New Perspective on Innate Antibodies in Mice

项目摘要 目前对细菌刺激的先天免疫反应的概念，如脂多糖(例如，脂多糖 来自这里使用的鼠伤寒沙门氏菌)很大程度上是基于取自 未受刺激的小鼠。然而，我们最近在活体小鼠模型中对内毒素刺激的发现表明 这些体外数据中的很大一部分不适合对体内必然发生的先天反应进行建模。 同样，我们的发现提出了关于如何将活体模型(B细胞转基因，TLR缺陷， 寄生虫感染等)对正常(基因完整)动物的内毒素反应。 具体地说，我们发现体内大部分内毒素刺激的浆细胞反应是由B-1a产生的 (CD5+B-1)细胞，其中大部分只在注射内毒素后才迁移到脾内。此外，我们发现， 体内对内毒素的即时反应是由驻留在脾和脾中的B-1a细胞产生的 令人惊讶的是，在1-2天内分化成浆细胞，而不需要进行细胞分裂。这是第一波 浆细胞分化在整体体内反应中所占比例相对较小，达到峰值 在第3天，主要由移居的B-1a细胞在分化为血浆之前(或同时)分裂产生 细胞。然而，早期反应人员的快速反应能力，可以比作原始的 免疫记忆可能是利用先天免疫系统填补缺口的关键，直到 适应性免疫系统可以接管这一任务。 这里提出的研究旨在提供对B细胞及其参与的机制的清晰认识 对入侵病原体的先天抗体反应，包括但不限于脂多糖。我们到目前为止的发现 证明我们可以有效地利用微小的功能B细胞亚群来调节这些反应 (0.1-3%的脾细胞分别来自未刺激或内毒素刺激的小鼠)。因此，我们现在建议 进一步定义区别居民B-1反应的细胞、解剖和分子机制 以及确定其他B细胞隔室和受体的程度 相互作用促成了天生的反应。总之，这些研究将为制定一项 复杂的天然免疫机制的综合和信息量模型 必须迅速产生抗体反应，以将入侵病原体造成的损害降至最低。

Project Summary Current concepts of innate immune responses to bacterial stimuli such as lipopolysaccharides (e.g., the LPS from S. typhemurium used here) are largely based on data from in vitro stimulation of spleen cells taken from unstimulated mice. However, our recent findings with LPS stimulation in an in vivo mouse model demonstrate that much of this in vitro data is not suitable for modeling innate responses, which occur perforce in vivo. Similarly, our findings raise questions about the how to relate data from in vivo models (B-cell transgenic, TLRdeficient, parasite infection, etc.) to LPS responses in normal (genetically intact) animals. Specifically, we find that the majority of the LPS-stimulated plasma cell response in vivo is produced by B-1a (CD5+ B-1) cells, most of which only migrate into the spleen after LPS injected. Further, we find that the immediate response to LPS in vivo is produced by the B-1a cells that are resident in the spleen and surprisingly differentiate into plasma cells within 1-2 days without undergoing cell division. This initial wave of plasma cell differentiation accounts for a relatively small proportion of the overall in vivo response, which peaks at day 3 and is largely produced by immigrant B-1a cells that divide before (or while) differentiating to plasma cells. However, the rapid response capabilities of the early responders, which can be likened to primitive immunologic memory, may be key to the ability to use the innate immune system to ¿fill in the gap¿ until the adaptive immune system can take over. Studies proposed here are designed to provide a clear view of the B cells and mechanisms that participate in innate antibody responses to invading pathogens, including but not restricted to LPS. Our findings to date demonstrate that we can work effectively with the tiny functional B cell subsets that mediate these responses (0.1-3% of spleen cells from unstimulated or LPS-stimulated mice, respectively). Thus, we now propose to further define the cellular, anatomical and molecular mechanisms that distinguish resident B-1 responses from those of immigrant B-1 cells, and to determine the extent to which other B cell compartments and receptor interactions contribute to the innate response. Together, these studies will provide grounds for developing a comprehensive and informative model of the complex innate immunity mechanisms involved in natural antibody responses that must be produced rapidly to minimize damage due to invading pathogens.