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.
Telethon Institute for Child Health Research, and Centre for Child Health Research, Faculty of Medicine and Dentistry, University of Western Australia, Perth, Western Australia.
Anthony
A
Bosco
Kathy L
KL
McKenna
Catherine J
CJ
Devitt
Martin J
MJ
Firth
Peter D
PD
Sly
Patrick G
PG
Holt
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