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区（MZ）B细胞之间的相互作用。MZ B细胞与循环系统相互作用，并通过T细胞非依赖性途径快速产生针对血源性病原体的保护性抗体，该途径仍然知之甚少。我们最近发现，人脾脏含有一种新的B细胞辅助中性粒细胞（NBH细胞）的亚群，其表型和基因表达谱与我们循环中存在的常规中性粒细胞（NC细胞）不同。在这个提议中，我们假设NC细胞通过IL-10依赖性途径（涉及滤泡周围窦状隙内皮细胞）进行脾重编程为NBH细胞。我们认为，窦状隙内皮细胞通过Toll样受体感受血生细菌后释放NC细胞吸引趋化因子和IL-10。我们还认为，IL-10从窦内皮细胞刺激NC细胞分化成NBH细胞具有强大的MZ B细胞刺激活性。将努力实现以下三个目标。目的1探讨脾窦内皮细胞通过Toll样受体感受细菌后诱导NC细胞重编程为NBH细胞的机制。目的2是阐明NBH细胞诱导MZ B细胞产生IgM、IgG和伊加类转换以及浆细胞分化的机制。目的3探讨NBH细胞诱导MZ B细胞V（D）J基因体细胞高突变和高亲和力抗体产生的机制。这些研究将通过利用来自健康个体和罕见原发性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会导致识别新的嗜中性粒细胞靶向策略，可以通过利用NBH细胞的B细胞辅助活性来增强疫苗诱导的抗体应答。 公共卫生相关性：MZ B细胞通过快速产生针对血液传播的微生物的抗体提供免疫保护。拟议的研究将探索一种新的免疫途径，涉及MZ B细胞和人脾脏中存在的独特嗜中性粒细胞群体之间的意外相互作用。我们的工作可能会导致开发新的疫苗策略，利用中性粒细胞的抗体诱导功能。!

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. PUBLIC HEALTH RELEVANCE: MZ B cells provide immune protection by rapidly producing antibodies against blood- born microbes. The proposed studies will explore a novel immune pathway involving an unexpected interplay between MZ B cells and a unique population of neutrophils present in the human spleen. Our work may lead to the development of novel vaccine strategies harnessing the antibody-inducing function of neutrophils. !