Publications

In the event of a radiation accident or attack, it will be imperative to quickly assess the amount of radiation exposure to accurately triage victims for appropriate care. RNA-based radiation dosimetry assays offer the potential to rapidly screen thousands of individuals in an efficient and cost-effective manner. However, prior to the development of these assays, it will be critical to identify those genes that will be most useful to delineate different radiation doses. Using global expression profiling, we examined expression changes in nonimmortalized T cells across a wide range of doses (0.15-12 Gy). Because many radiation responses are highly dependent on time, expression changes were examined at three different times (3, 8, and 24 h). Analyses identified 61, 512 and 1310 genes with significant linear dose-dependent expression changes at 3, 8 and 24 h, respectively. Using a stepwise regression procedure, a model was developed to estimate in vitro radiation exposures using the expression of three genes (CDKN1A, PSRC1 and TNFSF4) and validated in an independent test set with 86% accuracy. These findings suggest that RNA-based expression assays for a small subset of genes can be employed to develop clinical biodosimetry assays to be used in assessments of radiation exposure and toxicity.

In his clonal selection theory, Frank Macfarlane Burnet predicted that autoreactive lymphocytes are deleted to prevent autoimmunity. This and other principles of lymphocyte behavior outlined by Burnet guided many studies that lead to our current understanding of thymic selection. Thus, when the genetic mutation responsible for autoimmune polyglandular syndrome type 1 was mapped to the autoimmune regulator (AIRE) gene, and Aire was found to be highly expressed in thymic epithelium, studying the role of Aire in negative selection made sense in the context of modern models of thymic selection. We now know Aire is a transcription factor required for the expression of many tissue-specific antigens (TSAs) in the thymus. In the absence of functional Aire, human patients and mice develop multi-organ autoimmune disease because of a defect in thymic negative selection. In addition to its role in the thymus, recent work in our lab suggests that extrathymic Aire-expressing cells have an important role in the clonal deletion of autoreactive CD8+ T cells. In this review, we summarize the latest studies on thymic and peripheral Aire-expressing cells, as well as other TSA-expressing stromal cell populations in peripheral lymphoid organs. We also discuss theoretical differences in thymic and peripheral Aire function that warrant further studies.