The transcription factor Ets1 is highly expressed in B cells and plays a crucial role in regulating their differentiation into antibody-secreting cells (ASCs). Mice lacking Ets1 develop a lupus-like autoimmune disease and SNPs in the human ETS1 gene are associated with lupus susceptibility. We have recently defined Ets1 target genes in B cells. Intriguingly, several of the identified targets are involved in autoimmune responses in mice and/or humans. These include Ptpn22, Slamf6 (Ly108), Cr2 (CD21) and Stat4. The objective of this proposal is to understand how these target genes may contribute to the functions of Ets1 in B cells in mice and humans. The specific aims of the proposal are (1) to determine if restoring normal expression of Ptpn22, Cr2, Stat4 or Slamf6 reverses Ets1-/- B cell phenotypes, (2) to determine if a reduced level of Ets1 cooperates with altered Slamf6 expression to drive autoimmune symptoms and (3) to determine if Ets1 regulates similar target genes in human B cells as those we’ve identified in mouse B cells. The significance of these aims lies in the fact that they will allow us to predict the effects of alterations in Ets1 expression on human B cell responses in lupus.