title: Differential gene network analysis for the identification of asthma-associated therapeutic targets in allergen-specific T-helper memory responses.
abstract: BACKGROUND
  Asthma is strongly associated with allergic sensitization, but the mechanisms that determine why only a subset of atopics develop asthma are not well understood. The aim of this study was to test the hypothesis that variations in allergen-driven CD4 T cell responses are associated with susceptibility to expression of asthma symptoms.
  
  
  METHODS
  The study population consisted of house dust mite (HDM) sensitized atopics with current asthma (n = 22), HDM-sensitized atopics without current asthma (n = 26), and HDM-nonsensitized controls (n = 24). Peripheral blood mononuclear cells from these groups were cultured in the presence or absence of HDM extract for 24 h. CD4 T cells were then isolated by immunomagnetic separation, and gene expression patterns were profiled on microarrays.
  
  
  RESULTS
  Differential network analysis of HDM-induced CD4 T cell responses in sensitized atopics with or without asthma unveiled a cohort of asthma-associated genes that escaped detection by more conventional data analysis techniques. These asthma-associated genes were enriched for targets of STAT6 signaling, and they were nested within a larger coexpression module comprising 406 genes. Upstream regulator analysis suggested that this module was driven primarily by IL-2, IL-4, and TNF signaling; reconstruction of the wiring diagram of the module revealed a series of hub genes involved in inflammation (IL-1B, NFkB, STAT1, STAT3), apoptosis (BCL2, MYC), and regulatory T cells (IL-2Ra, FoxP3). Finally, we identified several negative regulators of asthmatic CD4 T cell responses to allergens (e.g. IL-10, type I interferons, microRNAs, drugs, metabolites), and these represent logical candidates for therapeutic intervention.
  
  
  CONCLUSIONS
  Differential network analysis of allergen-induced CD4 T cell responses can unmask covert disease-associated genes and pin point novel therapeutic targets.
authors.affiliation: Telethon Kids Institute, The University of Western Australia, Crawley, Australia. niamh.troy@telethonkids.org.au.
authors.forename: Niamh M
authors.initials: NM
authors.lastname: Troy
authors.affiliation: Telethon Kids Institute, The University of Western Australia, Crawley, Australia. Elysia.Hollams@telethonkids.org.au.
authors.forename: Elysia M
authors.initials: EM
authors.lastname: Hollams
authors.affiliation: Telethon Kids Institute, The University of Western Australia, Crawley, Australia. Pat.Holt@telethonkids.org.au.|Queensland Children's Medical Research Institute, The University of Queensland, Brisbane, Australia. Pat.Holt@telethonkids.org.au.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Holt
authors.affiliation: Telethon Kids Institute, The University of Western Australia, Crawley, Australia. Anthony.Bosco@telethonkids.org.au.
authors.forename: Anthony
authors.initials: A
authors.lastname: Bosco
mesh_terms: D000293:Adolescent; D000485:Allergens / Q000276:immunology*; D000818:Animals; D001249:Asthma / Q000235:genetics* / Q000276:immunology*; D016022:Case-Control Studies; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D007114:Immunization; D007156:Immunologic Memory / Q000235:genetics*; D008297:Male; D058990:Molecular Targeted Therapy; D039981:Pyroglyphidae / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D000485:Allergens