Studies of Paired Immunoglobulin-Like Receptors

描述（由申请方提供）：这些正在进行的研究的总体目标是确定小鼠中活化（PIR-A）和抑制（PIR-B）亚型的成对免疫球蛋白样受体家族的结构/功能关系。约85 kD的PIR-A和约125 kD的PIR-B是具有相似胞外区但具有不同跨膜区和胞质区的细胞表面糖蛋白。PIR-B由单个基因编码，在其胞质尾区含有三个基于酪氨酸的抑制基序。相比之下，PIR-A受体由多个Pira基因编码，并与衔接蛋白（Fc受体共同γ链（FcRgammac））非共价结合，形成细胞活化复合物。此外，最近鉴定的约110 kD的高度糖基化的PIR-A4受体在FcR γ缺陷细胞的表面上表达。PIR-A和PIR-B由许多造血细胞类型表达，包括B细胞、单核细胞/巨噬细胞、树突细胞、粒细胞、肥大细胞和巨核细胞/血小板，但不由T和NK细胞表达。PIR的细胞表面水平随着细胞分化和活化而增加。基于我们的初步数据，我们提出了总体假设，即P/R-A和PIR-B在宿主防御过程中的炎症、凝血、抗原呈递、过敏和体液免疫反应中发挥调节作用。将在以下特定目的中检验该假设：1）鉴定PIR配体; 2）确定基因靶向小鼠模型中PIR-B缺陷的功能后果; 3）确定PIR-A同种型在糖基化和与衔接蛋白结合方面的分子异质性。在这些小鼠模型中产生的数据显示出在为人类这种类型的调节机制的分析建立基础方面的希望，并且可以为疫苗开发，急性和慢性炎症反应的治疗以及过敏反应的治疗提出新的策略。

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.