The interplay of signaling pathways and Ets factors in B cell differentiation
Ets1 is a transcription factor that is highly expressed in B cells and T cells. Ets1 is important in regulating B cell differentiation to antibody secreting plasma cells, and Ets1 deficient mice develop lupus-like autoimmune disease caused by uncontrolled plasma cell differentiation and autoantibody production. In the family of Ets transcription factors, Ets2 is closely related to Ets1 as they share similar structure and have almost identical DNA binding domains. Here we demonstrated that Ets1, but not Ets2, is highly expressed in B cells and lymphoid organs and can inhibit plasma cell differentiation in vitro and in vivo. Our data is consistent with the possibility that the central region of Ets1 located between the Pointed domain and the DNA binding domain, may be important in specifying unique functions for Ets1 as opposed to Ets2. Despite the importance of Ets1 in regulating B cell differentiation, the signaling pathways regulating the expression of Ets1 in B cells were poorly understood. We found that Ets1 is down-regulated in B cells by positive BCR or TLR signaling in which PI3 kinase, Btk, IKK2 and JNK are involved. Signaling through inhibitory receptors is required to counteract positive BCR signals and to maintain an optimal Ets1 level to prevent autoreactive B cell differentiation and autoimmunity. Deficiencies in inhibitory pathways, such as a loss of the tyrosine kinase Lyn, the phosphatase SHP1 or membrane receptors CD22 and/or Siglec-G, result in enhanced BCR signaling and decreased Ets1 expression. Importantly, deficiencies in either inhibitory signaling or in Ets1 expression have also been associated with human autoimmune diseases. Restoring Ets1 expression in Lyn- or SHP1-deficient B cells inhibits their enhanced plasma cell differentiation, suggesting the potential of using Ets1 as a target for treating autoimmune disease. The IL-17 pathway is important in inducing inflammation and tissue damage in different autoimmune diseases, but its involvement in the pathogenesis of the autoimmune disease found in Ets1 knockout mice remains to be defined. By examining IL-17RA and Ets1 double knockout mice, we unexpectedly found that IL-17 signaling plays a protective role in the development of disease in Ets1 knockout mice. Double knockout mice develop severe skin inflammation associated with elevated levels of antibody production and enhanced isotype switch of B cells to IgG and IgE. We hypothesize that the inflammatory environment induced by chronic skin disease can drive the more severe autoimmune disease in double knockout mice as compared to single knockout Ets1 deficient mice. Further studies should be performed to test this hypothesis and find out the mechanisms of the interplay of Ets1 and IL-17 signaling in skin immunity. Our study suggests that long-term anti-IL-17 therapy for treating autoimmune disease should be used with caution.