Departments of Medicine, Microbiology and Immunology, Biochemistry and Molecular Biology, Division of Rheumatology, State University of New York, 750 East Adams Street, Syracuse, NY 13210, USA.
Nat Rev Rheumatol. 2013 Nov;9(11):674-86. doi: 10.1038/nrrheum.2013.147. Epub 2013 Oct 8.
Oxidative stress is increased in systemic lupus erythematosus (SLE), and it contributes to immune system dysregulation, abnormal activation and processing of cell-death signals, autoantibody production and fatal comorbidities. Mitochondrial dysfunction in T cells promotes the release of highly diffusible inflammatory lipid hydroperoxides, which spread oxidative stress to other intracellular organelles and through the bloodstream. Oxidative modification of self antigens triggers autoimmunity, and the degree of such modification of serum proteins shows striking correlation with disease activity and organ damage in SLE. In T cells from patients with SLE and animal models of the disease, glutathione, the main intracellular antioxidant, is depleted and serine/threonine-protein kinase mTOR undergoes redox-dependent activation. In turn, reversal of glutathione depletion by application of its amino acid precursor, N-acetylcysteine, improves disease activity in lupus-prone mice; pilot studies in patients with SLE have yielded positive results that warrant further research. Blocking mTOR activation in T cells could conceivably provide a well-tolerated and inexpensive alternative approach to B-cell blockade and traditional immunosuppressive treatments. Nevertheless, compartmentalized oxidative stress in self-reactive T cells, B cells and phagocytic cells might serve to limit autoimmunity and its inhibition could be detrimental. Antioxidant therapy might also be useful in ameliorating damage caused by other treatments. This Review thus seeks to critically evaluate the complexity of oxidative stress and its relevance to the pathogenesis and treatment of SLE.
氧化应激在系统性红斑狼疮（SLE）中增加，并导致免疫系统失调、细胞死亡信号的异常激活和处理、自身抗体产生和致命合并症。T 细胞中线粒体功能障碍促进高扩散性炎症脂质氢过氧化物的释放，将氧化应激扩散到其他细胞内细胞器，并通过血液传播。自身抗原的氧化修饰引发自身免疫，血清蛋白的这种修饰程度与 SLE 中的疾病活动和器官损伤具有惊人的相关性。在 SLE 患者和疾病动物模型的 T 细胞中，谷胱甘肽，主要的细胞内抗氧化剂，被耗尽，丝氨酸/苏氨酸蛋白激酶 mTOR 经历氧化还原依赖性激活。反过来，通过应用其氨基酸前体 N-乙酰半胱氨酸逆转谷胱甘肽耗竭，可改善狼疮易感小鼠的疾病活动；SLE 患者的初步研究结果阳性，值得进一步研究。在 T 细胞中阻断 mTOR 激活可以想象为 B 细胞阻断和传统免疫抑制治疗的一种耐受良好且廉价的替代方法。然而，自身反应性 T 细胞、B 细胞和吞噬细胞中的分区氧化应激可能有助于限制自身免疫，其抑制可能有害。抗氧化治疗也可能有助于改善其他治疗引起的损伤。因此，本综述旨在批判性地评估氧化应激的复杂性及其与 SLE 的发病机制和治疗的相关性。
