Studies of Paired Immunoglobulin-Like Receptors

描述（由申请人提供）：这些正在进行的研究的总体目标是确定小鼠中成对的免疫球蛋白样受体激活（PIR-A）和抑制（PIR-B）亚型的结构/功能关系。PIR-A约为85 kD， PIR-B约为125 kD，是细胞表面糖蛋白，具有相似的细胞外区域，但具有不同的跨膜和细胞质区域。PIR-B由一个基因编码，在其细胞质尾部含有三个基于酪氨酸的抑制基序。相反，PIR-A受体由多个Pira基因编码，并与一种接头蛋白Fc受体共同γ链（FcRgammac）非共价结合，形成细胞活化复合物。此外，最近发现的高度糖基化的PIR-A4受体约为110 kD，在fcrgammac缺陷细胞表面表达。PIR-A和PIR-B在许多造血细胞类型中表达，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，但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，我们提出了在宿主防御过程中，P/R-A和PIR-B在炎症、凝血、抗原呈递、过敏和体液免疫反应中发挥调节作用的总体假设。这一假设将在以下具体目标中得到验证：1)鉴定PIR配体；2)在基因靶向小鼠模型中确定PIR-B缺乏的功能后果；3)确定PIR-A异构体的糖基化和与接头蛋白的关联的分子异质性。在这些小鼠模型中产生的数据显示，有希望为分析人类这种类型的调节机制奠定基础，并可能为疫苗开发、急性和慢性炎症反应治疗以及过敏反应治疗提供新的策略。

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.