A network-based analysis of the late-phase reaction of the skin.
BACKGROUND
The late-phase reaction (LPR) of the skin is an in vivo model of allergic inflammation.


OBJECTIVE
We sought to identify disease-associated pathways in the LPR using a network-based analysis.


METHODS
The LPR was examined by means of DNA microarray analysis of skin biopsy specimens from 10 patients with allergic rhinitis and 10 healthy control subjects. The results were further analyzed in 2 different materials consisting of nasal fluids and allergen-challenged CD4(+) T cells from patients with allergic rhinitis.


RESULTS
The DNA microarray analysis revealed several genes of known relevance to allergy. The eosinophil marker Charcot-Leyden crystal protein (CLC) that encodes Charcot-Leyden crystal protein differed most in expression. A network-based analysis showed upregulation of IL-4- and CCL4-dependent pathways and downregulation of a TGF-beta-induced pathway. CCL4 is expressed by CD4(+) T cells and chemotactic for eosinophils. We hypothesized that allergen induces release of CCL4 from T(H)2 cells and that this contributes to influx of eosinophils. Further analysis showed increase of CCL4 protein in nasal fluids from allergic patients during the season. Allergen challenge of PBMCs resulted in proliferation of T(H)2 cells and increased production of CCL4 in CD4(+) T cells from allergic patients. An analysis of the DNA microarray data revealed a significant correlation between CCL4 and the eosinophil marker CLC.


CONCLUSIONS
A network-based analysis of the LPR showed increased activity of IL-4- and CCL4- dependent pathways and downregulation of the TGF-beta-induced pathway. Allergen-induced release of CCL4 from T(H)2 cells might contribute to influx of eosinophils during the LPR.


CONCLUSIONS
Involvement of multiple interacting pathways indicates that it might be difficult to identify one single mediator as a biomarker or drug target in allergic inflammation.
Benson
Mikael
M
Department of Pediatrics, Queen Silvia Children's Hospital, SE-41685 Gothenburg, Sweden. mikael.benson@vgregion.se
Langston
Michael A
MA
Adner
Mikael
M
Andersson
Bengt
B
Torinssson-Naluai
Asa
A
Cardell
Lars Olaf
LO
D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D054407:Chemokine CCL4; D019742:Chemokines, CC / Q000502:physiology; D006801:Humans; D015847:Interleukin-4 / Q000502:physiology; D019402:Macrophage Inflammatory Proteins / Q000502:physiology; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012221:Rhinitis, Allergic, Perennial / Q000276:immunology*; D006255:Rhinitis, Allergic, Seasonal / Q000276:immunology*; D015398:Signal Transduction; D012867:Skin / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000502:physiology
C066507:CCL4 protein, human; D054407:Chemokine CCL4; D019742:Chemokines, CC; D019402:Macrophage Inflammatory Proteins; D016212:Transforming Growth Factor beta; D015847:Interleukin-4