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一个持续存在的问题。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。先天反应激活因子（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。在小鼠腹腔脓毒症模型中，腹膜B1a B细胞通过模式识别受体识别细菌，迁移到脾脏，分化为IRA B细胞，并通过涉及细胞因子和生长因子GM-CS的机制保护机体免受压倒性感染。IRA B细胞，我们也在人体中发现，对于宿主如何清除细菌至关重要。我们现在在初步实验中表明，B1a B细胞和IRA B细胞也存在于胸膜腔中。缺乏IRA B细胞的小鼠很快就会死于细菌性气道感染，不能在肺部积累产生IgM的细胞，也不能产生分泌性IgM。

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.