Pathways activated during human asthma exacerbation as revealed by gene expression patterns in blood |
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Authors: | Bjornsdottir Unnur S Holgate Stephen T Reddy Padmalatha S Hill Andrew A McKee Charlotte M Csimma Cristina I Weaver Amy A Legault Holly M Small Clayton G Ramsey Renee C Ellis Debra K Burke Conor M Thompson Philip J Howarth Peter H Wardlaw Andrew J Bardin Phillip G Bernstein David I Irving Louis B Chupp Geoffrey L Bensch George W Bensch Gregory W Stahlman Jon E Karetzky Monroe Baker James W Miller Rachel L Goodman Brad H Raible Donald G Goldman Samuel J Miller Douglas K Ryan John L Dorner Andrew J Immermann Frederick W O'Toole Margot |
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Institution: | Department of Allergy/Clinical Immunology, University of Iceland, Reykjavík, Iceland. |
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Abstract: | BackgroundAsthma exacerbations remain a major unmet clinical need. The difficulty in obtaining airway tissue and bronchoalveolar lavage samples during exacerbations has greatly hampered study of naturally occurring exacerbations. This study was conducted to determine if mRNA profiling of peripheral blood mononuclear cells (PBMCs) could provide information on the systemic molecular pathways involved during asthma exacerbations.Methodology/Principal FindingsOver the course of one year, gene expression levels during stable asthma, exacerbation, and two weeks after an exacerbation were compared using oligonucleotide arrays. For each of 118 subjects who experienced at least one asthma exacerbation, the gene expression patterns in a sample of peripheral blood mononuclear cells collected during an exacerbation episode were compared to patterns observed in multiple samples from the same subject collected during quiescent asthma. Analysis of covariance identified genes whose levels of expression changed during exacerbations and returned to quiescent levels by two weeks. Heterogeneity among visits in expression profiles was examined using K-means clustering. Three distinct exacerbation-associated gene expression signatures were identified. One signature indicated that, even among patients without symptoms of respiratory infection, genes of innate immunity were activated. Antigen-independent T cell activation mediated by IL15 was also indicated by this signature. A second signature revealed strong evidence of lymphocyte activation through antigen receptors and subsequent downstream events of adaptive immunity. The number of genes identified in the third signature was too few to draw conclusions on the mechanisms driving those exacerbations.Conclusions/SignificanceThis study has shown that analysis of PBMCs reveals systemic changes accompanying asthma exacerbation and has laid the foundation for future comparative studies using PBMCs. |
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