Regulation of Immune Responses by IgE and Mast Cells

描述(由申请人提供)：过敏性疾病患者的IgE水平总是升高。这些人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可能促进过敏性致敏。最近来自该实验室的数据已经为IgE抗体在接触敏感性反应中建立了这样的功能，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来增强对表面应用的化学半抗原的免疫增敏。初步研究表明，在IgE-/-和肥大细胞缺陷(W/W‘)小鼠以及缺乏FcepsilonRI的动物中，对接触性致敏剂的反应明显减弱。免疫球蛋白E抗体支持刺激暴露皮肤中的肥大细胞以一种与单体IgE信号一致的非抗原方式产生细胞因子。肥大细胞和IgE缺陷动物的皮肤都有异常低水平的肿瘤坏死因子，这是一种肥大细胞细胞因子，以前被证明是接触敏感性的关键。皮内注射肿瘤坏死因子可完全恢复IgE-/-和W/W‘小鼠的触敏反应。对接触性致敏剂的肺部反应也依赖于IgE。这些发现提出了一种假设，即IgE启动真皮肥大细胞以产生刺激物诱导的肿瘤坏死因子和白介素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来驱动有效的免疫增敏。我们将以以下目的来检验这一假设： 接触敏感系统将用于建立肥大细胞和肥大细胞衍生细胞因子肿瘤坏死因子和白介素6对真皮树突状细胞和朗格汉斯细胞的影响。 呃.。肥大细胞对化学刺激物和促分泌剂反应的IgE抗体的“启动”功能和单体IgE信号的机制将在培养的肥大细胞和体内表征。 将使用职业性哮喘的小鼠模型来研究IgE抗体、肥大细胞、IL-6和肿瘤坏死因子在吸入接触性致敏剂后诱导呼吸道炎症中的作用。

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.