Inducible Regulatory B cells IBREG

描述(由申请人提供)：B细胞以其产生抗体的特殊能力为特征。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细胞通常并不被认为是细胞因子的主要来源。然而，很明显，B细胞也可以产生广泛的细胞因子，特别是在炎症条件下。我们已经确定了可诱导的B细胞亚群，它是在炎症反应中发展起来的，并通过产生细胞因子来帮助改善持续的炎症。细胞因子产生、可诱导的调节性B细胞被称为iBreg，它不仅具有控制炎性免疫反应的能力，而且还具有抑制动脉粥样硬化和肿瘤免疫的能力。这些发现表明，在几种病理生理条件下，效应性和调节性B细胞共存。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基础。我们的初步研究已经确定了一种先前未知的独特的IgM+MHC IIbright B细胞群，它存在于正常大肠中，并在炎症反应中显着扩张。独特的B细胞来自未成熟的过渡性和再循环的幼稚B2细胞池，可以在不分化为浆细胞的情况下进行扩增。有趣的是，它们都是以抗原非依赖的方式发展的，也以SLPI(分泌性白细胞蛋白酶抑制物)和BAFF(肿瘤坏死因子家族的B细胞激活因子受体)依赖的方式发展。这些独特的B细胞与iBreg有一些表型和功能特征，而iBreg以前被证明只在炎症条件下才在肠系膜淋巴结(MLN)中发育。基于这些数据，我们假设独特的肠道B细胞是iBreg的前体，在SLPI(用于抑制典型的NFkB途径，NFkB1)和BAFF(用于激活替代NFkB途径，NF：B2)的存在下，iBreg从大肠中的未成熟/幼稚的B细胞分化出来，然后进入MLN，在那里它们的免疫调节功能得到充分发挥。这项拨款申请旨在研究为什么MHC类IIbright B细胞在炎症竞争中特异地扩张，它们是如何发展的，它们是否代表iBreg的直接前体，以及MHC类IIbright B细胞衍生的iBreg的免疫调节能力是如何激发的。

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.