Regulation of Immune Responses by IgE and Mast Cells

IgE 和肥大细胞对免疫反应的调节

• 批准号: 6598688
• 负责人: Hans C Oettgen
• 金额: $ 36.32万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6598688
• 关键词: Langerhans' cell; antibody receptor; antigen antibody reaction; antigen presenting cell; cellular immunity; chemosensitizing agent; dendritic cells; enzyme linked immunosorbent assay; flow cytometry; immunoglobulin E; immunoregulation; interleukin 6; laboratory mouse; mast cell; polymerase chain reaction; respiratory hypersensitivity; skin hypersensitivity; tissue /cell culture; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Patients with allergic diseases invariably have elevated IgE levels. The acquisition of specific immune sensitivity to allergens in these same individuals is linked to their cumulative environmental allergen exposure. These associations suggest that IgE may promote allergic sensitization. Recent data from this laboratory have established such a function for IgE antibodies in contact sensitivity responses, where they enhance immune sensitization to epicutaneously-applied chemical haptens using a mechanism that requires their interaction with mast cells via FcEepsilonRI. Preliminary studies have shown that responses to contact sensitizers are markedly impaired in IgE-/- and mast cell-deficient (W/W') mice as well as animals lacking FcepsilonRI. IgE antibodies support the production of cytokines by mast cells in irritant-exposed skin in an antigen-independent manner consistent with monomeric IgE signaling. The skin of both mast cell- and IgE-deficient animals has abnormally low levels of TNF, a mast cell cytokine previously shown to be critical in contact sensitivity. Intradermal injection of TNF completely restores the contact sensitivity responses of IgE-/- and W/W' mice. Pulmonary responses to contact sensitizers are also IgE-dependent. These findings give rise to the hypothesis that IgE primes dermal mast cells for irritant-induced production of TNF and IL-6 and that these mast cell-derived cytokines activate tissue dendritic cells to drive effective immune sensitization. This hypothesis will be examined with the following aims: I. The contact sensitivity system will be used to establish the effects of mast cells and of mast cell-derived cytokines TNF and IL-6 on dermal dendritic cells and Langerhans cells. ll. The "priming" function of IgE antibodies for mast cell responses to chemical irritants and secretagogues and the mechanism of monomeric IgE signaling will be characterized in cultured mast cells and in vivo. III. A murine model of occupational asthma will be used to examine the roles of IgE antibodies, mast cells, IL-6 and TNF in the induction of airway inflammation following inhalation of contact sensitizers.

描述（由申请人提供）：过敏性疾病患者的 IgE 水平总是升高。这些个体对过敏原的特异性免疫敏感性的获得与他们累积的环境过敏原暴露有关。这些关联表明 IgE 可能促进过敏。该实验室的最新数据已经确定了 IgE 抗体在接触敏感性反应中的这种功能，它们使用一种需要通过 FcEepsilonRI 与肥大细胞相互作用的机制来增强对表皮应用的化学半抗原的免疫敏感性。 初步研究表明，IgE-/- 和肥大细胞缺陷 (W/W') 小鼠以及缺乏 FcepsilonRI 的动物对接触敏化剂的反应明显受损。 IgE 抗体支持暴露于刺激物的皮肤中肥大细胞以与单体 IgE 信号传导一致的抗原独立方式产生细胞因子。肥大细胞和 IgE 缺陷动物的皮肤中 TNF 水平异常低，TNF 是一种肥大细胞细胞因子，之前被证明对接触敏感性至关重要。皮内注射TNF可完全恢复IgE-/-和W/W'小鼠的接触敏感性反应。 肺部对接触致敏剂的反应也依赖于 IgE。这些发现提出了这样的假设：IgE 启动真皮肥大细胞以刺激物诱导产生 TNF 和 IL-6，并且这些肥大细胞衍生的细胞因子激活组织树突状细胞以驱动有效的免疫敏化。将对这一假设进行检验，目的如下： I.接触敏感性系统将用于确定肥大细胞以及肥大细胞衍生的细胞因子TNF和IL-6对真皮树突细胞和朗格汉斯细胞的影响。 二。 IgE 抗体对肥大细胞对化学刺激物和促分泌剂反应的“启动”功能以及单体 IgE 信号传导机制将在培养的肥大细胞和体内进行表征。 三．职业性哮喘小鼠模型将用于检查 IgE 抗体、肥大细胞、IL-6 和 TNF 在吸入接触致敏剂后诱导气道炎症中的作用。