HISTOPATHOLOGIC STUDIES OF ALLERGIC INFLAMMATION OF AIRWAYS

现在人们广泛认识到哮喘代表了 呼吸道疾病的表现特征是一种独特的慢性 炎症 在炎症过程中突出的是细胞内的细胞， 例如肥大细胞、嗜酸性粒细胞和T淋巴细胞。哮喘是最 与潜在的萎缩、吸入过敏原致敏相关，以及 免疫球蛋白E（IgE）的产生增加。如此过敏， 哮喘反应与辅助性T细胞的存在有关 以产生某些细胞因子为特征的淋巴细胞 表征辅助性T淋巴细胞的Th 2亚群。th 2细胞因子 包括白细胞介素（IL-4），参与IgE的产生， Th 2型淋巴细胞的分化; IL-5，参与募集， 活化和存活的循环嗜酸性粒细胞积累在一个 炎症部位;和IL-13，共享IL-4的许多特性 包括 刺激内皮细胞粘附分子的表达 血管内衬的细胞。我们的工作使用分段模型 人类受试者气道的过敏原攻击已经证明 嗜酸性粒细胞、嗜碱性粒细胞和辅助/记忆T细胞的特异性募集 淋巴细胞进入气道，以响应致敏的过敏原攻击。 个体这些发现表明，选择性机制参与了 对过敏原的炎症反应以及随后的免疫反应 呼吸道对特定过敏原的敏感性。所依据 涉及嗜酸性粒细胞和嗜碱性粒细胞募集的炎症反应 是Th 2型细胞因子包括IL-4，IL-5， IL-13。细胞募集发生的机制一直是 通过研究全身性皮质类固醇对 炎症反应。结果清楚地表明， 全身性皮质类固醇，包括显著减少 嗜酸性粒细胞、嗜碱性粒细胞和T淋巴细胞聚集到过敏原部位 挑战.这些对细胞内流的影响与 作为血液标志物的激肽生成和血浆渗出的抑制 容器 和气道渗透性。基因表达水平增加， IL-4和IL-5 以及甜菜碱特异性蛋白质的产生也 通过给予皮质类固醇来抑制。E-选择素的产生， 参与细胞募集的粘附分子之一也是 被皮质类固醇抑制细胞因子IL-2的产生也是 抑制类固醇管理，而表达的mRNA和 IFN γ的产生不受影响。全身给药 皮质类固醇不影响组胺的立即释放， 前列腺素D2与对肥大细胞介质缺乏影响一致 release.这些结果表明，许多招聘机制， 与过敏性炎症和哮喘有关的炎性细胞 受全身性皮质类固醇抑制，可能涉及 抑制细胞因子基因的表达、细胞因子的产生，和 诱导粘附分子。 我们最近对细胞募集机制的研究， 哮喘中的过敏性炎症集中在过敏原的募集上， 特异性T细胞的过敏原攻击的网站。利用对以下问题敏感的对象 多种过敏原并在不同时间用不同过敏原激发， 也就是说，尘螨或豚草过敏原，我们已经证明， 纯化的辅助性T细胞群是过敏原特异性T细胞群 通过体外对过敏原刺激的过敏原特异性反应检测。通过 刺激辅助性T细胞群与两种过敏原后，不同 过敏原的挑战，我们已经证明，即使在20 小时，似乎有一个过敏原驱动的招聘以前 致敏的T淋巴细胞在炎症部位聚集。的 结果表明，除了涉及招募的机制外， 炎症细胞的过敏原攻击的网站，有一个过敏原- 细胞反应的特定成分。这些发现表明， 抗原呈递细胞，例如 巨噬细胞或树突细胞可以是 参与过敏原特异性淋巴细胞 蓄积和免疫 使气道对进一步暴露于过敏原作出反应。等 机制可能是重要的延续和本地化 哮喘气道因暴露于过敏原而引起的炎症。 未来的研究将确定它是否是过敏原特异性T细胞 招募到过敏原激发部位的人群， 在混合细胞群中证明的Th 2细胞因子谱 在过敏性激发后累积。

It is now widely recognized that asthma represents the clinical manifestations of airways disease characterized by a unique form of chronic inflammation. Prominent in the inflammatory process are cells within the airways such as mast cells, eosinophils, and T lymphocytes. Asthma is most associated with underlying atrophy, sensitization to inhaled allergens, and elevations in production of immunoglobulin E (IgE). Such allergic and asthmatic responses are associated with the presence of helper T lymphocytes characterized by the production of certain cytokines characterizing the Th2-subset of helper T lymphocytes. Th2 cytokines include interleukin (IL-4), involved in IgE production and the differentiation of Th2 type lymphocytes; IL-5, involved in the recruitment, activation, and survival of circulating eosinophils accumulating in an inflammatory site; and IL-13, sharing many of the properties of IL-4 including stimulating the expression of adhesion molecules on endothelial cells lining the blood vessels. Our work using the model of segmental allergen challenge of the airways in human subjects has demonstrated specific recruitment of eosinophils, basophils, and helper/memory T lymphocytes into the airways in response to allergen challenge of sensitized individuals. These findings indicate selective mechanisms involved in the inflammatory response to allergen as well as the subsequent immunologic sensitization of the airway to exposure on a specific allergen. Underlying the inflammatory response involving recruitment of eosinophils and basophils is the expression and production of Th2 type cytokines including IL-4, IL-5, and IL-13. The mechanisms by which cellualr recruitment occurs has been further examined by studying the effect of systemic corticosteroids on the inflammatory response. Results clearly demonstrate multiple effects of systemic corticosteroids including significant decreases in the number of eosinophils, basophils and T lymphocytes recruited to the site of allergen challenge. These effects on cellular influx were associated with inhibition of kinin generation and plasma exudation as markers of blood vessel and airway permeability. Increased levels of gene expression for IL-4 and IL-5 as well as cytokine-specific protein production was also inhibited by the administration of corticosteroids. Production of E-selectin, one of the adhesion molecules involved in cellular recruitment was also inhibited by corticosteroids. Production of the cytokine IL-2 was also inhibited by steroid administration, while expression of mRNA and production of IFNgamma was not affected. Administration of systemic corticosteroids did not affect the immediate release of histamine and prostaglandin D2 consistent with a lack of effect on mast cell mediator release. These results indicate that many of the mechanisms of recruitment of inflammatory cells involved in allergic inflammation and asthma are inhibited by systemic corticosteroids and are likely to involve mechanisms inhibiting the expression of cytokine genes, cytokine production, and induction of adhesion molecules. Our most recent studies on the mechanisms of cellular recruitment in allergic inflammation in asthma have focused on the recruitment of allergen- specific T cells to the site of allergen challenge. Using subjects sensitized to multiple allergens and challenged at different times with different allergens, i.e., dust mite or ragweed allergens, we have demonstrated that within the purified helper T-cell population is an allergen-specific T cell population detected by allergen-specific responses to allergen stimulation in vitro. By stimulating helper T cell populations with both allergens following different allergen challenges in vivo, we have demonstrated that even within 20 hours, there appears to be an allergen-driven recruitment of previously sensitized T lymphocytes accumulating at the site of inflammation. The results suggest that in addition to mechanisms involving recruitment of inflammatory cells to the site of allergen challenge, there is an allergen- specific component to the cellular response. Such findings suggest that antigen-presenting cells such as macrophages or dendritic cells may be involved in allergen-specific lymphocyte accumulation and immunologic priming of the airway for response to further exposure to allergens. Such mechanisms may be important in the perpetuation and localization of inflammation in the asthmatic airway stimulated by exposure to allergen. Future studies will determine whether it is the allergen-specific T cell population recruited to the site of allergen challenge which is the source of the Th2 cytokine profile demonstrated in the mixed cell population accumulating following allergic challenge.