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 在免疫复合体疾病和宿主防御中都发挥着重要作用。 巨噬细胞和中性粒细胞表面表达FcGamma受体(FcGammaR) 哪一项1)与含有免疫球蛋白的免疫复合体相互作用以产生组织 但2)在宿主防御中也有清除包被免疫球蛋白的细菌的作用。在……里面 肺，Fc受体，更重要的是，单个Fc受体 很少有人研究。我们将使用转基因小鼠和特定基因缺陷的小鼠 FCR在体外和体内结合的分子和细胞生物学方法 阐明单个Fc受体在免疫动物模型中的作用 肺损伤。人和小鼠巨噬细胞都表达活化 与FCR伽马亚基相互作用的FcGammaRs FcGammaRI和FcGammaRIIIA。 我们已经确定FcGammaRI在FCR中是独一无二的，不仅在能力上 结合单体免疫球蛋白，但也通过其α和伽马传递信号 亚单位。人巨噬细胞和中性粒细胞也表达强大的激活FCR FcGammaRIIA，在小鼠中不存在，也不与y链相互作用。 我们现在有了FcGammaRIIA转基因(TG)小鼠，我们有 确定在巨噬细胞表面表达FcGammariA的程度类似 与人类一样，并增强了对包被免疫球蛋白的细胞的清除。我们的新奇鼠标 品系包括：1)单独缺乏FcGammaRI、FcGammaRIIIA的小鼠 或伽马链和2)小鼠对人类FcGammaRIIA(以及 FcGammariia杂交)是在我们实验室的参与下开发的。我们的 我们的数据提出的假设是，FcGammaRI在肺中扮演着一种 在炎症介质的释放中起主导作用，而FcGammaRIIA 在宿主防御中起着主导作用。阐明特定的角色(S) 肺中的白细胞FcGammaRs对发育具有潜在的重要意义 有效治疗的策略。另一个目标是定义分子 个体肺诱导特异性介质释放的机制 巨噬细胞FCR，特别是FcGammaRI。我们已经确定， 需要FcGammaRIα链的细胞质结构域(CY)才能释放 巨噬细胞IL-6的表达。我们将研究结构/功能关系 FcGammaRI参与了IL-6释放的信号传递。人类FcGammai和 人FcGammaRI的嵌合体，包含不能 与内源性小鼠FcGamma受体结合，将被转染到 小鼠巨噬细胞系。我们的假设是，基因中的特定序列 IL-6需要FcGammaRIα链CY，而不是伽马链 放手。

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.