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Pathways activated during human asthma exacerbation as revealed by gene expression patterns in blood

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journal contribution
posted on 24.10.2012, 09:11 by U. S. Bjornsdottir, S. T. Holgate, P. H. Howarth, P. S. Reddy, A. A. Hill, A. A. Weaver, R. C. Ramsey, D. G. Raible, S. J. Goldman, D. K. Miller, F. W. Immermann, M. O'Toole, C. M. McKee, C. I. Csimma, H. M. Legault, C. G. Small, D. K. Ellis, J. L. Ryan, A. J. Dorner, C. M. Burke, P. J. Thompson, Andrew J. Wardlaw, P. G. Bardin, D. I. Bernstein, L. B. Irving, G. L. Chupp, G. W. Bensch, J. E. Stahlman, M. Karetzky, J. W. Baker, R. L. Miller, B. H. Goodman
Background Asthma 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 Findings Over 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/Significance This study has shown that analysis of PBMCs reveals systemic changes accompanying asthma exacerbation and has laid the foundation for future comparative studies using PBMCs.

Funding

This work was funded by Pfizer, formerly Wyeth.

History

Citation

PLoS ONE, 2011, 6 (7)

Published in

PLoS ONE

Publisher

Public Library of Science

issn

1932-6203

eissn

1932-6203

Copyright date

2011

Available date

24/10/2012

Publisher version

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0021902

Language

en