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. CONCLUSION: 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. CLINICAL IMPLICATIONS: 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.
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 allergicpatients 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 allergicpatients. An analysis of the DNA microarray data revealed a significant correlation between CCL4 and the eosinophil marker CLC. CONCLUSION: 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. CLINICAL IMPLICATIONS: 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.
Authors: Joel Pekow; Urszula Dougherty; Yong Huang; Edward Gometz; Jeff Nathanson; Greg Cohen; Shawn Levy; Masha Kocherginsky; Nanda Venu; Maria Westerhoff; John Hart; Amy E Noffsinger; Stephen B Hanauer; Roger D Hurst; Alessandro Fichera; Loren J Joseph; Qiang Liu; Marc Bissonnette Journal: Inflamm Bowel Dis Date: 2013-03 Impact factor: 5.325
Authors: Reza Mobini; Bengt A Andersson; Jonas Erjefält; Mirjana Hahn-Zoric; Michael A Langston; Andy D Perkins; Lars Olaf Cardell; Mikael Benson Journal: BMC Syst Biol Date: 2009-02-12
Authors: Lina Mattson; Antonio Lentini; Danuta R Gawel; Tejaswi V S Badam; Mikael Benson; Torbjorn Ledin; Colm E Nestor; Mika Gustafsson; Jordi Serra-Musach; Janne Bjorkander; Zou Xiang; Huan Zhang Journal: J Immunol Res Date: 2016-12-19 Impact factor: 4.818
Authors: Mika Gustafsson; Måns Edström; Danuta Gawel; Colm E Nestor; Hui Wang; Huan Zhang; Fredrik Barrenäs; James Tojo; Ingrid Kockum; Tomas Olsson; Jordi Serra-Musach; Núria Bonifaci; Miguel Angel Pujana; Jan Ernerudh; Mikael Benson Journal: Genome Med Date: 2014-02-26 Impact factor: 11.117