Roles of FCRL Molecules in Innate Immunity

描述(由申请人提供)：先天的脾边缘区(MZ)和腹膜腔来源的(PEC)B1 B系细胞在体液免疫防御的早期阶段具有至关重要的作用，因为它们能够快速感知病原体并启动初级抗体反应。然而，它们对与生俱来的胸腺非依赖性刺激的强烈反应性以及参与疾病发病机制的机制基础尚不清楚。FCRL1-6(FCRL1-6)是一个多基因家族，编码具有复杂酪氨酸免疫调节功能的Ig样跨膜蛋白，由B细胞优先表达。它们在进化上的保守性以及与人类淋巴增生性疾病、自身免疫疾病、感染性疾病和免疫缺陷疾病的相关性日益增强，从而凸显了它们的免疫学意义。虽然这些关系暗示FCRL是致病因素，但到目前为止的研究表明，它们通常抑制B细胞抗原-受体(BCR)信号。最近发现一些代表分子与MHC相关蛋白和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确定。我们研究的长期目标是确定FCRL蛋白家族在正常和紊乱的免疫生物学中的作用。FCRL5是本研究的重点，在小鼠先天的MZ和B1B细胞中唯一表达，同时具有ITAM样和ITIM胞质序列，并通过招募Lyn和SHP-1对BCR信号产生双重调节作用。尽管它的分布是离散的，但人们对它或其他FCRL在先天性免疫中的影响知之甚少。中心假设是，FCRL5通过与最近定义的对应物相互作用，催化B细胞中先天的T细胞非依赖性反应。在支持初步数据的基础上，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。第二个目的将剖析FCRL5在调节先天类B细胞功能方面的机制影响。在目标3中，我们将表征FCRL5与一种新发现的配体之间的结构/功能相互作用。这项拟议的工作具有创新性，因为它利用了保守的物种间特征和体内方法，有望极大地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大的，因为他们将通过整合类先天B细胞中FCRL5的复杂信号和配体关系提供新的知识，并促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。这些结果预计将产生积极影响，因为它们将建立一个基本的翻译平台，提供对FCRL分子在免疫疾病中的致病影响的洞察，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.