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R01资助的正在进行的工作的结果所驱动的。这些正在进行的研究旨在深入了解B细胞与外源抗原和自身抗原反应的方式（“双反应性”B细胞）被调节以防止自身免疫的诱导。作为我们对这些研究的长期承诺的一部分，我们试图产生一种新的VH“敲入”小鼠，使用VH基因部分编码染色质/膦酸盐“双反应性”抗体。我们预计这个项目需要几年的时间，因此在RO1中没有讨论这个问题。然而，幸运的是，我们第一次尝试就成功了。这个新的基因敲入线可能为我们提供了在免疫应答之前和期间对染色质/砷酸盐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在生发中心受到外周耐受“检查点”的影响，以及该检查点是否通过克隆缺失、受体编辑或V基因超突变调控来运作。

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.