CD22 Regulation of B Lymphocyte Function and Survival

描述(申请人提供)：B淋巴细胞是体液免疫的中枢介质。B细胞功能异常导致许多自身免疫性疾病和与年龄相关的体液免疫缺陷，恶性B淋巴细胞是白血病和淋巴瘤的主要细胞类型。B细胞的功能是通过细胞表面分子来调节的，这些分子产生跨膜信号，调节细胞间的通讯，并直接在组织内定位淋巴细胞。除了B细胞抗原受体(BCR)复合体外，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测CD22的功能，CD22是一种B淋巴细胞特异性细胞表面受体。CD22是免疫球蛋白超家族中的一种凝集素样成员，可作为多种唾液酸化细胞表面和可溶性配体的黏附分子。CD22与配体的结合可以调节BCR和CD19产生的跨膜信号的正负效应。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的调节相互作用和SHIP有效的细胞内磷酸酶来促进自身免疫。我们认为CD22的黏附受体功能调节跨膜信号和BCR诱导的外周B细胞死亡。有四个特定的目标被设计来检验这一假说，并进一步确定CD22如何调节B细胞功能。在具体目标1中，通过分析表达缺乏配体结合活性的突变细胞表面CD22分子的小鼠新品系，将在体内评估CD22配体结合的功能意义和功能后果。在特定的目标2中，我们将使用CD22缺陷和突变小鼠的B细胞来剖析CD22如何调节B细胞的存活。特异性目标3将评估CD22细胞内信号转导通路。在具体目标4中，我们将评估CD22在自身免疫谱系发展中的作用，并确定CD22的参与是否会影响自身抗体产生的起始年龄或严重程度。由于CD22为调节体液免疫反应提供了一个重要的调节检查点，了解CD22的功能可能为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细胞异常提供机制。

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.