A New Model for Studying Antigen-driven B cell Tolerance

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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.

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