B-1 cells, IgM and Protective Humoral Immunity to Influenza

B-1 细胞、IgM 和流感保护性体液免疫

• 批准号: 10023157
• 负责人: Nicole Baumgarth
• 金额: $ 44.05万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10023157
• 关键词: Animal Model; Antibodies; Antibody Response; Antigen Presentation; Antigens; Applications Grants; Automobile Driving; B-Cell Activation; B-Lymphocytes; Binding; Birth; Bone Marrow; CD4 Positive T Lymphocytes; Cell Communication; Cell Differentiation process; Cell Lineage; Cell Proliferation; Cell physiology; Cells; Cessation of life; Chimera organism; Complex; Conceptions; Data; Development; Dose; Fc Receptor; Future; Gene Expression; Goals; Human; Humoral Immunities; IgM Fc receptor; Immune response; Immunity; Immunoglobulin G; Immunoglobulin M; Immunoglobulin-Secreting Cells; In Vitro; Individual; Infection; Influenza; Influenza A virus; Influenza B Virus; Knowledge; Learning; Lung; M cell; Mediastinal lymph node group; Mediating; Morbidity - disease rate; Mus; Nature; Neonatal; Plasma Cells; Pleural cavity; Population; Population Heterogeneity; Process; Production; Prophylactic treatment; Research Support; Respiratory System; Role; Severity of illness; Signal Transduction; Spleen; Supporting Cell; Testing; Therapeutic; Therapeutic Uses; Vaccines; Viral Load result; Virus Diseases; adaptive immune response; anti-influenza; burden of illness; design; draining lymph node; experimental study; flu activity; in vivo; influenza virus strain; influenza virus vaccine; influenzavirus; inhibitor/antagonist; microbial; mortality; natural antibodies; novel therapeutics; plasma cell development; prophylactic; reconstitution; response; self-renewal; therapeutic target; uptake

Influenza A and B virus infections induce robust innate and adaptive immune responses in the healthy human population, a response that is recapitulated with various animal models, including mice. Although these responses do not usually result in sterilizing, broadly reactive (heterosubtypic) immunity that protects from infection with all influenza strains, they do strongly reduce mortality rates and disease severity following heterosubtypic infections. A non-redundant component of this robust response is the production of “natural IgM”, spontaneously-produced antibodies that bind broadly to all test influenza virus strains. Natural IgM is produced in the steady-state by classical B-1 cells and by terminally-differentiated B-1- derived plasma cells in spleen and bone marrow and following influenza infection also in the draining lymph nodes by CD5+ B-1 cells mobilized from the pleural cavity. In their absence, or in the absence of the Fc- receptor for IgM (FcµR) on B cells, fully protective humoral immunity is not established, mice show increased lung viral loads, and they succumb to infection at increased rates. Thus, natural IgM and the cells responsible for their production are part of the “broadly protective” immunity to influenza, a complex and diverse response that significantly reduces disease burden and death among those infected. Elucidating what constitutes the most effective, mortality and morbidity-reducing, broad immunity to influenza is of high significance for the design of new therapeutic and prophylactic treatments, and is the long-term objective of this proposal. It is therefore responsive to PA-18-859, which aims to support research dedicated to the development of a universal influenza virus vaccine. Specific Aim 1 Is to determine the signals required for the terminal differentiation of B-1 cells to strongly IgM-secreting plasma cells (B-1PC). Using in vivo cell depletion and cell reconstitution experiments we will identify the signals required for B-1PC development. Gene expression and functional studies will determine the repertoires and anti-influenza activity of natural IgM from B-1PC and B-1 cells, respectively. Specific Aim 2 will investigate the effects of TLR and BCR-mediated signals on B-1 cell responses to influenza. We will test our hypothesis that a two-step process activates CD5+ B-1 cells: TLR-mediated signals induce cell proliferation and loss of the BCR signaling inhibitor CD5, enabling subsequent BCR-signals to drive specific B-1 cell responses. Finally, in Specific Aim 3 we will explore the mechanism underlying the non- redundant function of secreted IgM and of the FcµR in enhancing protective T-dependent IgG responses to influenza in vitro and in vivo. Expected results would provide conceptional advances for understanding natural IgM, CD5+ and CD5- B-1 cell function, and the fundamental processes underlying T-dependent B cell activation. The data would identify natural IgM as a critical prophylactic target for enhanced broad humoral immunity to influenza.

甲型和乙型流感病毒感染可在健康人群中诱发强大的先天性和适应性免疫反应 人类群体中，包括小鼠在内的各种动物模型都重现了这种反应。 这些反应通常不会产生保护性的、广泛反应性（异亚型）免疫。 由于感染所有流感病毒株，它们确实大大降低了死亡率和疾病严重程度 这种强烈反应的一个非冗余组成部分是异亚型感染后的产生。 “天然 IgM”，即自发产生的抗体，可与所有测试流感病毒株广泛结合。 天然 IgM 由经典 B-1 细胞和终末分化的 B-1- 在稳态下产生 脾脏和骨髓中的衍生浆细胞，以及流感感染后的引流淋巴液中的衍生浆细胞 淋巴结由从胸膜腔动员的 CD5+ B-1 细胞在不存在或不存在 Fc- 的情况下进行。 小鼠显示，B 细胞上的 IgM (FcµR) 受体，尚未建立完全保护性体液免疫 肺部病毒载量增加，因此，它们感染的几率也会增加。 负责产生流感病毒的细胞是流感“广泛保护性”免疫力的一部分，流感是一种复杂的疾病 多样化的应对措施可显着减少感染者的疾病负担和死亡。 阐明什么是最有效、降低死亡率和发病率的广泛免疫力 流感对于设计新的治疗和预防方法具有重要意义，并且是 因此，它响应 PA-18-859，旨在支持。 致力于开发通用流感病毒疫苗的研究具体目标 1 是 确定 B-1 细胞终末分化为强 IgM 分泌血浆所需的信号 使用体内细胞耗竭和细胞重建实验，我们将识别信号。 B-1PC 开发所需的基因表达和功能研究将确定其全部功能。 和来自 B-1PC 和 B-1 细胞的天然 IgM 的抗流感活性，分别为 Specific Aim 2。 我们将测试 TLR 和 BCR 介导的信号对 B-1 细胞对流感反应的影响。 我们的假设是两步过程激活 CD5+ B-1 细胞：TLR 介导的信号诱导细胞 BCR 信号抑制剂 CD5 的增殖和丢失，使后续的 BCR 信号能够驱动 最后，在具体目标 3 中，我们将探讨非-1 细胞反应的潜在机制。 分泌型 IgM 和 FcμR 在增强保护性 T 依赖性 IgG 反应中的冗余功能 体外和体内流感的预期结果将为理解提供概念上的进展。 天然 IgM、CD5+ 和 CD5- B-1 细胞功能，以及 T 依赖性 B 细胞的基本过程 这些数据将确定天然 IgM 作为增强广泛性的关键预防目标。 对流感的体液免疫。