Regulation of antibody production by innate signals

描述(由申请人提供)：本提案的目的是阐明人类先天免疫系统和边缘带(MZ)B细胞之间的相互作用。MZ B细胞与循环相连，通过T细胞非依赖的途径迅速产生针对血源性病原体的保护性抗体，但目前仍知之甚少。我们最近发现，人的脾含有一种新的B细胞辅助性中性粒细胞(NBH细胞)亚群，其表型和基因表达谱不同于我们循环中存在的传统中性粒细胞(NC细胞)。在这项建议中，我们假设NC细胞通过IL-10依赖的途径将脾重新编程为NBH细胞，该途径涉及小叶周围血窦内皮细胞。我们认为，正弦形内皮细胞通过Toll样受体感应到血源性细菌后，释放吸引NC细胞的趋化因子和IL-10。我们还认为，来自肝窦内皮细胞的IL-10刺激NC细胞分化为具有强大的MZ B细胞刺激活性的NBH细胞。将实现以下三个目标。目的1确定脾静脉窦内皮细胞通过Toll样受体感应细菌后，诱导NC细胞重编程为NBH细胞的机制。目的2阐明NBH细胞诱导MZ B细胞产生Ig M、Ig G和Ig A类转换以及浆细胞分化的机制。目的3探讨NBH细胞在MZ B细胞中诱导V(D)J基因体细胞超突变和高亲和力抗体产生的机制。这些研究将利用来自健康人和罕见的原发免疫缺陷患者的独特细胞和组织来剖析中性粒细胞和MZ B细胞之间的相互作用。这些研究的结果可能导致识别新的中性粒细胞靶向策略，该策略可能通过利用NBH细胞的B细胞辅助活性来增强疫苗诱导的抗体反应。

DESCRIPTION (provided by applicant): The goal of this proposal is to elucidate the interplay between the innate immune system and marginal zone (MZ) B cells in humans. MZ B cells interface with the circulation and rapidly produce protective antibodies to blood-born pathogens through a T cell- independent pathway that remains poorly understood. We recently found that the human spleen contains a novel subset of B cell helper neutrophils (NBH cells) with a phenotype and gene expression profile distinct from those of conventional neutrophils (NC cells) present in our circulation. In this proposal, we hypothesize that NC cells undergo splenic reprogramming into NBH cells through an IL-10-dependent pathway involving perifollicular sinusoidal endothelial cells. We contend that sinusoidal endothelial cells release NC cell- attracting chemokines and IL-10 upon sensing blood-born bacteria through Toll-like receptors. We also argue that IL-10 from sinusoidal endothelial cells stimulates NC cells to differentiate into NBH cells with powerful MZ B cell-stimulating activity. The following three aims will be pursued. Aim 1 is to determine the mechanisms by which splenic sinusoidal endothelial cells induce reprogramming of NC cells into NBH cells upon sensing bacteria through Toll-like receptors. Aim 2 is to elucidate the mechanisms by which NBH cells induce IgM production, IgG and IgA class switching, and plasma cell differentiation in MZ B cells. Aim 3 is to evaluate the mechanisms by which NBH cells induce V(D)J gene somatic hypermutation and high-affinity antibody production in MZ B cells. These studies will dissect the interplay between neutrophils and MZ B cells by taking advantage of unique cells and tissues from healthy individuals and patients with rare primary immunodeficiencies. Results from these studies may lead to the identification of novel neutrophil-targeting strategies that may enhance vaccine-induced antibody responses by harnessing the B cell helper activity of NBH cells.