Mechanisms of B Cell Survival and Death

每天产生数百万个表达自身反应性抗体的B细胞。关于小鼠的最新研究 表明新生成的未成熟B细胞与骨髓中的自身抗原发生反应 受体编辑和无能，而受体编辑在外周的很大一部分中起作用 保护性抗体库。这些最近的研究还表明，克隆删除，曾经认为 中枢耐受的主要机制，可能是在以下情况下执行的默认途径 自身反应性B细胞不能编辑它们的受体。自身反应性B细胞是这一模型的固有特征 必须存活一定的时间才能成功编辑它们的受体。单元格的差异 自身反应性和非自身反应性未成熟B细胞的存活最终控制着这些细胞的选择 并塑造外周B细胞谱系。因此，我们认为自身反应的生存窗口 未成熟的B细胞，在此期间发生受体编辑是绝对必要的发展 保护性外周抗体库。是什么在生理上控制着未成熟B细胞的寿命 在受体编辑过程中尚不清楚，尽管可能涉及到抗和促凋亡的调节活性 小路。除了受体编辑，产生一种特异的、有效的和无害的B细胞 谱系还依赖于在非-免疫球蛋白基因表达时停止进一步免疫球蛋白基因重排的信号 自身反应性BCR和介导性免疫球蛋白等位基因/同型排斥。这些通路的功能障碍 可能导致过度克隆性缺失导致免疫缺陷或自身反应性B细胞存活 导致了自身免疫力。 现有证据表明，非自身反应性B细胞抗原受体的表达 对非自身反应(初级和编辑的，可能是无能的)生存很重要的紧张性信号 未成熟的B细胞以及免疫球蛋白等位基因/同型排斥。我们认为，核因子-KBA途径， Baff-R信号和Bcl2家族正确翻译B细胞抗原受体信号调节细胞 寿命与免疫球蛋白基因重组。我们已经创造了小鼠品系，它们要么产生非 自身反应性或自身反应性未成熟B细胞以及bcr和bcr水平异常的其他菌株 Baff-R表达。利用这些生物工具，我们建议确定核因子-KB途径和 BCL-2家族调节原代未成熟B细胞的寿命，BCR的相对贡献是什么 BAFF-R信号转导细胞存活并建立Ig等位基因/同型排斥。 这个项目将有助于我们理解是什么调节了发育中的B细胞的寿命， 具体取决于细胞是否具有自身反应能力。此外，我们的发现将表明 自身反应性B细胞逃避耐受并最终分化为 自身抗体形成细胞。

Millions of B cells are generated daily that express autoreactive antibodies. Recent studies in mice indicate that newly generated immature B cells that react with autoantigens in the bone marrowundergo receptor editing and anergy, and that receptor editing contributes to a significant fraction of the peripheral protective antibody repertoire. These recent studies also suggest that clonal deletion, once thought the predominant mechanism of central tolerance, is probably a default pathway that is carried out when autoreactive B cells are unable to edit their receptors. It is intrinsic to this model that autoreactive B cells must survive for a certain amount of time in order to successfully edit their receptors. Differences in cell survival of autoreactive and non-autoreactive immature B cells ultimately control the selection of these cells and shape the peripheral B cell repertoire. Therefore, we propose that the window of survival of autoreactive immature B cells during which receptor editing takes place is absolutely essential for the development of a protective peripheral antibody repertoire. What physiologically controls the lifespan of immature B cells during receptor editing is not yet clear although likely involves the regulated activity of anti- and pro-apoptotic pathways. In addition to receptor editing, the generation of a specific, effective and innocuous B cell repertoire also relies on the signals that stop further Ig gene rearrangement upon expression of non- autoreactive BCRs and mediate immunoglobulin allelic/isotypic exclusion. Dysfunctions in these pathways may cause either excessive clonal deletion resulting in immunodeficiency or survival of autoreactive B cells resulting in autoimmunity. Available evidences indicate that the expression of non-autoreactive B cell antigen receptors generates tonic signals that are important for survival of non-autoreactive (primary and edited and possibly anergic) immature B cells as well as immunoglobulin allelic/isotypic exclusion. We propose that the NF-KBpathway, BAFF-R signaling and the Bcl-2 family properly translate B cell antigen receptor signaling to regulate cellular lifespan and immunoglobulin gene recombination. We have created mouse strains that generate either non- autoreactive or autoreactive immature B cells, and other strains that have abnormal levels of BCR and BAFF-R expression. Using these biological tools, we propose to determine how the NF-KB pathway and the Bcl-2 family regulate the lifespan of primary immature B cells, and what is the relative contribution of BCR and BAFF-R signaling to cell survival and establishment of Ig allelic/isotypic exclusion. This project will contribute to our understanding of what regulates the lifespan of developing B cells, in particular depending on whether the cells are autoreactive or not. Moreover, our findings will indicate possible mechanisms by which autoreactive B cells escape tolerance and eventually differentiate into autoantibody-forming cells.