Role of System xc in Asbestos Induced Autoimmune Responses

描述（由申请人提供）：系统性自身免疫性疾病（SAID）是复杂的、慢性的、难以治疗的，并且对患者具有破坏性。全球SAID患者的数量增长太快，不能完全归因于遗传易感性，这涉及环境因素。吸入石棉或二氧化硅已被证明会增加SAID的风险，如系统性狼疮，但其机制尚不清楚。当免疫系统开始犯错并损害我们自己的组织时，就会发生自身免疫，而一些可以过度刺激免疫系统的信号来自巨噬细胞。巨噬细胞与石棉的相互作用导致细胞毒性氧自由基的产生。一些巨噬细胞只是死亡，但有些存活下来：我们怀疑这些幸存者发出了过度刺激免疫系统的警报信号。该项目将探索一种假设，即生存机制和它们发送的信息是通过一种称为系统xc-的氨基酸转运蛋白连接的。系统xc-通过输入胱氨酸来保护细胞免受氧自由基的侵害，胱氨酸随后被制成谷胱甘肽（GSH），一种重要的细胞抗氧化剂。巨噬细胞中的GSH水平显著影响驱动T细胞和B细胞应答的信号，尽管尚不清楚GSH本身是否是信号。此外，通过系统xc-的胱氨酸输入与谷氨酸输出相结合，谷氨酸也可以对免疫应答产生显著影响。我们将证明石棉增加巨噬细胞上系统xc蛋白的表达和活性，这可以保护细胞免受氧自由基的侵害。接下来，我们将精确测量细胞释放的谷氨酸、半胱氨酸和GSH的量，并随后确定这些物质如何影响B细胞活化和抗体产生。这项研究揭示了一种新的令人兴奋的机制，环境因素可能会驱动自身免疫反应。如果石棉激活系统xc-不仅导致巨噬细胞存活，而且还影响免疫系统的自身免疫性，那么可能会开发新的疗法来阻断这种反应，从而大大改善自身免疫性结果。 公共卫生相关性：在巨噬细胞中，系统xc-的主要功能似乎是输入胱氨酸以补充谷胱甘肽合成的半胱氨酸，伴随着谷氨酸的输出，特别是在经历氧化应激的细胞中。半胱氨酸和谷氨酸等氨基酸可对细胞和体液免疫应答的平衡产生显著影响。由于石棉会引起氧化应激，本项目将测试系统xc-在导致自身抗体产生的免疫反应改变中起主要作用的假设。

DESCRIPTION (provided by applicant): 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.