Julie Chesné 1 , 2 , Richard Danger 2 , 3 , Karine Botturi 1 , 2 , Martine Reynaud-Gaubert 4 , Sacha Mussot 5 , Marc Stern 6 , Isabelle Danner-Boucher 1 , Jean-François Mornex 7 , 8 , 9 , 10 , Christophe Pison 11 , 12 , 13 , 14 , Claire Dromer 15 , Romain Kessler 16 , Marcel Dahan 17 , Olivier Brugière 18 , Jérôme Le Pavec 5 , Frédéric Perros 19 , 20 , 21 , Marc Humbert 19 , 20 , 21 , Carine Gomez 4 , Sophie Brouard 2 , 3 , Antoine Magnan 1 , 2 , * , the COLT Consortium
20 October 2014
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).
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.
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.
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.