Functional Role of Fc Receptor Homologs on B Lineage Cells

描述（由申请方提供）：本提案的目的是确定小鼠FcRH 3的功能作用，FcRH 3是新鉴定的Fc受体同源物（FcRH）多基因家族的成员。由这些遗传保守基因编码的蛋白质具有可变数量的五种不同亚型的IG结构域，并且在其胞质尾区具有保守的基于酪氨酸的激活和/或抑制信号传导基序。家族成员在外周B谱系亚群中差异表达，并可能在人B谱系恶性肿瘤中过表达;所有特征均强烈表明其功能是调节B细胞效应子应答。我们研究的长期目标是研究FcRH分子在先天性和获得性免疫中的生物学作用，并确定其功能在自身免疫和B系恶性肿瘤中是如何被颠覆的。FcRH 3是B细胞特异性基因，其表达模式是独特的。一组单克隆抗体通过细胞计数法鉴定其在MZ和B1 B细胞中的表达，并通过组织学鉴定其在脾MZ中的地形富集。与其具有ITIM和ITAM样序列一致，FcRH 3在B细胞中被酪氨酸磷酸化.然而，在与B细胞受体共连接后，FcRH 3信号传导能力似乎因表达它的位置和细胞类型而不同。这些结果表明FcRH 3是MZ和B1 B谱系细胞的新的免疫调节标志物。我们的初步数据已经导致了这样的假设，即FcRH 3是MZ和B1 B细胞发育和效应子功能的重要调节因子。这将在三个特定目的中进行测试：1）确定FcRH 3酪氨酸基序的信号传导潜力; 2）检查小鼠中FcRH 3缺乏的功能后果; 3）表征FcRH 3配体。本文提出的研究将阐明一个代表性家族成员作为确定Fc受体同系物家族在免疫中的生物学能力的模型的功能作用。人类和小鼠中代表性FcRH家族成员的共同结构特征和表达模式表明保守的生物学功能，并支持以下观点：充分了解鼠家族成员将深入了解其人类对应物的功能。

DESCRIPTION (provided by applicant): The goal of this proposal is to determine the functional role of mouse FcRH3, a member of the newly identified Fc receptor homolog (FcRH) multigene family. Proteins encoded by these phylogenetically conserved genes have variable numbers of Ig domains of five different subtypes and possess conserved tyrosine-based activating and/or inhibitory signaling motifs in their cytoplasmic tails. Family members are differentially expressed among peripheral B lineage subpopulations and may be overexpressed by human B lineage malignancies; all features that strongly suggest their function is to modulate B cell effector responses. The long-term objective of our studies is to investigate the biological role of FcRH molecules in innate and adaptive immunity, and determine how their functions are subverted in autoimmunity and B lineage malignancies. FcRH3 is a B cell specific gene that is unique in its expression pattern. A panel of monoclonal antibodies identifies its expression distinctly among MZ and B1 B cells cytometrically and its topographical enrichment in the splenic MZ histologically. Consistent with its possession of ITIM and ITAM- like sequences, FcRH3 is tyrosine phosphorylated in B cells. Following co-ligation with the B cell receptor, however, FcRH3 signaling capacity appears to differ as a function of location and the cell type that expresses it. Furthermore, preliminary findings do not support its function as an Fc receptor. These results suggest that FcRH3 is a novel immunoregulatory marker of MZ and B1 B lineage cells. Our preliminary data have led to the hypothesis that FcRH3 is an important regulator of MZ and B1 B cell development and effector function. This will be tested in three Specific Aims: 1) to determine the signaling potential of FcRH3 tyrosine-based motifs; 2) to examine the functional consequences of FcRH3 deficiency in mice; and 3) to characterize the FcRH3 ligand(s). The studies proposed here will clarify the functional role of one representative family member as a model for determining the biologic capacity of the Fc receptor homolog family in immunity. The shared structural features and expression patterns for representative FcRH family members in humans and mice indicate conserved biological function and support the idea that full understanding of murine family members will yield insight into the function of their human counterparts.