Extended time in space has been shown to have impacts on the immune system; while studies vary on the extent of the impact it appears that extended time in space results in reduction in immune capacity. With plans to return to the Moon and as well as a manned mission to Mars, a better understanding of the effect of zero gravity on the development and function of the immune system is paramount to the health of astronauts spending extended time in space. While, true, zero gravity cannot be studied in Earth bound experiments, microgravity can be simulated through a rotating wall vessel (RWV) culture system. Phosphatidylinositol (PI) and its phosphorylated derivatives play a critical role in maintaining cellular membranes as well as regulating cell signaling complexes. We have determined that the regulation of PI-4 Kinase is critical for the normal regulation of leukocytes, particularly lymphocytes. To better understand the cellular and molecular impact of microgravity on immune function we will evaluate simulated gravity on the cellular structures and dynamics related to PI composition in leukocyte cell lines. This will be accomplished by he evaluation of organelle structure and function, PI composition, PI-4K and PI-5K activity, and stress responses (particularly ER stress) in leukocyte cell lines cultured in simulated microgravity.
Lupus is a chronic autoimmune disease where the immune defence system attacks the cells, tissues, and organ systems rather than protecting the body against harmful pathogens, such as viruses and bacteria. More than 1.5 million Americans have lupus and over 90% are female, and women of color have two to three times higher risk of having Lupus. Antibodies produced by the immune system attack the skin, kidneys, heart, blood, brain, joints, and lungs and which is the leading cause of early onset kidney disease, cardiovascular disease, and stroke in women. The key to better health is the early detection of Lupus and therapeutic management; however Lupus is difficult to diagnose and often goes undiagnosed or misdiagnosed, sometimes for years.
To better understand Lupus it is important to characterize the process of how and why the immune system attacks its own body. The development of the immune system has several checks and balances to insure it is not harmful to its own body while protecting against harmful microorganisms. Antibodies are produced to detect and remove these harmful microorganisms. So why then do patients with Lupus produce antibodies that attack their own bodies? This is the key question that will be addressed by this project. A new idea will be explored that links a specific type of cellular stress with the uncoupling of the normal controls of the B lymphocytes—the cells that produce antibodies—and lead to the production of autoantibodies, the antibodies that attack one’s own body. Specific components of the cell membrane are required to maintain the normal function of the cells, this research will focus on one type of membrane component, phosphatidylinositol-4phosphate (PI4P for short), and the enzyme that produces PI4P and determine if defects in the regulation of this system are associated with inducing stress in B lymphocytes and allowing autoantibodies to be produced.
The project will use B Lymphocyte cell lines that can be easily cultured as a model of B lymphocytes in the body. These cell lines will be manipulated to alter the regulation of one of the processes associated with the production of PI4P and measure 1) the level of a specific type of cellular stress and 2) the ability of these cells to produce antibodies. This research will provide insight into a new model of autoantibody production and with a more detailed understanding of this process it is hoped that new diagnostic tools or therapies can be developed based on these findings.