Studies of Paired Immunoglobulin-Like Receptors

描述(申请人提供)：这些正在进行的研究的总体目标是确定一对免疫球蛋白样受体激活(PIR-A)和抑制(PIR-B)亚型家族在小鼠中的结构/功能关系。大约85kD的PIR-A和大约125kD的PIR-B是细胞表面糖蛋白，具有相似的胞外区，但具有不同的跨膜区和胞内区。Pir-B由单基因编码，其胞质尾部含有三个酪氨酸抑制基序。相反，PIR-A受体由多个Pira基因编码，并与Fc受体共同伽马链(FcRGammac)适配器蛋白非共价结合，形成细胞激活复合体。此外，最近发现的高度糖基化的约110kD的PIR-A4受体表达在FcRGammac缺陷细胞的表面。PIR-A和PIR-B由多种造血细胞表达，包括B细胞、单核/巨噬细胞、树突状细胞、粒细胞、肥大细胞和巨核细胞/血小板，T细胞和NK细胞不表达。细胞表面的PIR水平随着细胞分化和激活而增加。基于我们的初步数据，我们提出了P/R-A和PIR-B在宿主防御过程中在炎症、凝血、抗原提呈、过敏和体液免疫反应中发挥调节作用的总体假设。这一假说将在以下特定目标中得到验证：1)确定PIR-B配体；2)在基因靶向的小鼠模型中确定PIR-B缺乏的功能后果；3)确定PIR-A亚型的糖基化和与接头蛋白的结合的分子异质性。在这些小鼠模型中产生的数据显示出为分析人类这种类型的调控机制奠定基础的前景，并可能为疫苗开发、急性和慢性炎症反应的治疗以及过敏反应的治疗提供新的策略。

DESCRIPTION (provided by applicant): The overall goal of these ongoing studies is to define the structure/function relationships of a family of paired immunoglobulin-like receptors of activating (PIR-A) and inhibitory (PIR-B) isoforms in mice. PIR-A of approximately 85 kD and PIR-B of approximately 125 kD are cell surface glycoproteins having similar extracellular regions but with distinctive transmembrane and cytoplasmic regions. PIR-B is encoded by a single gene and contains three tyrosine-based inhibitory motifs in its cytoplasmic tail. In contrast, PIR-A receptors are encoded by multiple Pira genes and associate non-covalently with an adaptor protein, the Fc receptor common gamma chain (FcRgammac), to form a cell activation complex. In addition, the recently identified, heavily glycosylated PIR-A4 receptor of approximately 110 kD is expressed on the surface of FcRgammac-deficient cells. PIR-A and PIR-B are expressed by many hematopoietic cell types, including B cells, monocyte/macrophages, dendritic ceils, granulocytes, mast cells, and megakaryocyte/platelets, but not by T and NK cells. The cell surface levels of PIR increase as a function of cellular differentiation and activation. Based on our preliminary data, we propose the overall hypothesis that P/R-A and PIR-B play regulatory roles in inflammatory, coagulative, antigen-presenting, allergic, and humoral immune responses during host defense. This hypothesis will be tested in the following Specific Aims: 1) To identify the PIR ligands; 2) To determine the functional consequences of PIR-B deficiency in a gene-targeted mouse model; 3) To determine the molecular heterogeneity of PIR-A isoforms with respect to their glycosylation and association with adaptor proteins. The data generated in these mouse models show promise in establishing the foundation for the analysis of this type of regulatory mechanism in humans, and could suggest novel strategies for vaccine development, therapies for acute and chronic inflammatory responses, and treatments of allergic responses.