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。尽管有严格的中央耐受性 在检查点，一些表达自身反应性抗体的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以更高的数量破坏中枢耐受性，并且已经被免疫性疾病控制。 被描述为参与狼疮患者的疾病爆发。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细胞前体如何以及为什么经历或逃避中枢免疫， 人们对容忍的认识仍然很差。目前的中央公差模型只考虑了 抗原诱导的BCR信号传导的强度，其中增加与抗原的结合增加BCR信号传导， 容忍水平（所谓的“负面”模型）。然而，这个模型没有考虑到 紧张性BCR信号传导的贡献，这是一种促进细胞分化的配体非依赖性信号传导事件。 未成熟B细胞和成熟B细胞的存活。事实上，在非自身反应性中去除紧张性BCR信号， 不成熟的B细胞引起与经历耐受的自身反应性细胞相似的表型，包括 受体编辑的诱导。这一发现和其他发现并不完全符合B细胞耐受性的“阴性”模型。我们 我们的目标是重新评估中枢B细胞耐受性模型，以开发一种更准确地反映所有 实验观察。具体来说，我们建议测试两种替代模型的中央耐受性（“阴- 阳”和“阳性”），其中强直性BCR信号传导与抗原诱导的BCR信号传导组合或不组合 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内化如何有助于 到中枢B细胞耐受性。拟议的研究是重要的，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， 导致自身免疫性疾病的自身抗体，以及为什么某些个体的B细胞库 比其他人更有自我反应性

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.