title: Dysregulation of complement system and CD4+ T cell activation pathways implicated in allergic response.
abstract: Allergy is a complex disease that is likely to involve dysregulated CD4+ T cell activation. Here we propose a novel methodology to gain insight into how coordinated behaviour emerges between disease-dysregulated pathways in response to pathophysiological stimuli. Using peripheral blood mononuclear cells of allergic rhinitis patients and controls cultured with and without pollen allergens, we integrate CD4+ T cell gene expression from microarray data and genetic markers of allergic sensitisation from GWAS data at the pathway level using enrichment analysis; implicating the complement system in both cellular and systemic response to pollen allergens. We delineate a novel disease network linking T cell activation to the complement system that is significantly enriched for genes exhibiting correlated gene expression and protein-protein interactions, suggesting a tight biological coordination that is dysregulated in the disease state in response to pollen allergen but not to diluent. This novel disease network has high predictive power for the gene and protein expression of the Th2 cytokine profile (IL-4, IL-5, IL-10, IL-13) and of the Th2 master regulator (GATA3), suggesting its involvement in the early stages of CD4+ T cell differentiation. Dissection of the complement system gene expression identifies 7 genes specifically associated with atopic response to pollen, including C1QR1, CFD, CFP, ITGB2, ITGAX and confirms the role of C3AR1 and C5AR1. Two of these genes (ITGB2 and C3AR1) are also implicated in the network linking complement system to T cell activation, which comprises 6 differentially expressed genes. C3AR1 is also significantly associated with allergic sensitisation in GWAS data.
authors.affiliation: Department of Epidemiology and Biostatistics, Imperial College London, MRC-HPA Centre for Environment and Health, Imperial College London, London, United Kingdom.
authors.forename: Alexessander
authors.initials: A
authors.lastname: Couto Alves
authors.forename: Sören
authors.initials: S
authors.lastname: Bruhn
authors.forename: Adaikalavan
authors.initials: A
authors.lastname: Ramasamy
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: John W
authors.initials: JW
authors.lastname: Holloway
authors.forename: Anna-Liisa
authors.initials: AL
authors.lastname: Hartikainen
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Jarvelin
authors.forename: Mikael
authors.initials: M
authors.lastname: Benson
authors.forename: David J
authors.initials: DJ
authors.lastname: Balding
authors.forename: Lachlan J M
authors.initials: LJ
authors.lastname: Coin
mesh_terms: D000485:Allergens / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D011058:Pollen; D011951:Receptors, Complement / Q000235:genetics / Q000378:metabolism; D006255:Rhinitis, Allergic, Seasonal / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D000485:Allergens; D016207:Cytokines; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D011951:Receptors, Complement; C085567:complement C3a receptor