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      Systematic Analysis of Blood Cell Transcriptome in End-Stage Chronic Respiratory Diseases

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          Abstract

          Background

          End-stage chronic respiratory diseases (CRD) have systemic consequences, such as weight loss and susceptibility to infection. However the mechanisms of such dysfunctions are as yet poorly explained. We hypothesized that the genes putatively involved in these mechanisms would emerge from a systematic analysis of blood mRNA profiles from pre-transplant patients with cystic fibrosis (CF), pulmonary hypertension (PAH), and chronic obstructive pulmonary disease (COPD).

          Methods

          Whole blood was first collected from 13 patients with PAH, 23 patients with CF, and 28 Healthy Controls (HC). Microarray results were validated by quantitative PCR on a second and independent group (7PAH, 9CF, and 11HC). Twelve pre-transplant COPD patients were added to validate the common signature shared by patients with CRD for all causes. To further clarify a role for hypoxia in the candidate gene dysregulation, peripheral blood mononuclear cells from HC were analysed for their mRNA profile under hypoxia.

          Results

          Unsupervised hierarchical clustering allowed the identification of 3 gene signatures related to CRD. One was common to CF and PAH, another specific to CF, and the final one was specific to PAH. With the common signature, we validated T-Cell Factor 7 ( TCF-7) and Interleukin 7 Receptor ( IL-7R), two genes related to T lymphocyte activation, as being under-expressed. We showed a strong impact of the hypoxia on modulation of TCF-7 and IL-7R expression in PBMCs from HC under hypoxia or PBMCs from CRD. In addition, we identified and validated genes upregulated in PAH or CF, including Lectin Galactoside-binding Soluble 3 and Toll Like Receptor 4, respectively.

          Conclusions

          Systematic analysis of blood cell transcriptome in CRD patients identified common and specific signatures relevant to the systemic pathologies. TCF-7 and IL-7R were downregulated whatever the cause of CRD and this could play a role in the higher susceptibility to infection of these patients.

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          Most cited references 32

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          Cluster analysis and display of genome-wide expression patterns.

          A system of cluster analysis for genome-wide expression data from DNA microarray hybridization is described that uses standard statistical algorithms to arrange genes according to similarity in pattern of gene expression. The output is displayed graphically, conveying the clustering and the underlying expression data simultaneously in a form intuitive for biologists. We have found in the budding yeast Saccharomyces cerevisiae that clustering gene expression data groups together efficiently genes of known similar function, and we find a similar tendency in human data. Thus patterns seen in genome-wide expression experiments can be interpreted as indications of the status of cellular processes. Also, coexpression of genes of known function with poorly characterized or novel genes may provide a simple means of gaining leads to the functions of many genes for which information is not available currently.
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            Chronic obstructive pulmonary disease.

             Chris Barnes (2000)
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              Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice

              Interleukin 7 (IL-7) stimulates the proliferation of B cell progenitors, thymocytes, and mature T cells through an interaction with a high affinity receptor (IL-7R) belonging to the hematopoietin receptor superfamily. We have further addressed the role of IL-7 and its receptor during B and T cell development by generating mice genetically deficient in IL-7R. Mutant mice display a profound reduction in thymic and peripheral lymphoid cellularity. Analyses of lymphoid progenitor populations in IL-7R-deficient mice define precisely those developmental stages affected by the mutation and reveal a critical role for IL-7R during early lymphoid development. Significantly, these studies indicate that the phase of thymocyte expansion occurring before the onset of T cell receptor gene rearrangement is critically dependent upon, and mediated by the high affinity receptor for IL-7.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                20 October 2014
                : 9
                : 10
                Affiliations
                [1 ]UMR_S 1087 CNRS UMR_6291, l′Institut du Thorax, Université de Nantes, CHU de Nantes, Centre National de Référence Mucoviscidose Nantes-Roscoff, Nantes, France
                [2 ]Université de Nantes, Nantes, France
                [3 ]Institut National de la Santé et de la Recherche Médicale INSERM U1064, and Institut de Transplantation Urologie Néphrologie du Centre Hospitalier Universitaire Hôtel Dieu, Nantes, France
                [4 ]CHU de Marseille, Aix Marseille Université, Marseille, France
                [5 ]Centre Chirurgical Marie Lannelongue, Service de Chirurgie Thoracique, Vasculaire et Transplantation Cardiopulmonaire, Le Plessis Robinson, France
                [6 ]Hôpital Foch, Suresnes, France
                [7 ]Université de Lyon, Lyon, France
                [8 ]Université de Lyon 1, Lyon, France
                [9 ]INRA, UMR_S 754, Lyon, France
                [10 ]Hospices Civils de Lyon, Lyon, France
                [11 ]Clinique Universitaire Pneumologie, CHU de Grenoble, Grenoble, France
                [12 ]Université Joseph Fourier, Grenoble, France
                [13 ]Inserm U1055, Grenoble, France
                [14 ]European Institute of Systems Biology and Medicine, Lyon, France
                [15 ]CHU de Bordeaux, Bordeaux, France
                [16 ]CHU de Strasbourg, Strasbourg, France
                [17 ]CHU de Toulouse, Toulouse, France
                [18 ]Hôpital Bichat, Service de Pneumologie B et Transplantation Pulmonaire, Paris, France
                [19 ]Université Paris-Sud, Le Kremlin-Bicêtre, France
                [20 ]AP-HP, Service de Pneumologie, DHU Thorax Innovation, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
                [21 ]INSERM U999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France
                Helmholtz Zentrum München/Ludwig-Maximilians-University Munich, Germany
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: JC RD KB AM SB. Performed the experiments: JC RD. Analyzed the data: JC RD. Contributed reagents/materials/analysis tools: JC RD. Contributed to the writing of the manuscript: JC RD AM SB. Patient recruitment: KB MRG SM MS IDB JFM CP CD RK MD OB JLP FP MH CG.

                ¶ JC and RD are first authors on this work. SB and AM also contributed equally to this work and are senior authors on this work.

                ‡ Membership of the COLT Consortium is provided in the Acknowledgments.

                Article
                PONE-D-14-20804
                10.1371/journal.pone.0109291
                4203719
                25329529

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 14
                Funding
                This study was funded mainly by a grant from Vaincre La Mucoviscidose, the Programme National Hospitalier de Recherche Clinique, a CENTAURE foundation grant, an Agence de la Biomédecine Française (ABM) grant, and an ESOT grant. This work was realized in the context of the IHU-Cesti project thanks to French government financial support managed by the National Research Agency via the “Investment Into The Future” program ANR-10-IBHU-005. The IHU-Cesti project is also supported by Nantes Metropole and the Pays de la Loire Region. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Developmental Biology
                Fibrosis
                Cystic Fibrosis
                Cell Biology
                Cellular Types
                Animal Cells
                Immune Cells
                Computational Biology
                Genome Analysis
                Transcriptome Analysis
                Immunology
                Clinical Immunology
                Immune Deficiency
                Immune Response
                Lymphocyte Activation
                Medicine and Health Sciences
                Pulmonology
                Chronic Obstructive Pulmonary Disease
                Pulmonary Hypertension
                Respiratory Failure
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. Data are available from the GEO database at: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=epkbaewellmjhuv&acc=GSE38267.

                Uncategorized

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