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

甲型和乙型流感病毒感染在健康人中诱导强大的先天和获得性免疫反应 人类群体，这是一种反应，用包括小鼠在内的各种动物模型来概括。虽然 这些反应通常不会导致杀菌、广谱反应(异亚型)免疫，从而保护 由于感染了所有的流感毒株，它们确实大大降低了死亡率和疾病严重程度。 在异型感染之后。这种强健响应的一个非冗余组件是产品 在“天然IgM”中，自发产生的抗体与所有测试的流感病毒株广泛结合。 天然IgM是由经典的B-1细胞和终末分化的B-1细胞在稳定状态下产生的. 脾和骨髓中的来源浆细胞以及流感感染后引流淋巴中的来源浆细胞 结节内由CD5+B-1细胞从胸腔内动员。在他们缺席或财委会缺席的情况下- 小鼠显示，B细胞上的IgM受体(Fc？R)尚未建立起完全保护性体液免疫 肺部病毒载量增加，并以更高的速度死于感染。因此，天然的IgM和 负责它们产生的细胞是对流感的“广泛保护性”免疫力的一部分，流感是一种复合体 以及多样化的应对措施，大大减少了感染者的疾病负担和死亡。 阐明什么是最有效的、降低死亡率和发病率的、广泛的免疫 流感对于设计新的治疗和预防方法具有重要意义，是 这项提议的长期目标。因此，它对PA-18-859做出了回应，该决议旨在支持 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细胞向分泌强IgM血浆的终末分化所需的信号 细胞(B-1pc)。利用体内细胞耗尽和细胞重建实验，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这些曲目 B-1PC和B-1细胞来源的天然IgM分别具有抗流感活性。特定目标2将 研究TLR和BCR介导的信号在B-1细胞对流感反应中的作用。我们将测试 我们关于两步激活CD5+B-1细胞的假设：TLR介导的信号诱导细胞 BCR信号抑制物CD5的增殖和丢失，使后续的BCR信号能够驱动 B-1细胞的特异性反应。最后，在具体目标3中，我们将探索非 分泌型IgM和FcµR在增强保护性T依赖的免疫球蛋白应答中的冗余功能 在体外和体内对流感的影响。预期结果将为理解提供概念上的进步 自然免疫球蛋白、CD5+和CD5-B-1细胞功能及其T依赖性B细胞的基本过程 细胞激活。这些数据将确定天然免疫球蛋白M是增强广谱免疫的关键预防靶点。 对流感的体液免疫。

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.