Innate Response Activator B cells in Bacterial Lung Infection

描述(由申请人提供)：呼吸道感染是世界范围内死亡的主要原因，也是重症监护医学中的一个长期问题。呼吸道感染的死亡率正在上升，因此迫切需要开发替代治疗方法。先天反应激活物(IRA)B细胞是我们最近发现的一种独特的B细胞群，可以预防微生物败血症。在小鼠腹部脓毒症模型中，腹膜B1a B细胞识别带有模式识别受体的细菌，迁移到脾，分化为IRA B细胞，并通过涉及细胞因子和生长因子GM-CS的机制保护免受压倒性感染。我们在人类中也发现了IRA B细胞，它对宿主清除细菌至关重要。我们现在已经在初步实验中表明，B1a、B细胞和IRA B细胞也存在于胸腔中。缺乏IRA B细胞的小鼠很快就会死于细菌呼吸道感染，无法在肺部积聚产生IgM的细胞，也无法产生分泌型IgM。 此外，胸腔是积聚在肺部的IgMHigh B细胞的来源，而胸膜腔注射IRA B细胞前体到IRA B细胞敲除的胸膜可以恢复IgM反应并保护其免受细菌感染。在这里，我们将检验胸腔来源的IRA B细胞控制肺内天然抗体产生细胞的产生和积累的假设。我们认为，IRA B细胞是免疫防御和预防呼吸道感染的重要协调者。这个项目很重要，因为它基于一个强大的表型，具有明显的翻译潜力，它具有创新性，因为它探索了一个新发现的细胞的生物学，确定了一个以前未知的GM-CSF-IgM轴，并将胸腔确定为免疫细胞的重要枢纽。

DESCRIPTION (provided by applicant): Infection of the airways is a major cause of death worldwide and a persistent problem in critical care medicine. Mortality from airway infection is on the rise and thus there is an urgent need to develop alternative treatments. Innate response activator (IRA) B cells are a unique B cell population we recently discovered that protects against microbial sepsis. In a mouse abdominal sepsis model, peritoneal B1a B cells recognize bacteria with pattern recognition receptors, migrate to the spleen, differentiate to IRA B cells, and protect against overwhelming infection by mechanisms that involve the cytokine and growth factor GM-CS. IRA B cells, which we also identified in humans, are vital to how the host clears bacteria. We have now shown in preliminary experiments that B1a B cells and IRA B cells also reside in the pleural cavity. Mice lacking IRA B cells rapidly succumb to bacterial airway infection, fail to accumulate IgM-producing cells in the lungs, and fail to generate secretory IgM. Moreover, the pleural cavity is the source of IgMhigh B cells that accumulate in the lungs, whereas injection of pleural cavity IRA B cell precursors to the pleura of IRA B cell knockouts restores IgM responses and protects against bacterial infection. Here we will test the hypothesis that pleural cavity-derived IRA B cells control the generation and accumulation of natural antibody producing cells in the lung. IRA B cells, we propose, are essential coordinators of immune defense and protect against airway infection. The project is important because it is based on a strong phenotype and has clear translational potential and it is innovative because it explores the biology of a newly- discovered cell, identifies a previously unknown GM-CSF-IgM axis, and identifies the pleural cavity as an important hub for immune cells.