MS4A Family Members in Health and Disease

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细胞是白血病和淋巴瘤的主要细胞类型。B细胞的功能受细胞表面分子的调节，这些分子产生跨膜信号，调节细胞间的通讯，并指导淋巴细胞的发育。这些研究的目的是检测CD20，一种B细胞特异性细胞表面蛋白，以及我们最近发现的MS4A基因家族的其他成员在体内的功能。CD20是寡聚复合体的膜包埋组分，调节跨膜钙转运和细胞周期进程。抗CD20免疫治疗已成为非霍奇金淋巴瘤的标准治疗方法，并在自身免疫治疗方面显示出巨大的应用前景。尽管如此，人们对此知之甚少。 CD20在体内的作用以及为什么它是免疫治疗的有效靶点。由于机制和结果研究在人类和其他灵长类动物中是困难和昂贵的，我们开发了抗CD20单抗治疗的小鼠模型，使我们能够确定体内治疗效果的分子基础。我们推测CD20和其他MS4A家族成员的分子结构和功能使其成为有效治疗的独特靶点。为了验证这一假设，我们将确定CD20指导的疗法如何在体内调节B细胞功能，并确定MS4A基因家族的其他成员是否也是有效的免疫治疗靶点。在具体目标1中，将评估抗CD20单抗治疗在正常小鼠中的功能意义和后果。在具体目标2中，将确定B细胞清除的分子和细胞基础。在具体目标3中，将在小鼠淋巴瘤模型中评估单抗治疗的疗效和机制。具体目标4将重点研究在小鼠和人类中新发现的20个MS4A基因家族成员的结构和表达，以确定他们是否是合适的免疫治疗靶点。由于CD20为去除或调节B细胞的发育和功能提供了一个重要的调节检查点，了解它和其他MS4A家族成员的功能将为调节体液免疫和有效治疗人类疾病提供新的途径。

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 cells representing the primary cell type in leukemia and lymphoma. B cell function is regulated by cell-surface molecules that generate transmembrane signals, regulate intercellular communication, and direct lymphocyte development. The aim of these studies is to examine the in vivo function of CD20, a B cell-specific cell-surface protein, and other members of the MS4A gene family that we have recently identified. CD20 is a membrane embedded component of an oligomeric complex that regulates transmembrane Ca2+ transport and cell cycle progression. Anti-CD20 immunotherapy has become a standard treatment for non-Hodgkin's lymphoma, and shows great promise for the treatment of autoimmunity. Despite this, relatively little is known about the function of CD20 in vivo and why it is such an effective target for immunotherapy. Since mechanistic and outcome studies are difficult and expensive in humans and other primates, we have developed mouse models for anti-CD20 mAb therapy that allows us to determine the molecular basis for therapeutic efficacy in vivo. We hypothesize that the molecular structure and function of CD20 and other MS4A family members makes them unique targets for effective therapy. To test this hypothesis, we will determine how CD20-directed therapies regulate B cell function in vivo and determine whether other members of the MS4A gene family are also effective immunotherapy targets. In Specific Aim 1, the functional significance and consequences of anti-CD20 mAb therapy will be assessed in normal mice. In Specific Aim 2, the molecular and cellular basis for B cell clearance will be determined. In Specific Aim 3, the efficacy and mechanism of mAb therapy will be assessed in mouse models of lymphoma. Specific Aim 4 will focus on the structure and expression of 20 newly-identified members of the MS4A gene family in mouse and man to determine whether they are appropriate targets for immunotherapy. Since CD20 provides an important regulatory checkpoint for ablating or adjusting B cell development and function, a molecular understanding of how it and other MS4A family members function will provide new avenues for modulating humoral immunity and effectively treating human disease.