Proteinase-activated receptor-2 promotes allergic sensitization to an inhaled antigen through a TNF-mediated pathway.
The reason why particular inhaled Ags induce allergic sensitization while others lead to immune tolerance is unclear. Along with a genetic predisposition to atopy, intrinsic characteristics of these Ags must be important. A common characteristic of many allergens is that they either possess proteinase activity or are inhaled in particles rich in proteinases. Many allergens, such as house dust mite and cockroach allergens, have the potential to activate the proteinase-activated receptor (PAR)-2. In this study, we report that PAR-2 activation in the airways at the same time as exposure to inhaled Ags induces allergic sensitization, whereas exposure to Ag alone induces tolerance. BALB/c mice were administered OVA with a PAR-2 activating peptide intranasally. Upon allergen re-exposure mice developed airway inflammation and airway hyperresponsiveness, as well as OVA-specific T cells with a Th2 cytokine profile when restimulated with OVA in vitro. Conversely, mice given OVA alone or OVA with a PAR-2 control peptide developed tolerance. These tolerant mice did not develop airway inflammation or airway hyperresponsiveness, and developed OVA-specific T cells that secreted high levels of IL-10 when restimulated with OVA in vitro. Furthermore, pulmonary dendritic cell trafficking was altered in mice following intranasal PAR-2 activation. Finally, we showed that PAR-2-mediated allergic sensitization was TNF-dependent. Thus, PAR-2 activation in the airways could be a critical factor in the development of allergic sensitization following mucosal exposure to allergens with serine proteinase activity. Interfering with this pathway may prove to be useful for the prevention or treatment of allergic diseases.
Ebeling
Cory
C
Pulmonary Research Group, Department of Medicine, 550 Heritage Medical Research Center, University of Alberta, Edmonton, Alberta, Canada.
Lam
Tong
T
Gordon
John R
JR
Hollenberg
Morley D
MD
Vliagoftis
Harissios
H
D000485:Allergens / Q000276:immunology*; D000818:Animals; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism; D006967:Hypersensitivity / Q000276:immunology*; D007108:Immune Tolerance; D001239:Inhalation; D008168:Lung / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D044464:Receptor, PAR-2 / Q000819:agonists*; D018418:Th2 Cells / Q000276:immunology; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors / Q000502:physiology*
D000485:Allergens; D016207:Cytokines; D044464:Receptor, PAR-2; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors; D010047:Ovalbumin