Intrinsic and extrinsic control of B cells tolerance

描述（由申请人提供）：未成熟阶段是B细胞能够识别和响应多态抗原的第一个阶段。因此，这一阶段标志着内源性或自身抗原可以被识别，从而提供了最初的机会来清除有可能引发自身免疫性疾病的自反应性B细胞。我们最近发现，未成熟B细胞上的BCR在聚集后不能区隔成脂筏，这与这些细胞中的信号传导失败有关。基于我们的累积数据，我们认为BCR刺激的未成熟B细胞的内在或“硬连接”反应是凋亡，这表明缺失是这一阶段耐受的默认机制。然而，很明显，删除并不是消除自反应特异性的唯一机制。我们已经在骨髓中发现了一种细胞成分，它可以保护bcr刺激的B细胞免于凋亡，并将反应定向到持续的Ig轻链重组和受体编辑。这些研究的后续工作将集中在确定这些体外过程的机制以及确定它们在体内的免疫学相关性。提出了三个具体目标：(1)确定BCR在未成熟B细胞中是否无法区隔成脂筏，从而阻止了BCR信号的持续传递；(2)确定未成熟和成熟B细胞亚群中质膜胆固醇发育调控差异的机制，以及它们在BCR区隔化和BCR聚集后细胞命运决定中的作用；(3)确定BM保护细胞（BMPC）的细胞身份，确定其调节抗原刺激的未成熟B细胞凋亡反应的能力的细胞和生化过程，以及其在调节受体编辑中的特定作用。总之，这些研究将解决与诱导和维持免疫细胞对自身抗原耐受性相关的问题，并定义在B细胞发育的不同阶段，BCR信号传导所涉及的细胞命运决定过程。

DESCRIPTION (provided by applicant): The immature stage is the first at which the B cell can recognize and respond to polymorphic antigen. As such, this stage marks the point at which endogenous or self-antigens can be recognized thereby providing the initial opportunity to purge the repertoire of self-reactive B cells with the potential to initiate autoimmune disease. We have recently found that the BCR on immature B cells fails to compartmentalize into lipid rafts following aggregation and that this is associated with abortive signaling in these cells. We have argued based on our cumulative data, that the intrinsic or "hardwired" response of BCR stimulated immature B cells is apoptotic, suggesting that deletion is the default mechanism for tolerance at this stage. However, it is quite clear that deletion is not the sole mechanism for the elimination of self-reactive specificities. We have identified a cellular constituent in the bone marrow that can protect the BCR-stimulated B cell from apoptosis and redirect the response to continued Ig light chain recombination and receptor editing. The proposed continuation of these studies will focus on defining the mechanisms underlying these processes in vitro as well as to establish their immunological relevance in vivo. Three specific aims are proposed: (1) To determine if the intrinsic inability of the BCR to compartmentalize into lipid rafts in immature B cells prevents sustained BCR signaling; (2) To define the mechanisms accounting for developmental-regulated difference in plasma membrane cholesterol in immature and mature B cell subsets and their role in determining BCR compartmentalization and cell fate decisions consequent to BCR aggregation; and (3) To define the cellular identity of the BM protective cell (BMPC), the cellular and biochemical processes that determine its ability to modulate the apoptotic response of antigen-stimulated immature B cells, and its specific role in regulating receptor editing. Together, these studies will address issues relevant to the induction and maintenance of immune cell tolerance to self-antigens and define processes involved in cell fate decisions following BCR signaling at distinct stages of B cell development.