FcgRIIb protects fetus from allograft rejection

描述（由申请人提供）：小鼠卵黄囊（YS）的Fc3RIIb （RIIb）是否保护胚胎免受IgG介导的同种异体移植排斥反应，这是本申请的重点，从我们对人类胎盘如何处理母体IgG抗体的长期兴趣演变而来。人的胎盘将IgG从母体转运到胎儿循环，方便地处理宫内感染，并维持新生儿与母亲的充分补充保护性IgG抗体，直到婴儿自身的免疫系统成熟。在此过程中，IgG穿过两层胎盘细胞和间质。第一层是合体滋养细胞，表达胎盘转运蛋白FcRn，这是一种与22微球蛋白非共价连接的非经典MHC1分子。FcRn通过ph依赖的机制在细胞内吞囊泡中将IgG移动到第二细胞层内皮，内皮表达一种不同的Fc受体RIIb2， RIIb2可能作为内皮转运体，但更广为人知的是抑制免疫复合物（IC）介导的反应。此外，我们最近在小鼠YS（功能类似于IgG转运人胎盘的小鼠器官）中的研究表明，RIIb确实不是IgG转运体。最有可能的是，IgG通过非特异性胞饮作用被动地穿过内皮细胞。那么，RIIb有什么功能呢？一种可能性是绒毛内皮Fc受体的作用是捕获和消除母体IgG抗体，这些抗体是由母体外源（父本）抗原引起的，在向胎儿运输的过程中，这些抗体会与胎盘组织中表达的目标母体抗原结合在一起。最近的新数据显示，缺乏riib的胎儿往往不能在组织不相容的父母怀孕时存活下来。来自其他生物学领域的观察结果为这一过程提供了可信的机制；具体来说，内皮细胞和树突状细胞中的RIIb可以捕获内吞的免疫复合物，并将其不降解地移回细胞表面，在质膜上表达，这样它们就可以被邻近的巨噬细胞利用。内皮细胞溶酶体不再是必需的，内皮细胞本身也不再是降解的场所。在人类中，我们评估这一假设的能力受到严重限制。因此，我们转向小鼠模型，我们的直接目标是测试小鼠YS中表达的RIIb保护概念免受IgG抗体介导的同种异体移植排斥反应的特异性和关键预测。我们的具体目的是验证以下预测：1)YS RIIb在母体到胎儿的IgG直接转移途径中；2)组织不相容交配产生的缺乏YS RIIb的胎仔的存活率低于WT胎仔；3)在组织不相容的情况下，YS RIIb捕获IC并在细胞表面将其表达给巨噬细胞降解，而在没有RIIb的情况下，母体遭受IC介导的损伤。这个项目为我们对胎儿、同种异体移植物和Fc受体生物学的了解提供了基本的元素。它不仅会使人们对怀孕、健康的胎儿和新生儿有更敏锐的了解，而且会使人们有更大的能力来处理他们的疾病。除了怀孕之外，该项目还将我们对抑制受体Fc3RIIb的理解扩展到可能进一步了解免疫细胞生物学的领域。公共卫生相关性：该项目为我们对胎儿、同种异体移植物和Fc受体生物学的了解提供了基本要素。它不仅会使人们对怀孕、健康的胎儿和新生儿有更敏锐的了解，而且会使人们有更大的能力来处理他们的疾病。除了怀孕之外，该项目还将我们对抑制受体Fc3RIIb的理解扩展到可能进一步了解免疫细胞生物学的领域。

DESCRIPTION (provided by applicant): Whether Fc3RIIb (RIIb) of the mouse yolk sac (YS) protects the conceptus from IgG-mediated allograft rejection, the focus of this application, has evolved from our long term interest in how the human placenta handles maternal IgG antibody. The human placenta transports IgG from maternal to fetal circulation, handily dealing with intrauterine infection and sustaining the newborn with mother's full complement of protective IgG antibody until the infant's its own immune system matures. During the process IgG crosses two placental cell layers and interposed stroma. The first layer, syncytiotrophoblast, expresses the placental transporter, FcRn, a nonclassical MHC1 molecule noncovalently linked with 22 microglobulin. FcRn moves IgG by a pH-dependent mechanism across the cell in endocytic vesicles to the second cell layer, the endothelium, which expresses a different Fc receptor, RIIb2, which might potentially serve as an endothelial transporter but is more widely known to dampen immune complex (IC)-mediated responses. Further, our recent studies in the mouse YS, the mouse organ functionally analogous to the IgG transporting human placenta, indicate that, indeed, RIIb is not an IgG transporter. Most likely, IgG moves passively across the endothelium by nonspecific pinocytosis. What function, then, does RIIb serve? One possibility is that villus endothelial Fc receptors serve to trap and eliminate maternal IgG antibodies provoked by and directed toward foreign (paternal) antigen in the conceptus, antibodies that in the process of transport to the fetus would be complexed with their target conceptus antigens expressed in placental tissue. Recent new data show that RIIb-lacking fetuses tend not to survive pregnancies of histoincompatible parents. Observations from other areas of biology lend suggest a credible mechanism for this process; specifically, RIIb in endothelial and dendritic cells may capture endocytosed immune complexes and move them back, undegraded, to the cell surface, expressing them on the plasma membrane, so that they might then be available to neighboring macrophages. Endothelial cell lysosomes would not be essential and endothelial cells themselves would not be the site of degradation. In human our capacity to evaluate this hypothesis is severely limited. Thus, we move to a mouse model where our immediate goal is to test specific and critical predictions of the idea that RIIb expressed in the mouse YS protects the conceptus from IgG antibody-mediated allograft rejection. Our specific aims are to test the predictions that 1) YS RIIb is in the immediate IgG transfer pathway from mother to fetus; 2) Fetuses lacking YS RIIb, derived from histoincompatible matings, will be less viable than WT littermates; 3) Under histoincompatible situations YS RIIb captures IC and expresses them on the cell surface to macrophages for degradation, while in the absence of RIIb the conceptus suffers IC-mediated damage. This project contributes basic elements to our knowledge of fetal, allograft, and Fc receptor biology. It will yield not only a keener understanding of pregnancy and the healthy fetus and newborn, but a greater capacity to deal with their diseases. Quite apart from pregnancy the project extends our understanding of the inhibitory receptor, Fc3RIIb, into areas that may return further insight into immune cell biology. PUBLIC HEALTH RELEVANCE: This project contributes basic elements to our knowledge of fetal, allograft, and Fc receptor biology. It will yield not only a keener understanding of pregnancy and the healthy fetus and newborn, but a greater capacity to deal with their diseases. Quite apart from pregnancy the project extends our understanding of the inhibitory receptor, Fc3RIIb, into areas that may return further insight into immune cell biology.