Long-lived B cell Immunity in the Respiratory Tract

呼吸道中的长寿命 B 细胞免疫

基本信息

批准号：
8521064
负责人：
Nicole Baumgarth
金额：
$ 35.24万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8521064
关键词：
Adoptive Transfer Antibodies Antibody Formation Antigens Appearance Attenuated B-Lymphocytes Blood Vessels Cells Characteristics Custom Data Development Devices Gene Expression Gene Expression Profiling Generations Genetic Screening Goals Humoral Immunities Immune Immune response Immunity Immunization Immunoglobulin-Secreting Cells Inactivated Vaccines Infection Inflammation Inflammatory Influenza Influenza Hemagglutinin Integrins Kinetics Knowledge Label Licensing Life Longevity Lung Lung Capacity Lung Inflammation Maintenance Measures Microfluidic Microchips Modeling Mucosal Immune Responses Mucosal Immunity Mus Pathway interactions Plasma Cells Plasmablast Regulation Reporter Respiratory System Respiratory Tract Infections Respiratory physiology Respiratory tract structure Signal Transduction Site Source Staging Structure of germinal center of lymph node Structure of parenchyma of lung System Vaccination Vaccine Design Vaccines Virus Virus Diseases arm base chemokine chemokine receptor influenzavirus lymph nodes migration mimetics novel pathogen public health relevance research study response shear stress success

项目摘要

DESCRIPTION (provided by applicant): Respiratory tract infections induce strong and long-lasting humoral immune responses locally at the site, contributing significantly to immune protection from challenge infection. The mechanisms that induce and control protective local immune responses are currently not fully understood. The study is based on preliminary data in mice that implicate the rapidly induced extrafollicular foci B cell response as source for long-lived humoral immunity in the respiratory tract following influenza virus infection. The objective for this proposal is to identify the mechanisms that regulate this long-term local antibody response to influenza virus in the respiratory tract. In Specific Aim #1 the differentiation pathways and protective capacity of lung antibody-secreting cells following influenza virus infection will be measured in wildtype mice and in mice that lack formation of germinal centers (SAP-/- mice) or strong extrafollicular foci responses (following inactivated virus delivery) using BLIMP-1 reporter mice and a newly developed system for tracking of influenza hemagglutinin-specific, C12Id-expressing B cells ex vivo. Specific Aim #2 will study the mechanisms regulating the migration/retention of lung plasma cell precursors to the respiratory tract. They will assess the extent to which migration of virus-specific B cells/plasma cells from regional lymph nodes is required for the establishment of lung tissue plasma cell pools, and using genetic screening and a custom microfluidics device, will identify the integrins and chemokines/receptors responsible for the selective accumulation and/or retention of plasma cells the lung tissue under shear stress. Specific Aim #3 will use gene expression studies to determine the differentiation stage of plasma cells/precursors in the lung tissue and BrDU labeling studies to identify the mechanisms underlying the longevity of the antibody-secreting cells in the lung. Adoptive transfer studies will assess the requirements for antigen and/or infection-induced inflammatory signals for their maintenance. These studies will provide novel information on the characteristics and the B cell developmental pathways that generate the long-lived humoral immune responses in the respiratory tract, basic knowledge on B cell response regulation that can aid rationale vaccine design. PUBLIC HEALTH RELEVANCE: Protection from infections with influenza virus is contributed at least in part by antibody-secreting cells that establish in the lung following influenza virus infection. This study aims to understand how these cells are generated and what regulates their migration/maintenance in the lung. This basic information will provide potential avenues for rational vaccine design that aims to boost local/mucosal immune responses.

描述（由申请人提供）：呼吸道感染在该部位诱发强烈且持久的局部体液免疫反应，对抵抗攻击性感染的免疫保护有显着贡献。目前尚未完全了解诱导和控制保护性局部免疫反应的机制。该研究基于小鼠的初步数据，这些数据表明快速诱导的滤泡外病灶 B 细胞反应是流感病毒感染后呼吸道中长效体液免疫的来源。该提案的目的是确定调节呼吸道中流感病毒长期局部抗体反应的机制。在具体目标#1中，将在野生型小鼠和缺乏生发中心形成的小鼠（SAP-/-小鼠）或强滤泡外病灶反应（以下使用 BLIMP-1 报告小鼠和新开发的系统来离体追踪流感血凝素特异性、表达 C12Id 的 B 细胞。具体目标#2将研究调节肺浆细胞前体向呼吸道迁移/保留的机制。他们将评估建立肺组织浆细胞库所需的病毒特异性 B 细胞/浆细胞从区域淋巴结迁移的程度，并使用遗传筛查和定制微流体装置来识别整合素和趋化因子/负责浆细胞在剪切应力下选择性积累和/或保留肺组织的受体。具体目标#3 将利用基因表达研究来确定肺组织中浆细胞/前体的分化阶段，并利用 BrDU 标记研究来确定肺中抗体分泌细胞长寿的机制。过继转移研究将评估其维持所需的抗原和/或感染诱导的炎症信号。这些研究将提供有关在呼吸道中产生长效体液免疫反应的特征和 B 细胞发育途径的新信息，以及有助于疫苗设计合理性的 B 细胞反应调节的基础知识。公共卫生相关性：流感病毒感染后肺部建立的抗体分泌细胞至少部分有助于防止流感病毒感染。这项研究旨在了解这些细胞是如何产生的，以及是什么调节它们在肺部的迁移/维持。这些基本信息将为旨在增强局部/粘膜免疫反应的合理疫苗设计提供潜在途径。