Mechanisms of Regulatory B Cell Function

调节 B 细胞功能的机制

基本信息

批准号：
8726510
负责人：
Bonnie N Dittel
金额：
$ 39.25万
依托单位：
VERSITI WISCONSIN, INC.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8726510
关键词：
Activities of Daily Living Address Adverse effects Animal Model Antibodies Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity B-Lymphocytes BLR1 gene Binding Biological Biological Assay CCR6 gene CD36 gene Cell Communication Cell Count Cell Proliferation Cell physiology Cells Cessation of life Data Development Disease Employee Strikes Exhibits Experimental Autoimmune Encephalomyelitis Glucocorticoids Goals Homeostasis Human IgG1 Immune response Immunoglobulin D In Vitro Inflammation Interleukin-12 Knowledge Life Ligands Lymphocyte Activation MS4A1 gene Maintenance Mechanics Mediating Molecular Molecular Profiling Multiple Sclerosis Mus Myelin Basic Proteins Neuraxis Outcome Patients Phenotype Population Proteins Recovery Regulatory T-Lymphocyte Reporting Role Severities Signal Transduction Signaling Protein T-Lymphocyte Testing Transgenic Mice Tumor Necrosis Factor Receptor Wit base cell type in vivo mouse model novel prevent protein expression reconstitution

项目摘要

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a lifelong debilitating illness with no cures and limited treatment options. Thus new treatments are greatly needed. Using the animal model of MS, experimental autoimmune encephalomyelitis (EAE), we were the first to demonstrate that B cells were required for recovery from disease. These data revealed the potential of harnessing regulatory B cells or Breg for cellular based therapies. However, one major hurdle before this can be accomplished is a better understanding of how Breg control the extent of autoimmune inflammation. We have recently discovered that Breg control both the onset and severity of EAE by the homeostatic maintenance of CD4+Foxp3+ T regulatory cell (Treg) numbers. We found that when B cells were either genetically deficient (?MT) or depleted with anti-CD20 there was a significant reduction in the absolute number of Treg in mice. As for ?MT mice, B cell depletion with anti-CD20 abrogated EAE recovery. Reconstitution of ?MT with WT splenic B cells resulted in the homeostatic expansion of Treg and the subsequent recovery from EAE. These cumulative data solidify a role for Breg in controlling EAE via the maintenance of Treg cell numbers. These data are consistent with the known role of Treg in keeping autoimmune responses in check. When we investigated the mechanism whereby Breg regulate Treg numbers, we discovered that their expression of GITRL and SAP contributed to their ability to promote Treg proliferation and/or promote EAE recovery. The known role for SAP in promoting T cell:B cell interactions in adaptive immune responses suggests that Breg and Treg also directly interact. However, virtually nothing is known regarding the mechanics and biological outcomes of such interactions. When we investigated the phenotype of Breg with the capability of controlling Treg homeostasis we found that a novel population of follicular cells wit IgDlow-neg expression exhibited Breg activity. This population of follicular B cells has never been described indicating that we discovered a novel Breg phenotype. From the above cumulative data, we hypothesize that follicular IgD low-neg Breg control autoimmunity by promoting Treg homeostatic expansion via direct cell-cell interactions facilitated by SAP expression in B cells allowing GITRL:GITR binding promoting Treg proliferation. The testing of this hypothesis will allow us to understand the molecular mechanisms whereby Breg control autoimmunity with the goal of harnessing this knowledge for the development of new therapies. This hypothesis and goal will be achieved in three specific aims: Aim 1: Determine the role of GITRL and SAP in the functional ability of Breg to control Treg homeostasis; Aim 2: Determine the mechanism whereby SAP facilitates Breg:Treg interactions and Aim 3. Characterization and functional analysis of a novel IgDlow-neg follicular Breg.

描述（由申请人提供）：多发性硬化症（MS）是终生使人衰弱的疾病，没有治疗方法和有限的治疗选择。因此，非常需要新的治疗方法。使用MS的动物模型，实验性自身免疫性脑脊髓炎（EAE），我们是第一个证明B细胞从疾病中恢复需要B细胞的人。这些数据揭示了利用调节性B细胞或Breg用于基于细胞的疗法的潜力。但是，在此之前，一个主要的障碍是更好地理解布雷格如何控制自身免疫性炎症的程度。我们最近发现，布雷格通过CD4+ FOXP3+ T调节细胞（Treg）数字的稳态维护控制EAE的发作和严重程度。我们发现，当B细胞在遗传上缺乏（？mt）或用抗CD20耗尽时，小鼠的绝对数量显着减少。至于？mt小鼠，抗CD20的B细胞耗竭废除了EAE恢复。与WT脾脏B细胞的重建导致Treg的稳态扩张以及随后从EAE恢复。这些累积数据巩固了布雷格通过维持Treg细胞数量控制EAE的作用。这些数据与Treg在检查自身免疫反应中的已知作用一致。当我们研究布雷格调节Treg数字的机制时，我们发现它们的Gitrl和SAP的表达有助于它们促进Treg增殖和/或促进EAE恢复的能力。 SAP在促进T细胞中的已知作用：自适应免疫反应中B细胞相互作用表明Breg和Treg也直接相互作用。但是，关于这种相互作用的机械和生物学结果，几乎一无所知。当我们研究布雷格的表型具有控制Treg稳态的能力时，我们发现新的卵泡细胞具有Igdlow-neg-neg表达的表达，表现出Breg活性。从未描述过这种卵泡B细胞的种群，表明我们发现了一种新的Breg表型。从上述累积数据中，我们假设卵泡IgD低结局控制自身免疫通过通过直接的细胞 - 细胞相互作用促进TREG稳态扩张，而SAP在B细胞中促进了B细胞中的SAP表达，允许GITRL：GITR：GITR结合促进Treg的增殖。该假设的检验将使我们能够理解布雷格控制自身免疫的分子机制，目的是利用这一知识来开发新疗法。这一假设和目标将在三个特定目标中实现：目标1：确定gitrl和SAP在Breg控制Treg稳态的功能能力中的作用； AIM 2：确定SAP促进Breg的机制：Treg相互作用和目标3。对新型Igdlow-Neg-neg Follicular Breg的表征和功能分析。