Testing an alternative model of central B cell tolerance

项目摘要 自身反应性B细胞是自身免疫性疾病的关键因素。尽管中央有严格的宽容 检查点，一些表达自身反应抗体的B细胞离开骨髓进入循环。 此外，这些B细胞在自身免疫个体中以更高的数量打破了中枢耐受，并且一直是 被描述为参与狼疮患者的疾病发作。尽管新产生的 自身免疫中的自身反应性B细胞，自身反应性B细胞前体如何和为什么经历或逃逸中枢 对宽容的理解仍然很少。当前的中心公差模型只考虑了 抗原诱导的BCR信号的强度，其中与抗原的结合增加增加了BCR信号和 容忍程度(所谓的“负面”模式)。然而，该模型没有考虑到 强直刺激BCR信号的作用，这是一种促进分化的配体非依赖的信号事件 未成熟B细胞和成熟B细胞的存活。事实上，在非自身反应中，强直BCR信号的去除 未成熟的B细胞导致一种与经历耐受的自身反应细胞相似的表型，包括 受体编辑的诱导。这一发现和其他发现并不能很好地符合B细胞耐受的“负”模型。我们的 目标是重新评估中央B细胞耐受模型，以开发一个更准确地反映所有 实验观察。具体地说，我们建议测试两种可供选择的中枢耐受模型(“阴- 阳“和”阳性“)，其中强直的bcr信号与抗原诱导的bcr信号结合或不结合 调节自身反应性B细胞发育中的受体编辑和细胞分化。实验还将测试 BCR刺激的持续时间和数量，以及随后的Ag诱导的BCR内化是如何起作用的 到中枢B细胞耐受性。拟议的研究具有重要意义，因为它们将导致更好的 了解调节自身反应性B细胞发育的基本过程和 导致自身免疫性疾病的自身抗体，以及为什么一些人的B细胞库 比其他人更具自我反应性。

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.