Function of Fc Receptor Related Intracellular Proteins

我们已经鉴定FcRLA是Fc受体(FCR)和FCR样受体(FcRL)基因家族的新成员。 人类和老鼠。在造血细胞中，FcRLA是一种B细胞特异性基因。在人类中，FcRLA是 主要由生发中心B细胞表达，而FcRLA在小鼠体内尚未表达 被定义得很清楚。FcRLA蛋白具有预测的内质网(ER)靶向信号 该蛋白是一种胞内蛋白，缺乏N-连接的糖基化位点和跨膜区。 我们的初步数据表明，FcRLA是一种常驻ER蛋白，与免疫球蛋白在 细胞器。在Ramos IgM B细胞系中，它同时产生m的膜型(M)和分泌型(S) 重链，FcRLA优先与MS结合。我们假设FcRLA在早期起作用 免疫球蛋白分子的生物合成Ig-FcRLA复合体的组成和功能的定义是一个主要的 我们研究的目标。在目标1中，将定义Ig-FcRLA相互作用的特异性和特征以及其他 将确定FcRLA-LG综合体的组件。B细胞分化阶段对T细胞亚群的影响 复合体的组成将被确定。在目标2中，FcRLA在细胞系中的耗尽和过表达 将被用作识别其正常功能的手段。我们将在正常情况下检测FcRLA的表达 不同发育阶段的人B细胞及利用体外模型检测FcRLA的调节 表情。我们还将检测FcRLA在B细胞慢性淋巴细胞白血病中的表达，并将其与 与疾病严重程度的其他标志物一起表达。可获得的信息有限 小鼠FcRLA的表达，没有关于其功能的信息。在目标3中，抗小鼠FcRLA的单抗 将制作并在综合分析中使用。我们已经构建了一个靶向Fcrla基因 老鼠。在目标4中，我们将分析FcRLA缺乏对B细胞发育和功能的影响，并将 建立一个转基因小鼠，在其中FcRLA在B细胞分化过程中过表达，以测试 异位表达的影响。FcRLA可能在细胞内质量控制系统中发挥重要作用 确保抗体的正确产生。此外，它在人生发中心B细胞中的表达， 在发生增殖、抗体类别转换和抗体基因突变的地方，表明 FcRLA的表达可能导致自身免疫或免疫缺陷性疾病。

We have identified FcRLA as a new member of the Fc receptor (FcR) and FcR-like (FcRL) gene families of humans and mice. Among hemopoietic cells, FcRLA is a B cell-specific gene. In humans FcRLA is preferentially expressed by germinal center B cells but the expression of FcRLA in the mouse has not yet been well defined. The FcRLA protein has a predicted endoplasmic reticulum (ER)-targeting signal sequence, but lacks N-linked glycosylation sites and a transmembrane region and is an intracellular protein. Our preliminary data suggest that FcRLA is a resident ER protein that associates with immunoglobulin in this organelle. In the Ramos IgM B cell line, which produces both the membrane (m) and secretory (s) forms of m heavy chain, FcRLA preferentially associates with ms. We hypothesize that FcRLA functions early in the biosynthesis of Ig molecules. Definition of the composition and function of the Ig-FcRLA complex is a major goal of our studies. In Aim 1, the specificity and features of the Ig-FcRLA interaction will be defined and other components of the FcRLA-lg complex will be identified. The effect of B cell differentiation stage on the composition of the complex will be determined. In Aim 2, depletion and overexpression of FcRLA in cell lines will be used as a means to identify its normal function. We will examine the expression of FcRLA by normal human B cells at different developmental stages and use ex vivo models to examine the regulation of FcRLA expression. We will also examine FcRLA expression in B cell chronic lymphocytic leukemia and correlate its expression with other markers of disease severity. There is limited information available about the expression of mouse FcRLA and none about its function. In Aim 3, monoclonal antibodies to mouse FcRLA will be produced and used in a comprehensive analysis. We have constructed an Fcrla gene targeted mouse. In Aim 4 we will analyze the effect of FcRLA deficiency on B cell development and function and will generate a transgenic mouse in which FcRLA is overexpressed throughout B cell differentiation to test the effect of ectopic expression. FcRLA may play an essential role in the intracellular quality control system that ensures the correct production of antibodies. Moreover, its expression in human germinal center B cells, where proliferation, antibody class switching and mutation of antibody genes occurs, suggest that defects in FcRLA expression may lead to autoimmunity or immunodeficiency diseases.