FcgRIIb protects fetus from allograft rejection

描述(由申请人提供)：小鼠卵黄囊(YS)的Fc3RIIb(RIIb)是否保护胚胎免受免疫球蛋白G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免疫球蛋白抗体的长期兴趣演变而来。人类胎盘将免疫球蛋白从母体输送到胎儿循环，轻松应对宫内感染，并用母亲的全部保护性免疫球蛋白抗体维持新生儿，直到婴儿自身的免疫系统成熟。在这个过程中，免疫球蛋白穿过两个胎盘细胞层和插入的间质。第一层是合体滋养层细胞，表达胎盘转运蛋白FcRN，这是一种非经典的MHC1分子，与22微球蛋白非共价连接。FcRN通过一种pH依赖的机制将内吞小泡中的免疫球蛋白通过细胞移动到第二细胞层，即内皮，它表达一种不同的Fc受体RIIb2，它可能是一种内皮转运蛋白，但更广为人知的是抑制免疫复合物(IC)介导的反应。此外，我们最近对小鼠YS的研究表明，RIIb确实不是一种IgG转运体。YS是一种功能类似于运送人胎盘的免疫球蛋白的小鼠器官。最有可能的是，免疫球蛋白通过非特异性吞噬作用在血管内皮细胞中被动移动。那么，RIIB有什么作用呢？一种可能性是绒毛内皮细胞Fc受体可以捕获和清除由外源(父源)抗原引起的母体抗体，这些抗体在转运到胎儿的过程中会与其在胎盘组织中表达的靶向胎盘抗原复合。最近的新数据显示，缺乏RIIb的胎儿往往无法在组织不相容的父母的怀孕中存活下来。来自生物学其他领域的观察表明了这一过程的可靠机制；具体地说，内皮细胞和树突状细胞中的RIIb可能会捕获内吞的免疫复合物，并将其未降解地移回细胞表面，在质膜上表达它们，这样它们就可能被邻近的巨噬细胞所利用。内皮细胞溶酶体不是必需的，内皮细胞本身也不是降解的部位。在人类中，我们评估这一假设的能力是严重有限的。因此，我们转到一个小鼠模型，在那里我们的直接目标是测试RIIb在小鼠YS中表达的想法的特异性和批判性预测，即RIIb在小鼠YS中表达保护胚胎免受免疫球蛋白抗体介导的同种异体移植排斥。我们的具体目的是验证以下预测：1)YS RIIb处于从母亲到胎儿的即时免疫球蛋白转移途径；2)缺乏YS RIIb的胎儿，来自组织不相容的配对，将比WT胎的存活率低；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，以供巨噬细胞降解，而在没有RIIb的情况下，胚胎遭受IC介导的损伤。这个项目有助于我们对胎儿、同种异体移植和Fc受体生物学的基本知识。它不仅将产生对怀孕和健康的胎儿和新生儿的更敏锐的理解，而且还将产生更大的处理他们的疾病的能力。除了怀孕，该项目还将我们对抑制性受体Fc3RIIb的理解扩展到可能会进一步深入了解免疫细胞生物学的领域。公共卫生相关性：该项目为我们提供了有关胎儿、同种异体移植和Fc受体生物学的基本知识。它不仅将产生对怀孕和健康的胎儿和新生儿的更敏锐的理解，而且还将产生更大的处理他们的疾病的能力。除了怀孕，该项目还将我们对抑制性受体Fc3RIIb的理解扩展到可能会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.