Leukocyte Activating Fc Receptors in Immune Lung Injury

描述（由申请人提供）： 白细胞如多形核白细胞（PMN）和巨噬细胞， 在免疫复合物疾病和宿主防御中均具有重要作用。 巨噬细胞和中性粒细胞表面表达Fc γ受体（Fc γ R） 其1）与含有免疫复合物的IgG相互作用以产生组织 损伤，但2）也能清除宿主防御中IgG包被的细菌。在 肺，Fc受体，重要的是，单个Fc受体， 很少研究。我们将使用转基因小鼠和缺乏特异性 FcR在体外和体内结合的分子和细胞生物学方法中， 阐明单个Fc受体在免疫调节动物模型中的作用 肺损伤人类和小鼠巨噬细胞都表达激活的 与FcR γ亚基相互作用的FcR γ R FcR γ RI和FcR γ RIIIA。 我们已经确定FcgammaRI在FcR中是独特的，不仅在能力上， 结合单体IgG，但也通过其α和γ信号 亚单位。人巨噬细胞和中性粒细胞也表达有效的激活FcR Fc γ RIIA，其在小鼠中不存在并且不与γ链相互作用。 我们现在有可用的Fc γ RIIA转基因（TG）小鼠， 确定在巨噬细胞表面上以相似的程度表达Fc γ RIIA 并且具有增强的IgG包被的细胞的清除。我们的小说老鼠 品系包括：1）单独缺乏Fc γ RI、Fc γ RIIIA 或γ链和2）人Fc γ RIIA的小鼠TG（以及 Fc γ RIIA杂交）。我们 我们的数据表明，一个假设是，在肺中Fc γ RI起作用， 在炎症介质的释放中起主要作用，而Fc γ RIIA 在宿主防御中起主要作用。阐明具体机构的作用 肺中的白细胞Fc γ R对于发展中的 有效治疗的策略。另一个目标是定义分子 个体肺诱导的特异性介质释放的机制 巨噬细胞FcR，特别是Fc γ RI。我们确定 释放需要Fc γ RI α链的胞质结构域（CY 巨噬细胞IL-6我们将研究结构/功能关系， Fc γ RI参与IL-6释放的信号传导。人Fc γ RI和 人Fc γ RI的嵌合体，含有不能 与内源性鼠Fc γ受体相关的细胞将转染到 小鼠巨噬细胞系。我们的假设是， Fc γ RI α链CY，而不是γ链，是IL-6所需的 release.

DESCRIPTION (provided by applicant): Leukocytes such as polymorphonuclear leukocytes (PMN) and macrophages, play an important role both in immune complex disease and in host defense. Macrophages and PMN express on their surface Fcgamma receptors (FcgammaR) which 1) interact with IgG containing immune complexes to produce tissue damage, but 2) also function to clear IgG coated bacteria in host defense. In the lung, Fc receptors and, importantly, the individual Fc receptors have been little studied. We will employ transgenic mice and mice deficient in specific FcR in a combined in vitro and in vivo molecular and cell biology approach to elucidate the role of individual Fc receptors in an animal model of immune lung injury. Both human and mouse macrophages express the activating FcgammaRs FcgammaRI and FcgammaRIIIA which interact with a FcR gamma subunit. We have determined that FcgammaRI is unique among FcR not only in the ability to bind monomeric IgG, but also to signal through both its alpha and gamma subunits. Human macrophages and PMN also express the potent activating FcR FcgammaRIIA, which is absent in mice and does not interact with the y chain. We now have available FcgammaRIIA transgenic (TG) mice, which we have determined express FcgammaRIIA on the macrophage surface to a similar extent as humans and have enhanced clearance of IgG coated cells. Our novel mouse strains include: 1) mice individually lacking either FcgammaRI, FcgammaRIIIA or the gamma chain and 2) mice TG for human FcgammaRIIA (as well as FcgammaRIIA crosses) developed with the participation of our laboratory. Our hypothesis, suggested by our data, is that in the lung FcgammaRI plays a predominant role in the release of inflammatory mediators, while FcgammaRIIA plays a predominant role in host defense. Elucidating the role(s) of specific leukocyte FcgammaRs in the lung is potentially important for developing strategies for effective therapy. Another goal is to define the molecular mechanisms involved in specific mediator release induced by individual lung macrophage FcR, specifically FcgammaRI. We have determined that the cytoplasmic domain (CY) of the FcgammaRI alpha chain is required for release of macrophage IL-6. We will examine structure/function relationships of FcgammaRI involved in signaling for IL-6 release. Human FcgammaRI and chimeras of human FcgammaRI, containing transmembrane domains which cannot associate with endogenous murine Fcgamma receptors, will be transfected into a murine macrophage cell line. Our hypothesis is that specific sequences in the FcgammaRI alpha chain CY, but not the gamma chain, are required for IL-6 release.