Systemic lupus erythematosus (SLE) is characterized by loss of tolerance to nuclear antigens, autoantibody production, and immune complex mediated damage to multiple organs. Mice deficient in two SLE susceptibility genes, the tyrosine kinase Lyn and the transcription factor Ets1, have remarkably similar phenotypes. These include B cell hyperactivity, early accumulation of IgM-secreting plasma cells, production of IgG autoantibodies, and immune complex deposition in the kidney. Preliminary results indicate that Ets1 expression is dramatically reduced in Lyn-/- B cells. Furthermore, decreased expression of both genes has been observed in PBMCs of SLE patients. Given that Ets1 is known to limit B cell terminal differentiation, we hypothesize that Lyn normally restricts the formation of autoreactive plasma cells by promoting expression of Ets1 in B cells. We propose to characterize the functional interaction between Lyn and Ets1 via the following Specific Aims: 1) to define the mechanism by which Lyn controls Ets1 expression, and 2) to determine the consequences of reduced Ets1 expression for the plasma cell accumulation and autoimmune phenotypes of Lyn-/- mice. These studies will define and characterize a previously unidentified interaction between two SLE susceptibility loci, potentially illuminating a novel pathway that can be targeted therapeutically.
Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease characterized by the production of antibodies against oneself, which then cause tissue damage. We propose to test the idea that two lupus susceptibility genes, Lyn and Ets1, work together in a molecular pathway to prevent the differentiation of B cells into autoantibody producing cells. Our studies may suggest ideas to allow targeting of this novel pathway with newly-designed therapeutic regimens designed to limit autoantibody secretion.
|Luo, Wei; Mayeux, Jessica; Gutierrez, Toni et al. (2014) A balance between B cell receptor and inhibitory receptor signaling controls plasma cell differentiation by maintaining optimal Ets1 levels. J Immunol 193:909-20|
|Garrett-Sinha, Lee Ann (2013) Review of Ets1 structure, function, and roles in immunity. Cell Mol Life Sci 70:3375-90|