How FcRn Prolongs IgG Lifespan

描述（由申请人提供）：我们的目的是了解分子水平 水平背后的机制IgG的寿命长，这是4至20倍， 高于其他IG类。对这一机制的理解， 调节IgG寿命将使其以独特的方式进行治疗操作。 以增强抗体的保护作用和调节抗体的免疫功能。 自身抗体的有害方面 描述该机制的假设最初由Brambell在 20世纪60年代和最近的发现更新，说IgG是胞饮 非特异性地被身体的许多细胞转化为酸性囊泡， 它与对IgG具有高亲和力的完整膜蛋白结合;即， 新生儿Fc受体（FcRn），是一种β 2-微球蛋白相关的MHC 类I异二聚体。因此，IgG与FcRn复合，并从免疫缺陷中保存下来。 降解的命运，然后在细胞内囊泡中被运输回 质膜，在生理pH下，它与受体解离， 可以免费回收我们最近的发现迫使我们修改这一点 假设有两种方式。首先，我们的抗受体抗体定位FcRn， 不仅对胞质囊泡区室，而且对反式高尔基体也是如此。 网络（TGN），我们建议，作为一个水库贩运FcRn。 第二，我们在血管外间隙的细胞中发现了丰富的FcRn，如 上皮细胞、成纤维细胞、巨噬细胞和一些实质，此外， 内皮细胞因此，虽然内皮可能是IgG的接受部位， 降解，保护IgG免于降解的主要位点是， 我们认为，在这些血管外间隙的细胞中。适应性强， 在IgG寿命最长的抗体作用局部部位的组织中。 我们修改后的假设提出了各种预测供我们检验。我们 将通过几种方法精确确定FcRn在体内的表达位置 它定位在亚细胞水平，与 各种细胞区室的标记物。我们将确定IgG的途径 当它穿过细胞时， 与FcRn结合。我们将测试TGN是否作为FcRn的储存库， 它运输保护IgG不被降解的细胞。 我们对各种目标的技术方法是基础广泛和协作的 包括细胞和分子生物学、生物化学和 免疫学

DESCRIPTION (provided by applicant): Our aim is to understand at the molecular level the mechanism behind the lengthy lifespan of IgG, which is 4 to 20 times greater than the other Ig classes. An understanding of the mechanism by which IgG lifespan is regulated will enable its therapeutic manipulation in a unique manner both to enhance the protective effects of antibodies and to temper the harmful aspects of autoantibodies. The hypothesis describing the mechanism, originally proposed by Brambell in the 1960s and updated by recent findings, says that IgG is pinocytosed nonspecifically by many cells of the body into acidic vesicles where at low pH, it binds to an integral membrane protein with high affinity for IgG; namely, the neonatal Fc receptor (FcRn), which is a beta2-microglobulin associated MHC class I-like heterodimer. IgG thus complexed with FcRn and saved from a degradative fate, is then trafficked in intracellular vesicles back to the plasma membrane where, at physiologic pH, it dissociates from the receptor and is free to recycle. Our recent findings have compelled us to modify this hypothesis in two ways. First, our anti-receptor antibodies localize FcRn not only to a cytoplasmic vesicular compartment but as well to the trans-Golgi network (TGN), which we propose, serves as a reservoir for trafficking FcRn. Second, we find abundant FcRn in cells of the extravascular space, such as epithelium, fibroblasts, macrophages, and some parenchyma, in addition to endothelium. Thus, while endothelium may be the accepted site of IgG degradation, the predominant site where IgG is protected from degradation is, we propose, in these cells of the extravascular space. Adaptively, it is here in the tissues at local sites of antibody action where IgG lifespan is longest. Our modified hypothesis presents a variety of predictions for us to test. We will determine precisely by several means where FcRn is expressed in the body and where it is localized at the subcellular level, colocalizing it with markers of various cellular compartments. We will determine the route IgG takes as it moves through a cell, being deflected from the degradative pathway by binding to FcRn. And we will test whether TGN serves as a reservoir for FcRn as it trafficks about the cell protecting IgG from a degradative fate. Our technical approaches to the various aims are broad-based and collaborative and include the methods of cellular and molecular biology, biochemistry, and immunology.