Inducible Regulatory B cells IBREG

诱导型调节性 B 细胞 IBREG

基本信息

批准号：
8768445
负责人：
HANS-CHRISTIAN REINECKER
金额：
$ 38.28万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-01 至 2017-08-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：B细胞的特征在于它们产生抗体的特定能力。因此，抗体介导的免疫反应是B细胞发挥的主要机制。实际上，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。但是，很明显，B细胞还可以产生广泛的细胞因子，尤其是在炎症条件下。我们已经确定了可诱导的B细胞子集，该子群会响应炎症而发展，并通过细胞因子的产生来改善持续的炎症。称为“ IBREG”的产生细胞因子的，可诱导的调节性B细胞不仅具有控制炎症性免疫反应的能力，还可以抑制动脉粥样硬化和肿瘤免疫。这些发现表明在几种病理生理条件下效应子和调节性B细胞共存。该项目的长期目标是确定导致IBREG开发的机制，以便在利用IBREG来改善几个健康问题方面提供理由。我们的初步研究已经确定了先前未识别的独特的IgM+ MHC类IIBRIGHT B细胞群，该群体位于正常的大肠中，并因炎症而显着扩展。从不成熟的过渡和循环幼稚的B2细胞库中募集独特的B细胞，并且可以扩展而不会分化为浆细胞。有趣的是，他们以抗原独立的方式和SLPI（分泌白细胞蛋白酶抑制剂）和BAFF（TNF家族的B受体）依赖性的方式发展。这些独特的B细胞与IBREG共享了一些表型和功能性特征，以前仅在炎症条件下仅在肠系膜淋巴结（MLN）中发展出来。基于这些数据，我们假设独特的肠道B细胞代表了IBREG的前体，在存在SLPI的情况下，该数据与大肠中未成熟/天真的B细胞区分开来引起。该赠款应用旨在调查为什么MHC类IIBRIGHT B细胞在炎症的竞赛中特别扩展，它们的发展方式，它们是否代表IBREG的直接前体以及MHC类IIBRIGHT B细胞衍生的IBREG的免疫调节能力如何被引起。