title: Pathways activated during human asthma exacerbation as revealed by gene expression patterns in blood.
abstract: 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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Department of Allergy/Clinical Immunology, University of Iceland, Reykjavík, Iceland.
authors.forename: Unnur S
authors.initials: US
authors.lastname: Bjornsdottir
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Holgate
authors.forename: Padmalatha S
authors.initials: PS
authors.lastname: Reddy
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Hill
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: McKee
authors.forename: Cristina I
authors.initials: CI
authors.lastname: Csimma
authors.forename: Amy A
authors.initials: AA
authors.lastname: Weaver
authors.forename: Holly M
authors.initials: HM
authors.lastname: Legault
authors.forename: Clayton G
authors.initials: CG
authors.lastname: Small
authors.forename: Renee C
authors.initials: RC
authors.lastname: Ramsey
authors.forename: Debra K
authors.initials: DK
authors.lastname: Ellis
authors.forename: Conor M
authors.initials: CM
authors.lastname: Burke
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Thompson
authors.forename: Peter H
authors.initials: PH
authors.lastname: Howarth
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wardlaw
authors.forename: Phillip G
authors.initials: PG
authors.lastname: Bardin
authors.forename: David I
authors.initials: DI
authors.lastname: Bernstein
authors.forename: Louis B
authors.initials: LB
authors.lastname: Irving
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Chupp
authors.forename: George W
authors.initials: GW
authors.lastname: Bensch
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Bensch
authors.forename: Jon E
authors.initials: JE
authors.lastname: Stahlman
authors.forename: Monroe
authors.initials: M
authors.lastname: Karetzky
authors.forename: James W
authors.initials: JW
authors.lastname: Baker
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Miller
authors.forename: Brad H
authors.initials: BH
authors.lastname: Goodman
authors.forename: Donald G
authors.initials: DG
authors.lastname: Raible
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Goldman
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Miller
authors.forename: John L
authors.initials: JL
authors.lastname: Ryan
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dorner
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Immermann
authors.forename: Margot
authors.initials: M
authors.lastname: O'Toole
mesh_terms: D000328:Adult; D001249:Asthma / Q000097:blood* / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D025341:Principal Component Analysis; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*