Regulation of Immune Responses by IgE and Mast Cells

描述（由申请人提供）：过敏性疾病患者总是有IgE水平升高。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可能促进过敏致敏。该实验室最近的数据已经确定了IgE抗体在接触敏感性反应中的这种功能，其中它们通过一种需要它们通过FcEepsilonRI与肥大细胞相互作用的机制，增强了对表皮应用的化学半抗原的免疫致敏性。初步研究表明，IgE-/-和肥大细胞缺陷（W/W'）小鼠以及缺乏FcepsilonRI的动物对接触致敏剂的反应明显受损。IgE抗体支持刺激暴露皮肤肥大细胞产生细胞因子，其方式与单体IgE信号一致，不依赖抗原。肥大细胞和ige缺陷动物的皮肤都有异常低水平的TNF，一种肥大细胞细胞因子，先前被证明对接触敏感性至关重要。皮内注射TNF完全恢复IgE-/-和W/W'小鼠的接触敏感反应。肺部对接触致敏剂的反应也依赖于ige。这些发现提出了一种假设，即IgE为刺激诱导的真皮肥大细胞产生TNF和IL-6而启动，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致敏。这一假设将以以下目的进行检验：

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.