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）：该提案对NIH计划公告的响应，涉及莱姆伯氏症。该疾病是由B. burgdorferi（BB）引起的，是美国和欧洲最常见的节肢动物 - 传播疾病，每年报告的感染次数大量增加。螺旋体引起持续性感染和慢性疾病，患者患有关节炎和心脏炎。我们的长期目标是描述BB在完全免疫能力的宿主持续感染过程中逃避有效免疫力的机制。先前的研究已将抗体确定为疾病分辨率的主要免疫介质（但没有螺旋体的清除）和被动保护。尽管早期感染中的抗体在疾病解决和被动保护能力方面具有强大的功能，但随着疾病的发展，保护能力会减弱。该提案的目的是评估调节BB-特定体液反应的基础机制，以确定是否可以利用增强体液反应的治疗或预防性使用。基于初步发现，我们旨在检验以下假设：BB-特异性B细胞通过短寿命的浆细胞提供抗体反应，但由于缺乏功能性CD4辅助T细胞激活而导致较高亲和力B细胞和长期寿命的浆细胞。渗出症感染的鼠模型将用于执行三个特定目标。特定目标＃1将确定早期诱导的特异性IgM和/或IgG反应在多大程度上使用无法分泌某些​​Ig同种型的基因改变的小鼠积极抑制保护性免疫。具体目标＃2将测试BB是否将淋巴结B细胞反应从生发中心反应中驱动。这可能导致缺乏亲和力成熟和寿命，并且可能会随着时间的流逝而导致功能丧失，如莱姆伯氏症中所观察到的那样。测定将包括多色流式细胞仪，以确定诱导响应的性质和质量。此外，将确定响应的B细胞子集，并评估其对CD4 T细胞的调节。同样，长寿命浆细胞缺乏亲和力成熟和发育的程度将通过研究抗脱生物结合蛋白作为原型反应的抗体来确定BB特异性抗体反应中的功能缺陷。具体目标＃3将确定缺乏长期功能性B细胞反应诱导伯碱是由于主动抑制和/或功能性CD4辅助助手T细胞反应诱导的失败，还是B细胞对B细胞响应能力的固有缺陷是否有助于Lyme Borreliisos中缺乏生发性中心反应的基础。这些研究共同阐明了导致剧烈但最终缺乏B细胞反应失败的机制，以促进伯氏感染的清除。 公共卫生相关性：莱姆病是由tick虫咬伤引起的慢性残疾疾病。 tick将细菌（Borrelia burgdorferi）转移给患者，该细菌可以持续在包括关节和心脏在内的各种器官中，在这些器官中可能引起残疾疾病，例如慢性关节炎和心脏肌肉疾病。人体会产生一种免疫反应，最初可以抵御疾病，但无法清除感染。因此，如果未治疗感染，持续疾病很常见。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无法清除感染。对于这种日益普遍的疾病开发疫苗和治疗是必要的。