2001 B Cells
2016 New treatments, Target Identification, B-cells
Could flares in lupus be caused by the body’s inability to dispose of dead and dying cells, and can we figure out how to repair this disposal mechanism by comparing patients with mild and severe lupus?
The study and what it means to patients
“We are exploring if lupus flares can be caused by the production of autoantibodies that occurs when the body is unable to properly dispose of dead and dying cells. If so, finding a way to correct this defect will provide a potential target for new treatments.
The clearance of dying cells is critical for the immune system to function properly, and the body’s inability to properly dispose of these cells has been implicated in lupus. We recently discovered that defects in the disposal of dead cells leads to the accumulation of antigens and the subsequent production of autoantibodies to these antigens, and that this promotes many of the disease symptoms associated with lupus in mice.
In our new research, we will evaluate whether lupus patients exhibit this defect in the disposal of dead cells. We will enroll patients with both mild to severe disease and assess whether they are able to properly dispose of dying cells. In addition, we will determine whether there is a correlation between the increased disposal of dying cells and a decrease in disease activity.
The removal of apoptotic debris is important in maintaining immune tolerance as defects in clearance provide a source of nuclear antigens that chronically stimulate the B-cell antigen receptor, Toll-like receptors, or form immune complexes that promote Fc[gamma]R signaling. Herein we propose cross sectional and longitudinal studies to define whether a lysosomal acidification defect that underlies murine autoantibody secretion, BAFF production, and lupus nephritis is relevant in human SLE. Our preliminary data show that macrophages from MRL/lpr mice exhibit impaired lysosomal acidification that diminishes the degradation of IgG-immune complexes containing apoptotic debris (IgG-ICs) and promotes their recycling leading to the accumulation of nuclear antigens on the cell membrane. We hypothesize that defective lysosomal acidification contributes to human disease by sustaining Fc[gamma]R signaling and driving the activation of mTOR. As disease remits, surface IgG-ICs diminish, and during flare they increase. We will test this hypothesis by enrolling patients in different stages of disease activity and quantitating surface IgG, DNA, and nucleosome levels, the activation state of signaling effector of the PI3k/mTOR pathway, and the ability of MFs to acidify lysosomes. Patients who show accumulated IgG-ICs will then be followed longitudinally as their disease remits to assess whether the levels of IgG-ICs decline.
Some B cells, which normally lie dormant, are programmed to produce self-destructive antibodies (autoantibodies). These cells are turned on in people with lupus.
Dr. Vilen’s research asked if newly recognized proteins may be how the off-switch is overridden in lupus, and whether there may be treatment options that reverse this process.
With LRI funding for her novel idea, Dr. Vilen specifically pursued the question as to whether antigens from apoptotic cells are displayed on the surface of other immune cells to B cells, and whether this might provide a sufficiently strong activating signal to trigger autoantibody production.
Her major discoveries have shed light on the regulation of B cells in lupus, and in addition to publishing her work she has presented her research at two prestigious Keystone conferences (2004 and 2005), and has been invited to give seminars across the country.
“The research we initiated with the LRI award has identified how autoreactive B cells are regulated during innate immune responses….Clearly, the tolerance mechanisms that silence autoreactive cells must be powerful. Identifying them and understanding their dysregulation is of significant impact in lupus research,” said Dr. Vilen.
“Before my LRI award my research focused on B cell signaling and tolerance. The LRI award was instrumental in changing that focus toward disease and dysregulation of B cell responses. We continue to study SLE as our primary focus with all members of my laboratory (4 students and 2 post-docs) engaged in lupus-related research.” – Dr. Barbara Vilen, 2010
Low-affinity, Smith antigen-specific B cells are tolerized by dendritic cells and macrophages. Kilmon MA, Rutan JA, Clarke SH, Vilen BJ. J Immunol. 2005 Jul 1;175(1):37-41.
Dendritic cells from lupus-prone mice are defective in repressing autoreactive B cells. Gilbert, M.R., D.G. Carnathan, P.C. Cogswell, A.S. Baldwin Jr., B.J. Vilen. J Immunol. 2007 178:4803-4810.
Macrophages prevent the differentiation of autoreactive B cells by secreting CD40 ligand and IL-6. Kilmon M.A., N.J. Wagner, A. Garland, K. Aviszus, L. Wysoki, and B.J. Vilen. Blood 2007 110:1595-1602.
Dr. Vilen has received two major NIH-funded awards to continue the research she began with her LRI funding. In 2003, she was awarded a 5-year NIH grant of $1,012.500 in direct costs ($1,627,000 including indirect costs). In 2008 she was awarded a 4-year, $1 million grant to examine the role of dendritic cells and macrophages in lupus. She also has funding in the amount of $200,000 through the Arthritis Foundation, and has a patent application pending.
Rev. July 2010