Increased plasma cell differentiation, hyper-responsiveness to TLR9, and loss of peripheral B cell tolerance in mice lacking the transcription factor Ets-1
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Systemic Lupus Erythematosus (SLE) is a polygenic disease influenced by abnormalities in genes, environmental factors and the immune system. One of the critical factors contributing to the pathogenesis of SLE is dysregulated B cell activity leading to the production of autoantibodies and delivery of uncontrolled co-stimulatory help to T cells. In the current study we demonstrate that mice harboring a hypomorphic allele of the transcription factor Ets-1 develop lupus like disease characterized by hyperactive B cells, increased numbers of plasma cells, high titers of serum autoantibodies and immune complex deposition in end organs such as kidney. Our results show that Ets-1 is required for maintenance of peripheral B cell tolerance as Ets-1 p/p B cells that bear a transgenic BCR (anti-Hen Egg Lysozyme (HEL)) rapidly differentiate into anti-HEL secreting plasma cells upon chronic encounter with a soluble form of antigen (sHEL). Adoptive transfer experiments of Ets-1 deficient B cells into wild-type hosts reverses the activated state of Ets-1 p/p B cells, suggesting a role for B cell extrinsic factors in regulating the activated state. Consistent with these results transfer of wild-type B cells into Ets-1deficient host resulted in upregulation of activation markers. Ets-1 p/p B cells also have B cell intrinsic alterations that lead to their excessive differentiation into plasma cells. This is evidenced by the observation that they undergo enhanced plasmacytic differentiation in response to TLR7 and TLR9 ligands in vitro . To understand how Ets-1 regulates plasma cell formation in a B cell intrinsic manner, we focused on the mechanisms by which Ets-1 regulates pathways important for B cell differentiation. Our results demonstrate that Ets-1 physically associates with Blimp-1 "the master regulator of plasmacytic differentiation" resulting in an inhibition of Blimp-1 DNA binding. Moreover, Ets-1 can bind to the promoters of known Blimp-1 target genes and transactivate them leading to alleviation of Blimp-1 mediated repression of these genes. Our data support the notion that Ets-1 employs multiple mechanisms to prevent premature Blimp-1 expression and plasmacytic differentiation. Therefore downregulation of Ets-1 is a pre-requisite for efficient terminal differentiation of B cells. A better understanding of the cellular and molecular pathways by which Ets-1 regulates activation and terminal differentiation of B cells will shed light on the mechanisms underlying the pathogenesis of systemic autoimmune diseases such as SLE.