INTESTINAL AND PLACENTAL FC-RECEPTORS FOR IMMUNOGLOBULIN

肠和胎盘免疫球蛋白 FC 受体

• 批准号: 2889017
• 负责人: NEIL E SIMISTER
• 金额: $ 18.49万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-02-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2889017
• 关键词: antibody receptor; biological signal transduction; developmental genetics; female; gastrointestinal epithelium; gene rearrangement; genetic mapping; genetic regulation; human tissue; immunocytochemistry; immunoglobulin G; in situ hybridization; laboratory mouse; laboratory rat; placenta; placental transfer; protein structure function; protein transport; receptor binding; site directed mutagenesis; tissue /cell culture

DESCRIPTION (Adapted from the applicant's abstract): Acquisition of maternal antibodies is critical to the immunologic defense of the newborn. In suckling rats and mice, a receptor for the Fc region of immunoglobulin G (IgG) transports IgG from milk across the intestinal epithelium into the blood. This receptor, FcRn, for neonate, is similar in structure to class I major histocompatibility complex proteins. Late in gestation the same receptor appears to transport IgG across the fetal yolk sac in these species. Prenatal transport accounts for only a small fraction of the maternal IgG that rodents receive, but in humans IgG transport occurs mostly, and perhaps only, before birth. A homolog of FcRn is expressed in human placenta and is likely to mediate materno- fetal IgG transport. A major goal of this proposal is to determine whether human FcRn is indeed responsible for placental IgG transport. Specific aims toward this goal include the localization of FcRn in human placenta by immunocytochemistry and in situ hybridization. The presence of the receptor in one or both of the cellular barriers between maternal and fetal blood, the syncytiotrophoblast and fetal vessel endothelia, would be consistent with a transport role. The specificity of human FcRn for different human IgG subclasses, measured by a competitive binding assay, will be compared with the relative efficiency of placental transport of these subclasses. A relatively low affinity for IgG2, which is transported poorly, would suggest that FcRn has a role in IgG transport from mother to fetus. The molecular mechanism of transcytosis of IgG by FcRn is not known. The second major goal of this proposal is to determine how this process occurs. Specific aims related to this goal include the characterization of the trafficking of rat FcRn functionally expressed in the polarized Madin-Darby canine kidney cell line. Sorting signals in the cytoplasmic region of rat FcRn will be located by site-directed mutagenesis and expression of mutant receptors in MDCK cells. Proteins that interact with sorting signals will be sought using a yeast two-hybrid method. The clinical importance of maternal IgG for the immunologic defense of the neonate is well established. Because most IgG is transmitted to the fetus late in pregnancy, very premature infants have low serum IgG and are especially vulnerable to infection. Not all antibodies are beneficial, however: the health of the newborn may be compromised by the acquisition of anti-rhesus and anti-ABO antibodies. Transmission of autoantibodies in systemic lupus erythematosus, myasthenia gravis, and other autoimmune diseases of the mother may also be damaging to the fetus. This proposal aims to contribute to our understanding of the mechanism of antibody transport from mother to young, and thus to increase the basis for rational intervention in pregnancies complicated by potentially harmful maternal immune responses.

描述（根据申请人的摘要改编）： 孕产妇抗体对于免疫辩护至关重要 新生。 在哺乳的大鼠和小鼠中，FC区域的受体 免疫球蛋白G（IgG）从牛奶中运输IgG穿越肠道 上皮进入血液。 该受体FCRN，用于新生儿，相似 在I类主要组织相容性复合蛋白上。 晚的 在妊娠中，同一受体似乎在胎儿跨过IgG 这些物种中的蛋黄囊。 产前运输只有一个小账户 啮齿动物收到的母体IgG的一部分，但在人类IgG中 运输主要发生，甚至可能是出生前。 一个同源 FCRN在人胎盘中表达，可能会介导孕妇 胎儿IgG运输。 该提议的主要目标是确定人类FCRN是否是 确实负责胎盘IgG运输。 具体目标 该目标包括通过 免疫细胞化学和原位杂交。 存在 在母体和母体之间的一个或两个细胞屏障中的受体 胎儿血液，合成肌细胞和胎儿血管内皮，将 与运输角色保持一致。 人类FCRN的特异性 通过竞争性结合测定法测量的不同人类IgG亚类， 将与胎盘运输的相对效率进行比较 这些子类。 对IgG2的亲和力相对较低，是 运输差，表明FCRN在IgG运输中起作用 从母亲到胎儿。 FCRN尚不清楚通过FCRN对IgG的转胞细胞增多的分子机制。 这 该提案的第二个主要目标是确定该过程如何 发生。 与此目标有关的具体目的包括特征 在极化中功能表达的大鼠FCRN的运输 Madin-Darby犬肾细胞系。 在细胞质中排序信号 大鼠FCRN的区域将通过位置定向的诱变和 MDCK细胞中突变受体的表达。 相互作用的蛋白质 使用酵母双杂交方法寻求分类信号。 母体IgG在免疫防御的临床重要性 新生儿已经建立了。 因为大多数IgG传输到 胎儿在​​怀孕后期，早产的婴儿血清IgG低，并且 特别容易受到感染的影响。 并非所有抗体都是 但是，有益：新生儿的健康可能会受到 抗逆转和抗ABO抗体的采集。 传播 全身性红斑狼疮的自身抗体，肌无力，肌无力 母亲的其他自身免疫性疾病也可能损害 胎儿。 该建议旨在为我们理解 抗体从母亲到年轻的机理，因此 增加对怀孕的合理干预的基础 通过潜在有害的母体免疫反应。