FcgRIIb protects fetus from allograft rejection

描述（由申请人提供）：小鼠卵黄囊（YS）的Fc 3RIIb（RIIb）是否保护孕体免受IgG介导的同种异体移植物排斥反应，本申请的重点是从我们对人胎盘如何处理母体IgG抗体的长期兴趣中发展而来。人胎盘将IgG从母体循环转运到胎儿循环，轻松处理宫内感染，并用母亲的保护性IgG抗体的完全补充维持新生儿，直到婴儿自身的免疫系统成熟。在此过程中，IgG穿过两个胎盘细胞层和插入的基质。第一层是合体滋养层，表达胎盘转运蛋白FcRn，一种与22微球蛋白非共价连接的非经典MHC 1分子。FcRn通过pH依赖性机制将IgG在胞吞囊泡中穿过细胞移动到第二细胞层，即内皮，其表达不同的Fc受体RIIb 2，其可能潜在地充当内皮转运蛋白，但更广泛地已知其抑制免疫复合物（IC）介导的应答。此外，我们最近在小鼠YS（功能上类似于IgG转运人胎盘的小鼠器官）中的研究表明，RIIb确实不是IgG转运蛋白。最有可能的是，IgG通过非特异性胞饮作用被动地穿过内皮。那么，RIIb有什么功能呢？一种可能性是绒毛内皮Fc受体用于捕获和消除母体IgG抗体，该抗体由孕体中的外源（父亲）抗原激发并定向于该抗原，在转运至胎儿的过程中，抗体将与胎盘组织中表达的其靶孕体抗原复合。最近的新数据表明，缺乏RIIb的胎儿往往无法在组织不相容的父母怀孕中存活。来自其他生物学领域的观察结果表明了这一过程的可靠机制;具体而言，内皮细胞和树突细胞中的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，在质膜上表达它们，以便它们可以被邻近的巨噬细胞利用。内皮细胞溶酶体不是必需的，内皮细胞本身也不是降解位点。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，其中我们的直接目标是测试小鼠YS中表达的RIIb保护孕体免受IgG抗体介导的同种异体移植物排斥的想法的具体和关键预测。我们的具体目的是检验以下预测：1）YS RIIb处于从母体到胎儿的直接IgG转移途径中; 2）缺乏YS RIIb的胎儿，来自组织不相容的交配，将比WT同窝出生的胎儿存活率低; 3）在组织不相容的情况下，YS RIIb捕获IC并将其表达在细胞表面上以供巨噬细胞降解，而在没有RIIb的情况下，孕体遭受IC介导的损伤。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。它不仅将产生对怀孕和健康胎儿和新生儿的更敏锐的理解，而且还将产生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性受体Fc 3RIIb的理解扩展到可能进一步深入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。它不仅将产生对怀孕和健康胎儿和新生儿的更敏锐的理解，而且还将产生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性受体Fc 3RIIb的理解扩展到可能进一步深入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.