CD22 Regulation of B Lymphocyte Function and Survival

CD22 对 B 淋巴细胞功能和存活的调节

• 批准号: 6744297
• 负责人: THOMAS F TEDDER
• 金额: $ 25.6万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6744297
• 关键词: B cell receptor; B lymphocyte; CD19 molecule; CD22 molecule; autoantibody; autoimmunity; biological signal transduction; cell death; cell differentiation; humoral immunity; laboratory mouse; leukocyte activation /transformation; receptor binding

DESCRIPTION (provided by applicant): B lymphocytes are the central mediators of humoral immunity. Aberrant B cell function contributes to many autoimmune diseases and age-related defects in humoral immunity, with malignant B lymphocytes representing the primary cell type in leukemia and lymphoma. B cell function is regulated through cell-surface molecules that generate transmembrane signals, regulate intercellular communication, and direct lymphocyte localization within tissues. Other than the B cell antigen receptor (BCR) complex, relatively very little is known about the function and signal transduction pathways of most B cell-surface proteins. The aim of these studies is to examine the function of CD22, a B lymphocyte-specific cell-surface receptor. CD22 is a lectin-like member of the immunoglobulin superfamily that functions as an adhesion molecule for diverse sialylated cell-surface and soluble ligands. Ligand binding by CD22 may regulate both positive and negative effects of transmembrane signals generated through the BCR and CD19. Moreover, genetic alterations in CD22 ligand binding activity, structure, or expression may contribute to autoimmunity by altering its regulatory interactions with SHP 1 and SHIP, potent intracellular phosphatases. We propose that adhesion receptor function of CD22 regulates transmembrane signals and BCR-induced cell death in peripheral B cells. There are four specific aims designed to test this hypothesis and to further determine how CD22 regulates B cell function. In specific aim 1, the functional significance and functional consequences of CD22 ligand binding will be assessed in vivo by analyzing new lines of mice, which express mutated cell-surface CD22 molecules that lack ligand-binding activity. In specific aim 2, we will use B cells from CD22-deficient and -mutant mice to dissect how CD22 regulates B cell survival. Specific Aim 3 will assess CD22 intracellular signal transduction pathways. In specific aim 4, the role of CD22 in the development of an autoimmune repertoire will be assessed and we will determine whether CD22 engagement influences the age of onset or severity of autoantibody production. Since CD22 provides an important regulatory checkpoint for adjusting humoral immune responses, understanding CD22 function may provide mechanisms for modulating humoral immunity and the treatment of B cell abnormalities leading to immunodeficiency, autoimmunity or malignancy.

描述（由申请人提供）：B淋巴细胞是体液免疫的核心介质。 B 细胞功能异常会导致许多自身免疫性疾病和与年龄相关的体液免疫缺陷，其中恶性 B 淋巴细胞是白血病和淋巴瘤的主要细胞类型。 B 细胞功能通过细胞表面分子进行调节，这些分子产生跨膜信号、调节细胞间通讯并指导淋巴细胞在组织内的定位。除了 B 细胞抗原受体 (BCR) 复合物之外，人们对大多数 B 细胞表面蛋白的功能和信号转导途径知之甚少。这些研究的目的是检查 CD22（一种 B 淋巴细胞特异性细胞表面受体）的功能。 CD22 是免疫球蛋白超家族的凝集素样成员，充当多种唾液酸化细胞表面和可溶性配体的粘附分子。 CD22 的配体结合可以调节 BCR 和 CD19 产生的跨膜信号的正效应和负效应。此外，CD22 配体结合活性、结构或表达的遗传改变可能通过改变其与 SHP 1 和 SHIP（有效的细胞内磷酸酶）的调节相互作用而促进自身免疫。我们提出 CD22 的粘附受体功能调节外周 B 细胞中的跨膜信号和 BCR 诱导的细胞死亡。有四个具体目标旨在检验这一假设并进一步确定 CD22 如何调节 B 细胞功能。在具体目标 1 中，将通过分析表达缺乏配体结合活性的突变细胞表面 CD22 分子的新小鼠系，在体内评估 CD22 配体结合的功能意义和功能后果。在具体目标 2 中，我们将使用来自 CD22 缺陷和突变小鼠的 B 细胞来剖析 CD22 如何调节 B 细胞存活。具体目标 3 将评估 CD22 细胞内信号转导途径。在具体目标 4 中，将评估 CD22 在自身免疫库发展中的作用，我们将确定 CD22 的参与是否会影响自身抗体产生的发病年龄或严重程度。由于 CD22 为调节体液免疫反应提供了重要的调节检查点，因此了解 CD22 的功能可能会提供调节体液免疫和治疗导致免疫缺陷、自身免疫或恶性肿瘤的 B 细胞异常的机制。