Antigen Specific Response to Borrelia

对疏螺旋体的抗原特异性反应

• 批准号: 8103544
• 负责人: Jorge L. Benach
• 金额: $ 39.11万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-12-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8103544
• 关键词: Affinity; Antibodies; Antibody Formation; Antibody-Producing Cells; Antigens; Architecture; B cell repertoire; B-Lymphocytes; Bacteria; Biochemical; Biogenesis; Blood Circulation; Borrelia; Borrelia Infections; Borrelia burgdorferi; Cells; Cholesterol; Complement; Development; Disease; Epitopes; Glycolipids; Goals; Greater sac of peritoneum; Host Defense; Human; Image; Immune; Immune system; Immunity; Immunization; In Vitro; Infection; Lipids; Lipoproteins; Lyme Disease; Measures; Membrane; Membrane Lipids; Membrane Microdomains; Microbiology; Monoclonal Antibodies; Mus; Nature; Order Spirochaetales; Organ; Out-Migrations; Passive Immunization; Pathology; Pathway interactions; Peritoneal; Physiological; Positioning Attribute; Procedures; Production; Productivity; Progress Reports; Prokaryotic Cells; Proteins; Publications; Relapsing Fever; Resistance; Role; Source; Surface; T-Lymphocyte; Text; Ticks; Time; arm; bactericide; bioimaging; cell type; combat; complement system; in vivo; killings; novel; outer surface lipoprotein; pathogen; relapsing fever borrelia; research study; response; tool; unpublished works; weapons

DESCRIPTION (provided by applicant): The tick-borne Borreliae are the causative agents of relapsing fever and Lyme disease worldwide. Antibodies are the primary weapon of the mammalian immune system against both Borrelia infections. Some antibody responses have 'traditional' functions while others are more versatile and have novel functions and modes of action. A novel type of antibody to the Borrelia functions independently of the complement system in its bactericidal action, which is a unique and novel function for antibodies. The evidence for these bactericidal, complement independent antibodies is derived from both in vivo and in vitro studies. The main goal for this competitive renewal is to define the mechanism of action of the bactericidal, complement independent antibodies to Borrelia and to identify the cells that produce these antibodies. Both B. burgdorferi and relapsing fever Borreliae will be used for the experimental procedures. There is experimental evidence of colocalization of the outer surface and variable lipoproteins (Osp and Vmp) with cholesterol glycolipid domains in the outer membrane of the Borreliae. Depletion of the cholesterol leads to resistance to the bactericidal action of the antibodies. Therefore, the contribution of the Borrelia cholesterol glycolipids to the bactericidal action of the antibodies will be studied, particularly in the context of the outer membrane architecture of the antigenic determinants within the cholesterol-glycolipid domains. Imaging, structural, biophysical, and biochemical approaches will be used to determine the extent and nature of the ordered cholesterol glycolipid domains (lipid rafts) in the experiments planned for Specific Aim I. The existence of lipid rafts in a prokaryote such as Borrelia constitutes a paradigm shift in microbiology. The biogenesis of the bactericidal antibodies is the main goal of Specific Aim II. The cells that generate bactericidal antibodies can be distributed among the entire B cell repertoire. T cell independence of the bactericidal antibodies suggests the involvement of marginal zone B cells, but some of these antibodies appear to have undergone affinity maturation leading to the possibility of their being generated by other types of B cells, as well. At a time when the multiple functions of antibodies are being increasingly recognized and passive immunization is being revived as therapy for infectious and other diseases, the understanding of the versatile nature of the antibody response to Borrelia will be a significant contribution to host defense. PUBLIC HEALTH RELEVANCE: There are two types of infections with spirochetes of the genus Borrelia, the agents of Lyme disease, and several species of relapsing fever Borrelia. In this application, we will investigate the role of the lipids in the bactericidal action of antibodies to the Borrelia, document and characterize the lipid rafts, and determine the cell types that produce these unique antibodies.

描述（由申请方提供）：蜱传疏螺旋体是全球回归热和莱姆病的病原体。抗体是哺乳动物免疫系统对抗两种疏螺旋体感染的主要武器。一些抗体反应具有“传统”功能，而另一些则更通用，具有新的功能和作用模式。针对疏螺旋体的新型抗体在其杀菌作用中独立于补体系统发挥作用，这是抗体的独特和新颖的功能。这些杀菌、补体非依赖性抗体的证据来自体内和体外研究。这种竞争性更新的主要目标是定义针对疏螺旋体的杀菌、补体非依赖性抗体的作用机制，并鉴定产生这些抗体的细胞。都是B。伯氏疏螺旋体和回归热疏螺旋体将用于实验程序。 有实验证据表明，外表面和可变脂蛋白（Osp和Vmp）与疏螺旋体外膜中的胆固醇糖脂结构域共定位。胆固醇的消耗导致对抗体的杀菌作用的抗性。因此，将研究疏螺旋体胆固醇糖脂对抗体杀菌作用的贡献，特别是在胆固醇-糖脂结构域内抗原决定簇的外膜结构的背景下。将使用成像、结构、生物物理和生物化学方法确定特定目标I计划实验中有序胆固醇糖脂结构域（脂筏）的范围和性质。原核生物如疏螺旋体中脂筏的存在构成了微生物学的范式转变。 杀菌抗体的生物发生是特异性目标II的主要目标。产生杀菌抗体的细胞可以分布在整个B细胞库中。杀菌抗体的T细胞独立性表明边缘区B细胞的参与，但这些抗体中的一些似乎已经经历了亲和力成熟，导致它们也可能由其他类型的B细胞产生。在抗体的多种功能日益被认识到并且被动免疫作为传染病和其他疾病的疗法被复兴的时候，对疏螺旋体抗体应答的多功能性质的理解将对宿主防御做出重大贡献。 公共卫生相关性：有两种类型的感染螺旋体属的莱姆病的代理人，和几种回归热疏螺旋体。在本申请中，我们将研究脂质在疏螺旋体抗体杀菌作用中的作用，记录和表征脂筏，并确定产生这些独特抗体的细胞类型。