Bright misregulation and autoimmunity

The transcription factor Bright is tightly regulated throughout B cell differentiation in the mouse and human. Constitutive over-expression of Bright in the B lineage of FVB/N mice was associated with antinuclear antibodies (ANA) and other conditions consistent with a loss of B cell tolerance. However, recent studies suggest that the FVB/N strain displays traits commonly associated with autoimmune disease and strengthen the need for verification of the phenotype on more than one genetic background. Therefore, B cells from Bright transgenic mice on the non-autoimmune prone C57Bl/6 background (BrTg) were analyzed for defects at common B cell tolerance checkpoints. BrTg mice exhibit Btk-dependent production of ANAs and characteristics shared by other lupus-prone models such as polyclonal autoreactivity, hyper-responsiveness, and altered B cell development. However, key tolerance checkpoints that are defective in other lupus models remained intact in these mice. Receptor editing appeared normal as revealed by lambda and kappa light chain ratios. ANAs did not result from increased longevity or numbers of early transitional B cells. Furthermore, anergy appeared intact based on absolute cell numbers. These data suggest that Bright overexpression contributes to breaches in tolerance in alternative ways. In BrTg mice, mature marginal zone (MZ) B cells were increased and follicular (FO) B cells were decreased. Interestingly, the FO B cells that developed in these mice were hyper-responsive to proliferative signals and showed a gene expression profile similar to that of MZ B cells. These data demonstrate that Bright misregulation was sufficient to cause breaches in B cell tolerance and defects in B cells such that mature B cell development was biased towards the MZ. These results are intriguing given MZ B cells harbor autoreactive clones and are expanded in other lupus models. Together, these data highlight the importance of understanding how Bright expression is regulated. A promoter bashing approach identified two regulatory regions containing repressive or enhancing activity in a cloned putative Bright promoter sequence. Overall, we conclude that Bright transgenic animals are a novel model to study B cell tolerance. Together, these studies will provide a link between Bright misregulation and autoimmune disease.