Inducible Regulatory B cells IBREG

描述（由申请方提供）：B细胞的特征在于其产生抗体的特异性能力。因此，抗体介导的免疫应答是B细胞发挥作用的主要机制。事实上，与T细胞相比，B细胞通常不被认为是细胞因子的主要来源。然而，很明显，B细胞也可以产生广谱的细胞因子，特别是在炎症条件下。我们已经鉴定了可诱导的B细胞亚群，其响应于炎症而发展，并通过产生细胞因子而有助于改善进行中的炎症。被称为“iBreg”的产生精氨酸的可诱导调节性B细胞具有不仅控制炎性免疫应答而且抑制动脉粥样硬化和肿瘤免疫的能力。这些结果表明，在几种病理生理条件下，效应和调节B细胞的共存。该项目的长期目标是确定导致iBreg发展的机制，以便为利用iBreg改善几个健康问题提供理论依据。我们的初步研究已经确定了一个以前未确定的独特的IgM+ MHC II类亮B细胞群体，居住在正常大肠和扩大显着的炎症反应。独特的B细胞从未成熟的过渡和再循环幼稚B2细胞库中募集，并且可以扩增而不分化成浆细胞。有趣的是，它们以抗原非依赖性方式和SLPI（分泌性白细胞蛋白酶抑制剂）和BAFF（来自TNF家族的B细胞活化因子的受体）依赖性方式发展。这些独特的B细胞与iBreg具有一些表型和功能特征，此前已证明iBreg仅在炎症条件下在肠系膜淋巴结（MLN）中发育。基于这些数据，我们假设独特的肠B细胞代表iBreg的前体，其在SLPI（用于抑制经典NF κ B途径，NF κ B1）和BAFF（用于激活替代NF κ B途径，NF：B2）存在下与大肠中的未成熟/幼稚B细胞分化，然后归巢到MLN中，在MLN中完全引发其免疫调节功能。该资助申请旨在研究为什么MHC II类B细胞在炎症竞争中特异性扩增，它们如何发育，它们是否代表iBreg的直接前体，以及如何引发MHC II类B细胞衍生的iBreg的免疫调节能力。 公共卫生相关性：我们身体中的生物反应由许多不同细胞类型的相互作用控制，以抑制不良健康状况的发展（1）。我们最近鉴定了一种称为iBreg的新型细胞亚群，其在炎症条件下特异性诱导，并且能够改善疾病（2-4）。该项目旨在剖析iBreg开发中涉及的机制。我们相信，这项研究将为开发一种新的免疫疗法提供重要的干预措施，以解决各种健康问题，包括感染，自身免疫性疾病，癌症和动脉粥样硬化。

DESCRIPTION (provided by applicant): B cells are characterized by their specific ability to produce antibodies. Therefore, the antibody-mediated immune responses are the major mechanism played by B cells. Indeed, as compared to T cells, B cells have not typically been considered to be a major source of cytokines. However, it is evident that B cells can also produce a wide spectrum of cytokines particularly under inflammatory conditions. We have identified inducible B cell subset that develops in response to inflammation and contributes to the improvement of ongoing inflammation through the production of cytokines. The cytokine-producing, inducible regulatory B cells termed "iBreg" possess the ability to not only control inflammatory immune responses but also inhibit atherosclerosis and tumor immunity. These findings suggest the coexistence of effector and regulatory B cells in several pathophysiological conditions. The long-term objective of this project is to identify the mechanism leading to iBreg development in order to provide a rationale in utilizing iBreg to improve several health problems. Our preliminary study has identified a previously unidentified unique IgM+ MHC class IIbright B cell population that resides in normal large intestine and expands markedly in response to inflammation. The unique B cells were recruited from immature transitional and recirculating naive B2 cell pools and could expand without differentiation into plasma cells. Interestingly, they developed both in antigen-independent manner and in SLPI (secretory leukocyte protease inhibitor) and BAFF (receptor of B cell activation factor from the TNF family)-dependent manners. These unique B cells shared some phenotypic and functional features with iBreg that has previously been shown to develop in mesenteric lymph nodes (MLN) only under inflammatory condition. Based on these data, we hypothesize that the unique intestinal B cells represent a precursor of iBreg, which differentiates from immature/naive B cells in the large intestine in the presence of SLPI (for inhibition of canonical NFkB pathway, NFkB1) and BAFF (for activation of alternative NFkB pathway, NF:B2) and then homes into MLN where their immune regulatory function is fully elicited. This grant application aims at investigating why MHC class IIbright B cells specifically expand in the contest of inflammation, how they develop, whether they represent an immediate precursor of iBreg, and how immune regulatory ability of MHC class IIbright B cell-derived iBreg is elicited. PUBLIC HEALTH RELEVANCE: Biological responses in our bodies are controlled by the interactions of many different cell types to suppress the development of undesirable health conditions (1). We have recently identified a novel cell subset termed iBreg, which is specifically induced under inflammatory conditions and is capable of improving the disease (2-4). This project aims at dissecting the mechanism involved in the development of iBreg. We believe that the study proposed would provide important intervention to develop a novel immune therapy for resolving diverse health problems, including infection, autoimmune diseases, cancer, and atherosclerosis.