HISTOPATHOLOGIC STUDIES OF ALLERGIC INFLAMMATION OF AIRWAYS

现在人们普遍认为哮喘代表着临床上的 以一种独特的慢性呼吸道疾病为特征的呼吸道疾病的表现 发炎。炎症过程中突出的是内皮细胞 如肥大细胞、嗜酸性粒细胞和T淋巴细胞等。哮喘是最常见的 与潜在的萎缩、对吸入性过敏原的敏感有关，以及 提高免疫球蛋白E(IgE)的产量。如此过敏和 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 辅助性T淋巴细胞的Th2亚群的特征。Th2细胞因子 包括白介素4(IL-4)，参与IgE的产生和 Th2型淋巴细胞的分化；参与募集的IL-5， 循环中聚集的嗜酸性粒细胞的激活和存活 炎症部位；和IL-13，具有许多IL-4的特性 包括刺激内皮细胞上黏附分子的表达 排列在血管里的细胞。我们的工作使用分段模型 人类受试者呼吸道过敏原的挑战已经证明 嗜酸性粒细胞、嗜碱性粒细胞和辅助/记忆T细胞的特异性招募 淋巴细胞进入呼吸道对致敏变应原的反应 个人。这些发现表明，选择性机制参与了 对变应原的炎症反应以及随后的免疫学 呼吸道对暴露在特定过敏原上的敏化。潜在的 涉及嗜酸性粒细胞和嗜碱性粒细胞募集的炎症反应 是表达和产生Th2型细胞因子，包括IL-4，IL-5， 和IL-13。发生细胞募集的机制是 通过研究全身性皮质类固醇对 炎症反应。结果清楚地表明， 全身性皮质类固醇激素，包括 嗜酸性粒细胞、嗜碱性粒细胞和T淋巴细胞被招募到变应原部位 挑战。这些对细胞内流的影响与 抑制激肽生成和血浆渗出作为血液标志物 血管和呼吸道通透性。基因表达水平的提高 IL-4和IL-5以及细胞因子特异性蛋白的产生也 被给予皮质类固醇药物抑制。E-选择素的产生， 参与细胞募集的黏附分子之一也是 被皮质类固醇抑制。细胞因子IL-2的产生也 给予类固醇激素后，其表达受到抑制。 IFNGamma的生产没有受到影响。系统的管理 皮质类固醇不影响组胺的即刻释放和 前列腺素D2与肥大细胞介体缺乏作用一致 放手。这些结果表明，许多招募机制 参与过敏性炎症和哮喘的炎性细胞 被全身性皮质类固醇抑制，可能涉及机制 抑制细胞因子基因的表达、细胞因子的产生和 黏附分子的诱导。 我们对细胞募集机制的最新研究 哮喘的过敏性炎症主要集中在过敏原的募集上- 特异性T细胞对变应原部位的攻击。使用敏感的对象 多种过敏原，并在不同的时间用不同的过敏原挑战， 即尘螨或豚草变应原，我们已经证明在 纯化的辅助性T细胞群是一种过敏原特异性T细胞群 通过体外对过敏原刺激的过敏原特异性反应来检测。通过 用两种过敏原刺激辅助性T细胞群 体内的过敏原挑战，我们已经证明，即使在20 几个小时后，似乎有过敏原驱动的招募之前 致敏T淋巴细胞聚集在炎症部位。这个 结果表明，除了涉及招聘的机制外， 炎症细胞对部位的过敏原发起挑战，有一种过敏原- 细胞反应的特定成分。这些发现表明， 巨噬细胞或树突状细胞等抗原提呈细胞可能是 参与过敏原特异性淋巴细胞聚集和免疫学 为进一步暴露在过敏原中作出反应而对呼吸道进行预置。是这样的 机制可能在永久化和本地化方面很重要 因接触变应原而引起的哮喘呼吸道炎症。 未来的研究将确定它是否是过敏原特异性T细胞 人口招募到过敏原挑战的地点，这是来源 混合细胞群体中Th2细胞因子的表达 在过敏挑战后积聚。

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.