A New Model for Studying Antigen-driven B cell Tolerance

描述(由申请人提供)：本提案中描述的实验是由目前由R01资助的正在进行的工作的结果激励的。这些正在进行的研究旨在深入了解与外来抗原和自身抗原反应的B细胞(“双反应”B细胞)如何被调节以防止诱导自身免疫。作为我们长期致力于这些研究的一部分，我们试图利用VH基因部分编码染色质/Arsonate“双重反应”抗体，产生一种新的VH“敲击”小鼠。我们预计这个项目需要几年的时间，因此，在RO1中没有讨论这一点。然而，幸运的是，我们第一次尝试就成功了。这一新的敲击线可能为我们提供了在免疫反应之前和期间对染色质/Arsonate B细胞的发育命运进行非常高分辨率实验的能力。在这里，我们建议评估“双反应性”B细胞克隆的后代是否受到生发中心的外周耐受“检查点”的影响，以及该检查点是否通过克隆性缺失、受体编辑或调节V基因的过度突变而起作用。

DESCRIPTION (provided by applicant): The experiments described in this proposal were motivated by the results of ongoing work currently being funded by an R01. These ongoing studies are designed to provide insight into the manner in which B cells reactive with both foreign and autoantigens ("dual reactive" B cells) are regulated to prevent the induction of autoimmunity. As part of our long term commitment to these studies, we attempted to generate a new line of VH "knockin" mice, using a VH gene that partially encodes chromatin/arsonate "dual reactive" antibodies. We expected this venture to take several years and, as such, this was not discussed in the RO1. However, to our good fortune we succeeded on the first attempt. This new knockin line may provide us with the ability to conduct very high resolution experiments on the developmental fate of chromatin/arsonate B cells both prior to and during the immune response. Here, we propose to evaluate whether the progeny of "dual reactive" B cells clones are subjected to a peripheral tolerance "checkpoint" in the germinal center, and whether this checkpoint operates via clonal deletion, receptor editing, or regulation of V gene hypermutation.