Identification of novel Th2-associated genes in T memory responses to allergens.
Atopic diseases are associated with hyperexpression of Th2 cytokines by allergen-specific T memory cells. However, clinical trials with recently developed Th2 inhibitors in atopics have proven disappointing, suggesting underlying complexities in atopy pathogenesis which are not satisfactorily explained via the classical Th1/Th2 paradigm. One likely possibility is that additional Th2-associated genes which are central to disease pathogenesis remain unidentified. The aim of the present study was to identify such novel Th2-associated genes in recall responses to the inhalant allergen house dust mite. In contrast to earlier human microarray studies in atopy which focused on mitogen-activated T cell lines and clones, we concentrated on PBMC-derived primary T cells stimulated under more physiological conditions of low dose allergen exposure. We screened initially for allergen-induced gene activation by microarray, and validated novel genes in independent panels of subjects by quantitative RT-PCR. Kinetic analysis of allergen responses in PBMC revealed an early wave of novel atopy-associated genes involved in signaling which were coexpressed with IL-4 and IL-4R, followed by a later wave of genes encoding the classical Th2 effector cytokines. We further demonstrate that these novel activation-associated Th2 genes up-regulate in response to another atopy-associated physiological stimulus bacterial superantigen, but remain quiescent in nonphysiological responses in primary T cells or cell lines driven by potent mitogens, which may account for their failure to be detected in earlier microarray studies.
Bosco
Anthony
A
Telethon Institute for Child Health Research, and Centre for Child Health Research, Faculty of Medicine and Dentistry, University of Western Australia, Perth, Western Australia.
McKenna
Kathy L
KL
Devitt
Catherine J
CJ
Firth
Martin J
MJ
Sly
Peter D
PD
Holt
Patrick G
PG
D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000485:Allergens / Q000008:administration & dosage; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000008:administration & dosage; D002648:Child; D016207:Cytokines / Q000235:genetics; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000235:genetics / Q000276:immunology; D007156:Immunologic Memory / Q000235:genetics*; D066298:In Vitro Techniques; D007700:Kinetics; D008875:Middle Aged; D008925:Mites / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
D000485:Allergens; D039741:Antigens, Dermatophagoides; D016207:Cytokines