IGE MEDIATED BRONCHIAL RESPONSES TO ALLERGEN

哮喘患者支气管粘膜嗜酸性粒细胞炎症，气道表现出两种不同的生理反应：支气管对非特异性刺激的高反应性（BHR）和吸入特异性过敏原后急性过敏原诱导的气流阻塞。哮喘和IgE产生之间有很强的临床和流行病学相关性。IgE的多种既定功能可能与哮喘的病理生理有关，IgE及其受体的阻滞剂目前正在作为潜在的治疗药物进行研究。许多小鼠哮喘模型，包括在本实验室建立的模型，已被用于研究哮喘反应的两个重要方面的发病机制：过敏原诱导的气道粘膜嗜酸性粒细胞炎症和BHR。使用先前通过基因靶向产生的IgE缺陷小鼠（IgE-/-），我们已经证明嗜酸性粒细胞气道炎症和BHR（对非特异性刺激的敏感性增加）都可以通过IgE不依赖的途径产生。然而，到目前为止，现有的模型还不能分析该疾病的其他关键特征，如吸入过敏原引起的急性气流阻塞，以及ige介导的支气管粘膜局部细胞和体液免疫反应的扩增。目前，P.I.已经建立了研究这些反应的新方法，并将用于检验关于IgE作用的几种假设。我们假设过敏原特异性IgE是吸入过敏原后急性气流阻塞的关键触发因素，并将通过对过敏原致敏野生型和IgE-/-小鼠的支气管激发研究来解决这个问题。我们已经证明IgE增强了CD23的表达，并提出这种上调增强了携带IgE的B细胞通过CD23向过敏原特异性T细胞呈递抗原的能力。这一假设将通过测试来自野生型、IgE-/和CD23-/小鼠的B细胞向抗原特异性T细胞呈递抗原的能力来研究。此外，我们认为IgE促进了抗原在炎症支气管粘膜中的聚焦，导致在反复暴露过敏原的情况下增强细胞和体液反应，并为过敏扩散现象提供了一种机制。我们将比较野生型和IgE-/-小鼠在支气管过敏原暴露后，在主动诱导或被动给药特异性IgE存在和不存在的情况下的免疫反应。

Patients with asthma have an eosinophilic inflammation of the bronchial mucosa and display two distinct physiologic responses of the airways: bronchial hyperreactivity to nonspecific stimuli (BHR) and acute allergen-induced airflow obstruction following inhalation of specific allergens. There are strong clinical and epidemiological correlations between asthma and IgE production. Multiple established functions of IgE may contribute to asthmatic pathophysiology and blockers of IgE and its receptors are currently being studied as potential therapeutic agents. A number of murine models of asthma, including those established in this laboratory, have been utilized to examine the pathogenesis of two of the important aspects of the asthmatic response: allergen-induced eosinophilic inflammation of the airway mucosa and BHR. Using IgE-deficient mice (IgE-/-) previously generated by gene-targeting, we have shown that both eosinophilic airways inflammation and BHR (increased sensitivity to non-specific stimuli) can arise by IgE-independent pathways. To date, however, the existing models have not permitted analysis of other crucial features of the disease, acute airflow obstruction provoked by allergen inhalation and IgE-mediated amplification of local cellular and humoral immune responses in the bronchial mucosa. Novel approaches for the study of these responses have now been established by the P.I. and will be used to examine several hypotheses regarding the role of IgE. We hypothesize that allergen-specific IgE is a critical trigger of acute airflow obstruction following allergen inhalation and will address this question by bronchoprovocation studies in allergen-sensitized wild-type and IgE-/- mice. We have shown that IgE enhances CD23 expression and propose that this upregulation enhances the ability of B cells bearing IgE via CD23 to present antigen to allergen specific T cells. This hypothesis will be studied by testing the ability of B cells from wild-type, IgE-/-and CD23-/- mice to present antigen to antigen-specific T cells. Furthermore, we propose that IgE facilitates antigen focusing in the inflamed bronchial mucosa, leading to enhanced cellular and humoral responses in settings of recurrent allergen exposure and providing a mechanism for the phenomenon of allergic spread. We will compare the immune responses of wild-type and IgE-/- mice following bronchial allergen exposure performed in the presence and absence of actively-induced or passively administered specific IgE.