosis (15, 16), heart transplant rejection (17), pulmonary hypertension associated with scleroderma (18), and lung cancer (19), among others, we hypothesized that PBMC gene expression patterns may be predictive of poor outcomes in IPF patients. For this purpose, we examined PBMC gene expression in two independent cohorts and identified a signature of 52 genes significantly associated with transplant-free survival (TFS) in both cohorts.…”

Section: Introductionmentioning

confidence: 99%

Peripheral Blood Mononuclear Cell Gene Expression Profiles Predict Poor Outcome in Idiopathic Pulmonary Fibrosis

et al. 2013

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We aimed to identify peripheral blood mononuclear cell (PBMC) gene expression profiles predictive of poor outcomes in idiopathic pulmonary fibrosis (IPF) by performing microarray experiments of PBMCs in discovery and replication cohorts of IPF patients. Microarray analyses identified 52 genes associated with transplant-free survival (TFS) in the discovery cohort. Clustering the microarray samples of the replication cohort using the 52-gene outcome-predictive signature distinguished two patient groups with significant differences in TFS. We studied the pathways associated with TFS in each independent microarray cohort and identified decreased expression of “The costimulatory signal during T cell activation” Biocarta pathway and, in particular, the genes CD28, ICOS, LCK, and ITK, results confirmed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). A proportional hazards model, including the qRT-PCR expression of CD28, ICOS, LCK, and ITK along with patient’s age, gender, and percent predicted forced vital capacity (FVC%), demonstrated an area under the receiver operating characteristic curve of 78.5% at 2.4 months for death and lung transplant prediction in the replication cohort. To evaluate the potential cellular source of CD28, ICOS, LCK, and ITK expression, we analyzed and found significant correlation of these genes with the PBMC percentage of CD4+CD28+ T cells in the replication cohort. Our results suggest that CD28, ICOS, LCK, and ITK are potential outcome biomarkers in IPF and should be further evaluated for patient prioritization for lung transplantation and stratification in drug studies.

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Altered Immune Phenotype in Peripheral Blood Cells of Patients with Scleroderma‐Associated Pulmonary Hypertension

Cited by 51 publications

References 43 publications

A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis

A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis

Microarray analysis in pulmonary hypertension

Peripheral Blood Mononuclear Cell Gene Expression Profiles Predict Poor Outcome in Idiopathic Pulmonary Fibrosis

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