HISTOPATHOLOGIC STUDIES OF ASTHMA

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 通常与潜在的萎缩，对吸入过敏原的敏感性， 和免疫球蛋白E（IgE.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的产生和分化， Th 2型淋巴细胞; IL-5，参与募集，激活， 在炎症部位积聚的循环嗜酸性粒细胞的存活; 和IL-13，共享IL-4的许多特性，包括刺激 粘附分子在血液内皮细胞上的表达 船舶.我们的工作使用的模型，节段性过敏原的挑战， 人类受试者的气道已经证明了特异性募集 嗜酸性粒细胞、嗜碱性粒细胞和辅助/记忆T淋巴细胞进入气道 对致敏性免疫球蛋白过敏原攻击的应答。这些发现 表明参与炎症反应的高度选择性机制 过敏原以及随后的免疫致敏性 气道暴露于特定抗原。在炎症的基础上 涉及嗜酸性粒细胞和嗜碱性粒细胞募集的反应是 Th 2型细胞因子包括IL-4、IL-5和 IL-13。特异性细胞募集发生的机制有 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抑制 激肽产生和血浆渗出作为血管和 气道通透性IL-4和IL-5的基因表达水平增加， 以及甜菜碱特异性蛋白质的产生，也受到抑制， 给予皮质类固醇。 E-选择素的产生， 参与细胞募集的粘附分子也受到抑制， 皮质类固醇激素也抑制细胞因子IL-2的产生 施用，而mRNA的表达和IFN γ的产生 没有受到影响。给予全身性皮质类固醇并不影响 组胺和前列腺素D2的立即释放与 缺乏肥大细胞介质释放作用。这些结果表明，许多 的机制，招募炎症细胞参与过敏性 全身性皮质类固醇抑制炎症和哮喘， 可能涉及抑制细胞因子基因表达的机制， 细胞因子的产生和粘附分子的诱导。 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细胞群是变应原特异性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先前 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， 抗原呈递细胞如巨噬细胞或树突细胞可以 参与过敏原特异性淋巴细胞的积累和免疫 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 招募到过敏原激发地点的人群，这是过敏原的来源 在混合细胞群中证明的Th 2细胞因子谱 在过敏原激发后积累。

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 often 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 induviduals. These findings indicate highly selective mechanisms involved in the inflammatory response to allergen as well as the subsequent immunologic sensitization of the airway to exposure of a specific antigen. 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 specific cellular 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 of 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-drivem 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 lymphocyts 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 allergen challenge.