Gene expression in CD4+ T-cells reflects heterogeneity in infant wheezing phenotypes.

Although a marked increase in the reporting of wheezing symptoms since the mid-1970s has been described, the underlying immunopathology of the different wheezing phenotypes has not been clarified. Since differences in gene expression might be involved, the objective of the present study was to identify gene expression profiles in CD4+ T-cells from two distinct infant wheezing phenotypes. The gene expression profiles of peripheral CD4+ T-cells were compared by means of microarray analysis of six transient wheezers, six persistent wheezers and seven healthy controls. The differentially expressed genes were subsequently validated by RT-PCR. The differential gene expression profiles reflected common immunological pathways involved in apoptosis or proliferation of T-cells. Furthermore, both wheezing phenotypes showed decreased expression of the complement component 5 receptor 1 gene, a gene involved in the regulation of bronchial responsiveness. Moreover, differences in gene expression profiles were found in genes involved in the immune response against respiratory syncytial virus, such as those encoding signal transducer and activator of transcription 1 and an inflammatory mediator showing enhanced production in asthma (prostaglandin E(2) receptor 2). The present findings suggest that clinical symptoms of wheeze are reflected in common immunological pathways, whereas differences between wheezing phenotypes are, in part, reflected in distinct gene expression profiles.

Systemic inflammation in COPD visualised by gene profiling in peripheral blood neutrophils.

BACKGROUND: The inflammatory process in chronic obstructive pulmonary disease (COPD) is characterised by the presence of neutrophils in the lung that are able to synthesise de novo several inflammatory mediators. The local chronic persistent inflammatory response is accompanied by systemic effects such as cytokine induced priming of peripheral leucocytes and muscle wasting. The preactivation or priming of peripheral blood neutrophils was used to gain more insight into the mechanisms of this systemic inflammatory response. METHODS: Gene arrays were performed on peripheral blood neutrophils obtained from healthy donors after stimulation in vitro with tumour necrosis factor (TNF)-alpha, granulocyte-macrophage colony stimulating factor (GM-CSF), or both. The expression of many inflammatory genes was regulated in these cells following stimulation. The expression of inflammatory genes in peripheral blood neutrophils in healthy subjects and those with COPD was measured by real time RT-PCR after stimulation with TNFalpha, GM-CSF, interleukin (IL)-8, fMLP, TNFalpha + GM-CSF, and lipopolysaccharide (LPS). RESULTS: The genes regulated in the gene array with TNFalpha/GM-CSF stimulated neutrophils included cytokines (such as IL-1beta), chemokines (such as IL-8), and adhesion molecules (such as ICAM-1). Disease severity as measured by forced expiratory volume in 1 second (FEV(1)) in COPD patients correlated with expression of several of these genes including IL-1beta (r = -0.540; p = 0.008), MIP-1beta (r = -0.583; p = 0.003), CD83 (r = -0.514; p = 0.012), IL-1 receptor 2 (r = -0.546; p = 0.007), and IL-1 receptor antagonist (r = -0.612; p = 0.002). CONCLUSIONS: These data are consistent with the hypothesis that progression of COPD is associated with the activation of neutrophils in the systemic compartment. De novo expression of inflammatory mediators by peripheral blood neutrophils suggests a pro-inflammatory role for these cells in the pathogenesis of COPD.