Roles of FCRL Molecules in Innate Immunity

描述（由申请人提供）：先天样脾边缘区（MZ）和腹膜腔源性（PEC） B1 B细胞系在体液免疫防御的早期阶段通过快速感知病原体和增加一抗反应共享至关重要的作用。然而，它们对先天胸腺非依赖性刺激的强烈反应和参与疾病发病机制的机制基础尚不清楚。一个名为FCR-like （FCRL1-6）的多基因家族编码具有复杂酪氨酸免疫调节功能的igg样跨膜蛋白，这些蛋白优先由B细胞表达。它们在进化上的保守性以及与人类淋巴增生性、自身免疫、感染性和免疫缺陷疾病的日益密切的联系，强调了它们的免疫学意义。虽然这些关系暗示fcrl是致病因素，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，大多数由B细胞表达的FCRL分子的内源性配体和体内功能尚未明确。我们研究的长期目标是确定FCRL蛋白家族在正常和紊乱免疫生物学中的作用。FCRL5是本研究的重点，在小鼠的先天样MZ和B1 B细胞中唯一表达，具有itam样和ITIM细胞质序列，并通过募集Lyn和SHP-1对BCR信号通路产生双重调控作用。尽管其分布离散，但对其或其他fcrl在先天免疫中的影响知之甚少。核心假设是FCRL5通过与最近定义的对应物相互作用催化B细胞的先天T细胞非依赖性反应。基于支持的初步数据，提出了三个具体目标。第一个目标将确定FCRL5缺乏对先天反应的影响。第二个目标将剖析FCRL5在调节先天样B细胞功能中的机制影响。在Aim 3中，我们将表征FCRL5与新发现的配体之间的结构/功能相互作用。这项工作具有创新性，因为它利用了保守的物种间特征和体内方法，有望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重要的，因为它们将通过整合先天样B细胞中FCRL5的复杂信号传导和配体关系提供新的知识，并推进我们对这些相互作用在调节先天防御反应中的生理影响的理解。预计这些结果将产生积极影响，因为它们将建立一个基本的转化平台，提供对FCRL分子在免疫疾病中的致病影响的见解，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.