Long-lived B cell Immunity in the Respiratory Tract

描述（由申请人提供）：呼吸道感染在该部位引起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，将使用BLIMP-1报告小鼠和新开发的用于离体追踪流感血凝素特异性、表达C12Id的B细胞的系统，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（灭活病毒递送后）中测量流感病毒感染后肺抗体分泌细胞的分化途径和保护能力。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池所需的病毒特异性 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，将识别负责浆细胞在剪切应力下选择性积累和/或保留肺组织的整合素和趋化因子/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。

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.