How FcRn Prolongs IgG Lifespan

描述(申请人提供)：我们的目标是在分子水平上理解 将免疫球蛋白寿命延长4至20倍背后的机制拉平 比其他Ig班级都要大。对这一机制的理解 调节免疫球蛋白的寿命将使其在一种独特的治疗操作中 既能增强抗体的保护作用，又能缓和 自身抗体的有害方面。 描述这一机制的假说最初是由Brambell在 20世纪60年代，最近的发现更新了，说免疫球蛋白是吞噬的 非特异性地被身体的许多细胞转化为酸性小泡，在低pH值下， 它结合到与免疫球蛋白有高亲和力的完整膜蛋白上，即， 新生儿Fc受体(FcRN)是一种与β2微球蛋白相关的MHC 类I类杂二聚体。因此，免疫球蛋白与FcRN络合，并从 降解的命运，然后在细胞内的小泡中被贩运回 质膜，在生理pH下，它与受体解离， 是免费回收的。我们最近的发现迫使我们修改了这一点 假设有两种方式。首先，我们的抗受体抗体定位FcRN而不是 只到细胞质的囊泡室，也到跨高尔基体 我们提出的网络(TGN)是贩运FcRN的储藏库。 其次，我们在血管外间隙的细胞中发现了丰富的FcRN，如 上皮、成纤维细胞、巨噬细胞和一些实质细胞 内皮细胞。因此，虽然内皮细胞可能是免疫球蛋白的可接受部位 降解，保护免疫球蛋白免受降解的主要部位是， 我们建议，在这些血管外空间的细胞中。适应性地，它就在这里 在抗体作用部位的局部组织中，免疫球蛋白的寿命最长。 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地确定FcRN在体内的表达位置 在亚细胞水平上定位的地方，与 不同细胞隔间的标记。我们会确定免疫球蛋白的路线 当它在细胞中移动时，会偏离降解途径 绑定到FcRN。我们将测试TGN是否作为FcRN的储备库 它在细胞间进行交易，以保护免疫球蛋白免受退化的命运。 我们对各种目标的技术方法是广泛的和协作的 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.