Roles of FCRL Molecules in Innate Immunity

FCRL 分子在先天免疫中的作用

• 批准号: 9195687
• 负责人: RANDALL S DAVIS
• 金额: $ 36.75万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9195687
• 关键词: Agonist; Antibody Response; Antigens; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Binding; Biology; Body cavities; Cell Lineage; Cell physiology; Cells; Cellular biology; Charge; Communicable Diseases; Complex; Cytoplasmic Tail; Data; Development; Disease; Family; Family member; Fc Receptor; Genes; Greater sac of peritoneum; Host Defense; Human; ITIM; IgE; IgG Receptors; Immune; Immune System Diseases; Immune response; Immune system; Immunobiology; Immunoglobulin Domain; Immunoglobulins; Immunologic Deficiency Syndromes; Immunologics; Impairment; Innate Immune Response; Integral Membrane Protein; Knowledge; Ligands; Link; Location; Lymphocyte; Lymphoid Tissue; Lymphoproliferative Disorders; MHC Class II Genes; Mediating; Mission; Modeling; Molecular; Multigene Family; Mus; NF-kappa B; Natural Immunity; Orthologous Gene; Outcome; PTPN6 gene; Pathogenesis; Pathogenicity; Pathway interactions; Peritoneal; Phosphoric Monoester Hydrolases; Physiological; Pleural; Positioning Attribute; Prevention; Property; Protein Family; Proteins; Public Health; Receptor Activation; Receptor Signaling; Receptors, Antigen, B-Cell; Recruitment Activity; Regulation; Research; Risk; Role; Signal Transduction; Single Nucleotide Polymorphism; Stimulus; Structure; T-Lymphocyte; Testing; Thymus Gland; Toll-like receptors; Tyrosine; United States National Institutes of Health; Vaccination; Virulence Factors; Work; antimicrobial; base; blood filter; body cavity; defense response; disorder prevention; extracellular; immunoregulation; in vivo; innovation; insight; leukemia/lymphoma; member; novel; novel therapeutic intervention; pathogen; promoter; public health relevance; receptor; response; src-Family Kinases

 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 on 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.

 描述（由申请人提供）：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增强一抗反应，在体液免疫防御的最早阶段具有至关重要的重要性。然而，人们对它们对先天胸腺独立刺激的强烈反应以及参与疾病发病机制的机制基础知之甚少。称为 FCR 样 (FCRL1-6) 的多基因家族编码 Ig 样跨膜蛋白，具有复杂的基于酪氨酸的免疫调节功能，优先由 B 细胞表达。它们的免疫学意义因其进化保守性以及与人类淋巴增殖性疾病、自身免疫性疾病、感染性疾病和免疫缺陷性疾病的日益密切的联系而得到强调。尽管这些关系表明 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。最近发现一些代表物与 MHC 相关蛋白以及免疫球蛋白相互作用；然而，B细胞表达的大多数FCRL分子的内源配体和体内功能尚未明确。我们研究的长期目标是确定 FCRL 蛋白家族在正常和扰动免疫生物学中的作用。 FCRL5是本提案的重点，由小鼠先天性MZ和B1 B细胞独特表达，具有ITAM样和ITIM细胞质序列，并通过招募Lyn和SHP-1对BCR信号传导发挥双重调节影响。尽管其分布离散，但人们对其或其他 FCRL 对先天免疫的影响知之甚少。中心假设是 FCRL5 通过与最近定义的对应物相互作用来催化 B 细胞中先天的 T 细胞独立反应。基于支持初步数据，提出了三个具体目标。第一个目标将确定 FCRL5 缺陷对先天反应的影响。第二个目标将剖析 FCRL5 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 FCRL5 和新发现的配体之间的结构/功能相互作用。拟议的工作具有创新性，因为它利用了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重大的，因为它们将通过在先天样 B 细胞中整合 FCRL5 的复杂信号传导和配体关系来提供新知识，并增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转化平台，深入了解 FCRL 分子在免疫疾病中的致病影响，并揭示疾病预防和治疗的新途径。