Testing an alternative model of central B cell tolerance

测试中央 B 细胞耐受的替代模型

• 批准号: 9332820
• 负责人: Roberta Pelanda
• 金额: $ 19.44万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-10 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9332820
• 关键词: Affinity; Antibodies; Antigen Presentation; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B cell repertoire; B-Lymphocytes; Binding; Blood Circulation; Bone Marrow; Cell Differentiation process; Cell Survival; Cells; Clonal Deletion; Development; Disease; Endocytosis; Event; Excision; Flare; Goals; Immunoglobulins; In Vitro; Individual; Lead; Length; Ligands; Lupus; Mature B-Lymphocyte; Mediating; Methods; Modeling; Mouse Strains; Mus; Patients; Phenotype; Physiologic pulse; Predisposition; Process; Public Health; Receptor Inhibition; Receptor Signaling; Receptors, Antigen, B-Cell; Research; Signal Transduction; T-Lymphocyte; Testing; Transgenic Mice; Yin-Yang; autoreactive B cell; autoreactivity; base; central tolerance; cytokine; experimental study; improved; in vivo; novel; receptor; receptor internalization; synthetic protein

Project Summary Autoreactive B cells are key contributors to autoimmune diseases. Despite a stringent central tolerance checkpoint, some B cells expressing autoreactive antibodies leave the bone marrow and enter the circulation. These B cells, moreover, break central tolerance in higher numbers in autoimmune individuals, and have been described to participate in disease flares in lupus patients. Despite the importance of newly generated autoreactive B cells in autoimmunity, how and why autoreactive B cell precursors undergo or escape central tolerance remains poorly understood. The current model of central tolerance takes into account only the strength of antigen-induced BCR signaling where increasing binding to antigen increases BCR signaling and the level of tolerance (a so called “negative” model). This model, however, does not take into account the contribution of tonic BCR signaling, a ligand-independent signaling event that promotes differentiation of immature B cells and survival of mature B cells. In fact, removal of tonic BCR signals in nonautoreactive immature B cells causes a phenotype similar to that of autoreactive cells undergoing tolerance, including the induction of receptor editing. This and other findings do not fit well the “negative” model of B cell tolerance. Our goal is to re-evaluate the model of central B cell tolerance to develop one that more accurately reflects all experimental observations. Specifically, we propose to test two alternative models of central tolerance (“yin- yang” and “positive”) where tonic BCR signaling in combination or not with antigen-induced BCR signaling regulates receptor editing and cell differentiation in developing autoreactive B cells. Experiments will also test how the duration and amount of BCR stimulation, and the ensuing Ag-induced BCR internalization contribute to central B cell tolerance. The proposed studies are significant because they will lead to a better understanding of the fundamental processes regulating the development of autoreactive B cells and autoantibodies that contribute to autoimmune disorders, and why the B cell repertoire of some individuals is more autoreactive than others.

项目摘要 自动反应性B细胞是自身免疫性疾病的关键因素。尽管中央宽容严格 检查点，一些表达自动反应性抗体的B细胞离开骨髓并进入循环。 此外，这些B细胞在自身免疫性个体中打破了中央耐受性，并且已经存在 被描述为参与狼疮患者的疾病耀斑。尽管很重要 自身免疫中的自动反应性B细胞，自动反应性B细胞前体如何以及为什么逃脱中央 耐受性仍然很少理解。当前的中央公差模型仅考虑 抗原诱导的BCR信号的强度，其中增加与抗原的结合增加了BCR信号传导和 公差水平（所谓的“负”模型）。但是，该模型没有考虑到 补品BCR信号的贡献，这是一种与配体无关的信号事件，促进了分化的 未成熟的B细胞和成熟B细胞的存活。实际上，去除非辅助性中的补品BCR信号 未成熟的B细胞引起的表型类似于具有耐受性的自动反应性细胞，包括 诱导受体编辑。该发现和其他发现不太适合B细胞耐受性的“负”模型。我们的 目标是重新评估中央B细胞耐受性的模型，以更准确地反映出所有模型 实验观察。特别是，我们建议测试两个中央公差的替代模型（“ yin-- yang和“阳性”）其中滋补bcr信号与抗原诱导的BCR信号结合不 调节自动反应性B细胞中的受体编辑和细胞分化。实验也将测试 BCR刺激的持续时间和数量以及随之而来的AG诱导的BCR内在化有助于 到中央B细胞的耐受性。拟议的研究很重要，因为它们将导致更好 了解应对自动反应性B细胞发展的基本过程和 导致自身免疫性疾病的自身抗体，以及某些人的B细胞曲目为什么 比其他人更自动反应。