2006 Cell Signaling
2016 Genetics, DNA
How does a specific gene, Ets1, increase patients' production of autoantibodies?
The study and what it means to patients
“Our research will explore why in some lupus patients a specific gene, Ets1, produces lower levels of a protein that helps restrict production of autoantibodies. With this insight, we aim to identify ways potential treatments could restore proper levels of this important protein and reduce autoantibody production in lupus patients.”
The Ets1 gene creates a protein also called Ets1that regulates how B cells block the production of antibodies. As a result, some lupus patients who have low levels of this protein have high levels of autoantibodies. Our research will improve our understanding of why some patients who have low levels of the Ets1 protein have increased levels of autoantibodies, how B cells from human lupus patients with low levels of the Ets1 protein are different from normal B cells and what happens when we increase the Ets1 protein to try and affect B cells. We can then suggest ways we might restore the Ets1’s levels and develop new treatments for lupus.
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.
Recent studies indicate that some people with lupus get better with a lowering of the number of B cells in their body. Normally, B cells produce antibodies designed to protect against foreign substances.
Working in mice, Dr. Garett-Sinha has found that a particular protein-Ets-1-limits the output of antibodies in B cells, including the kind of self-reactive antibodies that cause so much damage in lupus.
With LRI funding, she will further investigate this protein and hopefully generate findings that help in designing effective and less toxic therapies that control the B cell output of autoantibodies.
Ets-1 regulates plasma cell differentiation by interfering with the activity of the transcription factor Blimp-1. John, S.A., Clements, J.L., Russell, L.M. and Garrett-Sinha, L.A. 2008. J Biol Chem. 283:951-62.
IL-17 and the Th17 lineage in systemic lupus erythematosus. Garrett-Sinha, L.A., John, S.A. and Gaffen, S.L. 2008. Curr Opin Rheumatol. 20:519-25.
Blimp1: A conserved transcriptional repressor critical for differentiation of many tissues. John SA, Garrett-Sinha LA. Exp Cell Res. 2008 Dec 3.
2008 IP3 receptor-mediated Ca++ release in naive CD4 T cells dictates their cytokine program. Nagaleekar V, Diehl S, Juncadella I, Charland C, Garrett-Sinha, LA, Muthusamy N, Anguita J, Rincon M. J Immunol. 181:8315-22.
Dr. Garrett-Sinha is the subcontractor for an Alliance for Lupus Research award given to Dr. Sarah Gaffen at the University of Pittsburgh. As a subcontractor, Dr. Garrett-Sinha receives $6,600 to participate in the study aimed at defining signaling cascades downstream of the IL17R-C subunit, and to explore the possibility of interrupting IL-17 signaling as a therapeutic mechanism to treat lupus.