Systemic autoimmune diseases (SAID) are complex, chronic, hard to treat, and devastating to patients. The number of people with SAID is increasing worldwide too quickly to be attributed entirely to genetic predisposition, implicating environmental factors. Inhalation of asbestos or silica has been shown to increase the risk of SAID such as systemic lupus, but the mechanism is not well understood. Autoimmunity occurs when the immune system starts making mistakes and damages our own tissues, and some signals that can over-stimulate the immune system come from macrophages. Interaction of macrophages with asbestos leads to production of cytotoxic oxygen radicals. Some of the macrophages simply die, but some survive: We suspect that these survivors are sending out alarm signals that over-stimulate the immune system. This project will explore the hypothesis that the mechanism of survival and the messages they send are linked via an amino acid transporter called System xc-. System xc- protects cells from oxygen radicals by importing cystine, which is subsequently made into glutathione (GSH), a critical cell antioxidant. GSH levels in macrophages significantly affect the signals driving T cell and B cell responses, though it is unclear whether the GSH itself is the signal. In addition, cystine import via System xc- is coupled with glutamate export, and glutamate can also have dramatic effects on immune responses. We will demonstrate that asbestos increases the expression and activity of System xc- protein on macrophages, and that this protects the cells from oxygen radicals. Next we will measure exactly how much glutamate, cysteine and GSH are released from the cells, and subsequently determine how these affect B cell activation and antibody production. The proposed study reveals a novel and exciting mechanism by which environmental factors may drive autoimmune responses. If the activation of System xc- by asbestos causes macrophages to not only survive but also influence the immune system toward autoimmunity, new therapies might be developed to block this response, dramatically improving autoimmune outcomes. PUBLIC HEALTH RELEVANCE: In macrophages, the main function of System xc- appears to be the import of cystine to replenish cysteine for glutathione synthesis, with concomitant export of glutamate, particularly in cells undergoing oxidative stress. Amino acids such as cysteine and glutamate can have dramatic effects on the balance of cellular and humoral immune responses. Because asbestos causes oxidative stress, this project will test the hypothesis that System xc- plays a major role in the altered immune responses that lead to autoantibody production.