Innate Immune Function of FcERI-Bearing Cells

自从大约40年前发现以来，免疫球蛋白(LG)E抗体可能是最核心的 已知的导致过敏性炎症和疾病的因素。鉴于它在以下方面的作用 长期以来，从嗜碱性粒细胞和肥大细胞释放组胺和白三烯C4(LTC4)一直是 认识到，这种免疫球蛋白在调节其他IgE受体功能方面的性质 人们对细胞知之甚少。特别是，这种免疫球蛋白还已知可以结合和调节 树突状细胞(DC)的功能，它是已知的最强大的抗原提呈细胞(APC) 通过激活原始T细胞来启动免疫反应，以实现效应器的功能。我们初步的体外数据 最近在树突状细胞中发现了新的表型和功能变化，这些变化是由于 这些细胞的表面。具体地说，这些数据暗示了一种机制，即通过交联来产生过敏原 Ige/受体复合体，对DC中正常情况下的特定先天免疫反应进行反向调节 在自然界中支持Th1(即抗过敏)。因此，IgE可以很好地促进DC向APC的成熟 通过阻止这些细胞中的细胞因子反应来促进过敏性疾病，这些细胞因子通常阻止 过敏性炎症的进展。通过使用奥马珠单抗在体内耗尽IgE，AIMS 在这个项目中提出的应该提供“概念证明”，而IgE确实在其中发挥了关键作用 调节DC的先天免疫和获得性免疫能力，从而调节其他免疫的活性 依赖DC功能和/或受DC功能调节的细胞。在目标1中，我们将监测IgE受体的丢失。 猫和食物过敏患者接受奥马珠单抗治疗后树突状细胞的表达及研究 用于特定的先天免疫反应和体外过继免疫反应的变化。目标2.表型和 与先天免疫和获得性免疫相关的功能标记物也将在人类嗜碱性粒细胞中/在其上进行监测 在奥马珠单抗给药后。我们假设相关细胞因子(IL-4和IL-13)显著 这些细胞不仅能对过敏原作出反应，还能对特定的先天免疫刺激做出反应， 会因免疫球蛋白E耗竭而受到抑制。最后，我们已经证明，接触过敏原会诱导 血液嗜碱性粒细胞的全身性“启动”效应，与DC的先天免疫反应成反比。在……里面 目的3.我们将探索使用奥马珠单抗消耗IgE的效果，以更好地确定这一作用 免疫球蛋白在这些临床相关的反应中，包括发生在肺部的反应。总的来说， 这些研究应该会解开围绕着IgE在抑制先天免疫中扮演的角色的谜团 反应，并为过敏性疾病状态的病理生理学和治疗提供新的见解。

Since its discovery some forty years ago, immunoglobulin (lg)E antibody is perhaps the most central factor known contributing to the pathogenesis of allergic inflammation and disease. Whereas its role in triggering histamine and leukotriene C4 (LTC4) release from basophils and mast cells has long been appreciated, the nature of this immunoglobulin in modulating the function of other IgE receptor-bearing cells is poorly understood. In particular, this immunoglobulin is also known to bind and modulate the function of dendritic cells (DC), which are the most potent antigen-presenting cells (APCs) known to initiate immune responses by activating naive T cells for effector functions. Our preliminary in vitro data has recently identified novel phenotypic and functional changes in DC upon cross-linking IgE on the surface of these cells. Specifically, these data imply a mechanism were allergen, by cross-linking IgE/receptor complexes, counter-regulates specific innate immune responses in DC that are normally pro-Th1 (i.e. anti-allergic) in nature. Thus, IgE may very well augment the maturation of DC into APC that promote allergic disease by preventing cytokine responses in these cells that normally prevent progression of allergic inflammation. By depleting IgE in vivo using omalizumab administration, the Aims presented in this project should provide "proof-of-concept" that IgE does, indeed, play a critical role in regulating innate and adaptive immune capabilities of DC and consequently the activity of other immune cells dependent of and/or regulated by DC function. In Aim 1. we will monitor the loss of IgE receptor expression on DC from Cat and Food allergic subjects receiving omalizumab and investigate these cells for changes in specific innate and adoptive immune responses ex vivo. In Aim 2. phenotypic and functional markers related to innate and adaptive immunity will also be monitored in/on human basophils following omalizumab administration. We hypothesis that relevant cytokines (IL-4 and IL-13) prominently secreted by these cells in response to allergen, but also in response to specific innate immune stimuli, will additionally be inhibited with IgE depletion. Finally, we have shown that allergen exposure induces systemic "priming" effects in blood basophils, which inversely relate to DC innate immune responses. In Aim 3. we'll explore the effect of depleting IgE using omalizumab to better define the role of this immunoglobulin in these clinically relevant responses, including those occurring in the lung. Overall, these studies should resolve mystery surrounding the role IgE plays in suppressing innate immune responses, and provide new insights into the pathophysiology and treatment of allergic disease states.