Functional Role of Fc Receptor Homologs on B Lineage Cells

描述(由申请人提供)：这项建议的目的是确定小鼠FcRH3的功能，FcRH3是新发现的Fc受体同源(FcRH)多基因家族的成员。这些在系统发育上保守的基因编码的蛋白质具有5个不同亚型的Ig结构域，并在其细胞质尾部具有保守的基于酪氨酸的激活和/或抑制信号基序。家族成员在外周B细胞亚群中有不同的表达，并且可能在人类B细胞系恶性肿瘤中过度表达；所有这些特征都强烈表明它们的功能是调节B细胞的效应性反应。我们研究的长期目标是研究FcRH分子在天然免疫和获得性免疫中的生物学作用，并确定它们在自身免疫和B系恶性肿瘤中的功能是如何被颠覆的。FcRH3是一种B细胞特异性基因，其表达模式是独一无二的。一组单抗用细胞计量学方法明确了其在MZ和B1B细胞中的表达，并在组织学上证实了其在脾MZ组织中的分布丰富。与其具有ITIM和ITAM样序列一致，FcRH3在B细胞中是酪氨酸磷酸化的。然而，在与B细胞受体共连接后，FcRH3的信号容量似乎随着位置和表达它的细胞类型的不同而不同。此外，初步发现并不支持其作为Fc受体的功能。这些结果表明，FcRH3是MZ和B1B系细胞的一种新的免疫调节标记。我们的初步数据导致了FcRH3是MZ和B1 B细胞发育和效应功能的重要调节因子的假设。这将在三个特定的目标中进行测试：1)确定基于FcRH3酪氨酸基序的信号潜力；2)检查FcRH3缺乏在小鼠中的功能后果；以及3)表征FcRH3配体(S)。本文提出的研究将阐明一个具有代表性的家族成员作为确定Fc受体同源家族在免疫中的生物学能力的模型的功能作用。在人类和小鼠中具有代表性的FcRH家族成员的共同结构特征和表达模式表明了保守的生物学功能，并支持这样的观点，即对小鼠家族成员的充分了解将有助于对其人类同行的功能的洞察。

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.