B cells can be activated to differentiate into antibody-secreting plasma cells (PCs), a process crucial for normal immune function. However, unregulated B cell differentiation can lead to the production of autoantibodies and the development of autoimmune diseases such as systemic lupus erythematosus (SLE). Therefore, B cell differentiation is under tight control. Stimulation of B cells via the B cell receptor (BCR)or Toll-like receptors (TLRs) induces activation, proliferation and differentiation by influencing the expression and activity of transcription factors in the nucleus of the B cell. Counterbalancing these activation pathways are inhibitory signaling pathways dependent on a number of cell surface receptors (for example, CD22 and Siglec-G) that are phosphorylated by the tyrosine kinase Lyn. This results in the recruitment of phosphatases such as SHP1 that reverse activation of signaling proteins in the BCR and TLR cascades. Better understanding of the negative and positive pathways controlling B cell differentiation will provide new clues into how they might be manipulated to limit B cell activation in autoimmune diseases. We have recently identified the transcription factor Ets1 to be a crucial target that is downregulated by positive BCR or TLR signaling, and whose expression is maintained by inhibitory signaling cascades. Because Ets1 blocks B cell differentiation to plasma cells, its regulation is a key event in determining the fate of B cells upon stimulation. In the absence of Ets1 or Lyn, which maintains Ets1 expression, mice accumulate plasma cells and autoantibodies. Therefore maintenance of appropriate Ets1 levels in B cells is important to prevent autoimmunity. In this proposal we will define the causes and consequences of Ets1 downregulation in B cells.
In Aim 1, we will further characterize the mechanisms controlling Ets1 expression in B cells.
In Aim 2, we will determine the consequences of failure to downregulate Ets1 in B cells for both humoral immune responses and the development of autoimmunity using mice in which Ets1 can be inducibly expressed in B cells.
In Aim 3, we will determine whether Ets1 is similarly downregulated by activating signals in primary human B cells, whether SLE- associated Ets1 polymorphisms affect control of Ets1 expression, and whether B cells from SLE patients demonstrate reduced Ets1 expression or more efficient Ets1 downregulation. Taken together, these studies will further our understanding of the molecular mechanisms of B cell differentiation and may reveal novel therapeutic approaches for diseases such as SLE.

Public Health Relevance

B cells differentiate into plasma cells, which secrete antibodies that are important for the immune system to eliminate pathogens. However, if this process is not tightly controlled, autoantibodies can be produced which then cause inflammation and tissue damage. Here we will characterize a signaling pathway in B cells that controls plasma cell differentiation and determine how it is dysregulated in autoimmune disease. These studies may shed light on new therapeutic approaches to either increase antibodies to promote immune responses against harmful pathogens or decrease autoantibodies in autoimmune diseases such as lupus.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Johnson, David R
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University of Texas Sw Medical Center Dallas
Internal Medicine/Medicine
Schools of Medicine
United States
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Davis, Laurie S; Reimold, Andreas M (2017) Research and therapeutics-traditional and emerging therapies in systemic lupus erythematosus. Rheumatology (Oxford) 56:i100-i113
Satterthwaite, Anne B (2017) Bruton's Tyrosine Kinase, a Component of B Cell Signaling Pathways, Has Multiple Roles in the Pathogenesis of Lupus. Front Immunol 8:1986
Zharkova, Olga; Celhar, Teja; Cravens, Petra D et al. (2017) Pathways leading to an immunological disease: systemic lupus erythematosus. Rheumatology (Oxford) 56:i55-i66
Garrett-Sinha, Lee Ann; Kearly, Alyssa; Satterthwaite, Anne B (2016) The Role of the Transcription Factor Ets1 in Lupus and Other Autoimmune Diseases. Crit Rev Immunol 36:485-510