Proteinase-activated receptor-2 promotes allergic Sensitization to an inhaled antigen through a TNF-Mediated pathway
Proteinase-activated receptor-2 promotes allergic Sensitization to an inhaled antigen through a TNF-Mediated pathway
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DOI：
10.4049/jimmunol.179.5.2910
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发表时间：
2007-09-01
影响因子：
4.4
通讯作者：
Vliagoftis, Harissios
中科院分区：
文献类型：
--
作者：
Ebeling, Cory;Lam, Tong;Vliagoftis, Harissios
为什么特定的吸入AGS会引起过敏反应，而其他AGS则会导致免疫耐受，其原因尚不清楚。除了特应性的遗传易感性，这些AGS的内在特征也必须是重要的。许多过敏原的一个共同特征是，它们要么具有蛋白酶活性，要么被吸入富含蛋白酶的颗粒中。许多过敏原，如屋尘螨和蟑螂过敏原，都有激活蛋白酶激活受体(PAR)-2的潜力。在这项研究中，我们报告了在吸入AGS的同时，呼吸道中PAR-2的激活诱导过敏反应，而单独暴露于Ag则诱导耐受。给BALB/c小鼠鼻腔注射含有PAR-2激活肽的OVA。当过敏原再次暴露时，小鼠出现呼吸道炎症和气道高反应性，以及在体外用OVA重新刺激时具有Th2细胞因子特征的OVA特异性T细胞。相反，单独服用卵清蛋白或含有PAR-2控制肽的卵清蛋白的小鼠出现耐受性。这些耐受小鼠没有出现呼吸道炎症或气道高反应性，并在体外用OVA重新刺激时产生了分泌高水平IL-10的OVA特异性T细胞。此外，小鼠鼻腔内PAR-2激活后，肺树突状细胞的转运也发生了改变。最后，我们证明了PAR-2介导的变态反应性致敏是肿瘤坏死因子依赖性的。因此，呼吸道中PAR-2的激活可能是黏膜暴露于具有丝氨酸蛋白酶活性的过敏原后发生过敏反应的关键因素。干扰这一途径可能被证明对预防或治疗过敏性疾病有用。
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.