Humoral responses to Lyme Borreliosis: A mouse model

对莱姆疏螺旋体病的体液反应：小鼠模型

• 批准号: 7464576
• 负责人: STEPHEN WILLIAM BARTHOLD
• 金额: $ 37.62万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7464576
• 关键词: A Mouse; Affinity; Antibodies; Antibody Formation; Antigen-Presenting Cells; Arthritis; Arthropods; B-Lymphocyte Subsets; B-Lymphocytes; Bacteria; Binding Proteins; Biological Assay; Biological Response Modifiers; Bite; Borrelia; Borrelia Infections; Borrelia burgdorferi; CD4 Positive T Lymphocytes; Carditis; Chronic; Chronic Disease; Classification; Data; Defect; Development; Disease; Europe; Failure; Fc Receptor; Feedback; Flow Cytometry; Heart; Heart failure; Helper-Inducer T-Lymphocyte; Immune response; Immune system; Immunity; Immunocompetent; Immunoglobulin G; Immunoglobulin M; Infection; Infectious Diseases Research; Joints; Lead; Life; Longevity; Lyme Disease; Lymphoid Tissue; Mediating; Modeling; Mus; Myocardium; Myopathy; NIH Program Announcements; Nature; Numbers; Order Spirochaetales; Organ; Patients; Plasma Cells; Process; Prophylactic treatment; Public Health; Recurrence; Regulation; Reporting; Resolution; Role; Shapes; Signal Transduction; Structure of germinal center of lymph node; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Ticks; Time; Tissues; Vaccines; base; biodefense; day; design; disabling disease; lymph nodes; mouse model; prophylactic; prototype; response

DESCRIPTION (provided by applicant): This proposal, which is responsive to the NIH Program Announcement on Non-Biodefense Emerging Infectious Diseases Research Opportunities, is concerned with Lyme borreliosis. This disease is caused by B. burgdorferi (Bb) and is the most commonly reported arthropod-borne illness in the US and Europe with the number of reported infections raising each year. The spirochetes cause persistent infections and chronic disease with bouts of arthritis and carditis in untreated patients. Our long-term objective is to delineate the mechanisms with which Bb evades effective immunity during persistent infection of fully immunocompetent hosts. Previous studies have identified antibodies as a main immune mediator of disease resolution (but not clearance of the spirochete) and passive protection. While antibodies in early infection are strongly functional with respect to disease-resolution and passive protective capacity, the protective capacity wanes as disease progresses. The objective of this proposal is to assess the mechanisms underlying the regulation of the Bb- specific humoral response, to ascertain whether strengthening of humoral responses could be exploited for therapeutic or prophylactic use. Based upon preliminary findings, we aim to test the hypothesis that Bb- specific B cells provide antibody responses by short-lived plasma cells at the expense of higher affinity B cells and long-lived plasma cells due to a lack of functional CD4 helper T cell activation. A murine model of Borrelia infection will be used to conduct three Specific Aims. Specific Aim #1 will determine the extent to which the early-induced specific IgM and/or IgG responses actively inhibit protective immunity using genetically altered mice unable to secrete certain Ig isotypes. Specific Aim #2 will test whether Bb drives lymph node B cell responses away from germinal center responses. This could result in the lack of affinity maturation and longevity and could cause a loss of functionality over time, as observed in Lyme Borrelioses. Assays will include multicolor flow cytometry to determine the nature and quality of the induced response. Furthermore, the responding B cell subsets will be identified and their regulation by CD4 T cells will be assessed. Also, the extent to which a lack of affinity maturation and development of long-lived plasma cells underlies the functional defect in the Bb-specific antibody responses will be determined by studying antibodies to decarin-binding protein as a prototype response. Specific Aim #3 will determine whether the lack of long- term functional B cell response induction to Borrelia is due to active inhibition and/or a failure of functional CD4 helper T cell response induction or whether an intrinsic defect in the ability of B cells to respond to T cell help underlies the lack of germinal center responses seen in Lyme Borreliosis. Together these studies will elucidate mechanisms that lead to the failure of the vigorous but ultimately deficient B cell response to facilitate clearance from Borrelia infection. PUBLIC HEALTH RELEVANCE: Lyme Disease is a chronic disabling disease resulting from a tick-bite. The tick transfers a bacterium, Borrelia burgdorferi, to the patient, which can persist in various organs, including the joints and heart, where it can cause disabling disease such as chronic arthritis and heart muscle disease. The body develops an immune response that can initially fend off disease but cannot clear the infection. Thus, if infections are not treated continuing disease is common. This proposal aims to determine why the immune response that is sufficient to help to reduce disease ultimately fails to clear the infection. Such information is necessary to develop vaccines and treatments for this increasingly prevalent disease.

描述（由申请人提供）：该提案是对NIH关于非生物防御新兴传染病研究机会的计划公告的回应，涉及莱姆病。这种病是由B引起的。Burgdorferi（Bb）是美国和欧洲最常见的节肢动物传播疾病，每年报告的感染数量都在增加。在未经治疗的患者中，螺旋体会引起持续感染和慢性疾病，并伴有关节炎和心脏炎。我们的长期目标是描绘的机制，Bb逃避有效的免疫力在持续感染的完全免疫活性的主机。以前的研究已经确定抗体作为疾病解决（但不是螺旋体的清除）和被动保护的主要免疫介质。虽然早期感染中的抗体在疾病解决和被动保护能力方面具有很强的功能，但随着疾病的进展，保护能力减弱。该提案的目的是评估Bb特异性体液应答调节的潜在机制，以确定是否可以将体液应答的增强用于治疗或预防用途。基于初步的发现，我们的目的是测试的假设，即B B-特异性B细胞提供的抗体反应的短寿命的浆细胞在较高的亲和力B细胞和长寿命的浆细胞由于缺乏功能性的CD 4辅助T细胞活化的代价。疏螺旋体感染的鼠模型将用于进行三个特定目的。具体目标#1将使用不能分泌某些IG同种型的遗传改变小鼠确定早期诱导的特异性IgM和/或IgG应答主动抑制保护性免疫的程度。具体目标#2将测试B B是否驱动淋巴结B细胞应答远离生发中心应答。这可能导致亲和力成熟和寿命的缺乏，并可能导致功能随时间的推移而丧失，如在莱姆疏螺旋体病中所观察到的。试验将包括流式细胞术，以确定诱导反应的性质和质量。此外，将鉴定应答B细胞亚群，并评估其受CD 4 T细胞的调节。此外，在何种程度上缺乏亲和力成熟和发展的长寿浆细胞的基础上的功能缺陷，在B b特异性抗体反应将确定通过研究抗体的十氢萘结合蛋白作为原型反应。具体目标#3将确定缺乏对疏螺旋体的长期功能性B细胞应答诱导是否是由于功能性CD 4辅助T细胞应答诱导的主动抑制和/或失败，或者B细胞应答T细胞辅助的能力的内在缺陷是否是莱姆疏螺旋体病中所见的生发中心应答缺乏的基础.总之，这些研究将阐明导致有力但最终缺陷的B细胞应答未能促进疏螺旋体感染的清除的机制。 公共卫生相关性：莱姆病是一种慢性致残性疾病，由蜱叮咬引起。蜱虫将一种细菌Borrelia burgdorferi转移到患者身上，这种细菌可以在各种器官中持续存在，包括关节和心脏，在那里它可以引起慢性关节炎和心肌疾病等致残性疾病。身体产生免疫反应，最初可以抵御疾病，但不能清除感染。因此，如果感染不治疗，持续的疾病是常见的。该提案旨在确定为什么足以帮助减少疾病的免疫反应最终未能清除感染。这些信息对于为这种日益流行的疾病开发疫苗和治疗方法是必要的。