Roles of FCRL Molecules in Innate Immunity

描述（由申请方提供）：先天样脾边缘区（MZ）和腹膜腔来源（PEC）B1 B谱系细胞通过快速感知病原体和建立一级抗体应答，在体液免疫防御的最早阶段具有至关重要的作用。然而，它们对先天性胸腺非依赖性刺激的强烈反应性和参与疾病发病机制的机制基础知之甚少。FCRL 1 -6是一个多基因家族，编码具有复杂的酪氨酸免疫调节功能的Ig样跨膜蛋白，优先由B细胞表达。它们的免疫学意义通过它们的进化保守性和与人类淋巴增生性、自身免疫性、感染性和免疫缺陷性疾病的日益增长的关联而得到强调。尽管这些关系暗示FCRL是致病因子，但迄今为止的研究表明它们通常抑制B细胞抗原受体（BCR）信号传导。最近已经发现几种代表与MHC相关蛋白以及免疫球蛋白相互作用;然而，由B细胞表达的大多数FCRL分子的内源性配体和体内功能尚未被确定。我们研究的长期目标是确定FCRL蛋白家族在正常和干扰免疫生物学中的作用。FCRL 5是本研究的重点，它在小鼠中由先天样MZ和B1 B细胞独特表达，具有ITAM样和ITIM胞质序列，并通过募集林恩和SHP-1对BCR信号传导发挥双重调节作用。尽管其离散分布，但对其影响或其他FCRL在先天免疫中的影响知之甚少。中心假设是FCRL 5通过与最近定义的对应物相互作用催化B细胞中的先天性T细胞非依赖性应答。根据初步数据，提出了三个具体目标。第一个目标将确定FCRL 5缺陷对先天反应的影响。第二个目标将剖析FCRL 5在调节先天性B细胞功能中的机制影响。在目标3中，我们将表征FCRL 5和新发现的配体之间的结构/功能相互作用。拟议的工作是创新的，因为它利用保守的种间特征和体内方法，预计将大大改变我们对先天免疫中这些受体的理解。这项研究的贡献将是显着的，因为他们将提供新的知识，通过整合复杂的信号和配体的关系FCRL 5在先天性B细胞和推进我们的理解，这些相互作用的生理影响，在调节先天防御反应。这些结果预计将产生积极的影响，因为它们将建立一个基本的翻译平台，为FCRL分子在免疫疾病中的致病影响提供深入了解，并揭示疾病预防和治疗的新途径。

DESCRIPTION (provided by applicant): Innate-like splenic marginal zone (MZ) and peritoneal cavity-derived (PEC) B1 B lineage cells share critical importance at the earliest stages of humoral immune defense by rapidly sensing pathogens and mounting primary antibody responses. However, the mechanistic basis for their robust responsivity to innate thymus- independent stimuli and involvement in disease pathogenesis is poorly understood. A multigene family termed FCR-like (FCRL1-6) encodes Ig-like transmembrane proteins with complex tyrosine-based immunoregulatory function that are preferentially expressed by B cells. Their immunologic significance is underscored by their evolutionary conservation and growing associations with human lymphoproliferative, autoimmune, infectious, and immunodeficiency disorders. Although these relationships implicate the FCRLs as pathogenic factors, studies thus far indicate that they generally inhibit B cell antigen-receptor (BCR) signaling. Several representatives have recently been found to interact with MHC-related proteins as well as immunoglobulins; however, the endogenous ligands and in vivo functions of most FCRL molecules expressed by B cells have not yet been defined. The long-term objective of our studies is to determine the role of the FCRL protein family in normal and perturbed immunobiology. FCRL5, the focus of this proposal, is uniquely expressed by innate-like MZ and B1 B cells in mice, has both ITAM-like and ITIM cytoplasmic sequences, and exerts dual-regulatory influence on BCR signaling by recruiting Lyn and SHP-1. Despite its discrete distribution, little is known about its impact or that of other FCRLs in innate immunity. The central hypothesis is that FCRL5 catalyzes innate T cell-independent responses in B cells through interactions with a recently defined counterpart. Based on supporting preliminary data three Specific Aims are proposed. The first Aim will determine the impact of FCRL5 deficiency on innate responses. The second Aim will dissect the mechanistic influence of FCRL5 in regulating innate-like B cell functions. In Aim 3 we will characterize structure/function interactions between FCRL5 and a newfound ligand. The proposed work is innovative because it harnesses conserved interspecies features and in vivo approaches that are expected to substantially shift our understanding of these receptors in innate immunity. The contributions of this study will be significant because they will provide new knowledge by integrating complex signaling and ligand relationships for FCRL5 in innate-like B cells and advancing our understanding of the physiologic impact of these interactions in regulating innate defense responses. These outcomes are anticipated to have a positive impact because they will establish a fundamental translational platform that provides insight into the pathogenic influence of FCRL molecules in immune disorders and reveals new avenues for disease prevention and treatment.