Strickland F M, Mau T, O'Brien M, Ghosh A, Richardson B C, Yung R
Department of Medicine, University of Michigan, Ann Arbor MI, USA.
Lupus (Los Angel). 2017 Apr;2(1). Epub 2017 Jan 10.
Lupus flares are triggered by environmental agents that cause oxidative stress, but the mechanisms involved are unclear. The flares are characterized by oxidative modifications of proteins by 4-hydroxynonenals, malondialdehydes, carbonyls and nitration. These modifications have been proposed to induce and perpetuate lupus flares by "altered self" mechanisms. An epigenetically altered CD4+CD28+ T cell subset, caused at least in part by nitration of T cell signaling molecules, is found in patients with active lupus, and nitrated T cells are sufficient to cause lupus-like autoimmunity in animal models. The relation of protein 4-hydroxynonenals, malondialdehydes, carbonyls and nitration to lupus flares though, is unknown. We tested if the size of the epigenetically altered subset is related to disease activity and one or more of these oxidative modifications in lupus patients. We also tested the relationship between subset size, disease activity and the same oxidative modifications in Sjogren's syndrome, another autoimmune disease also associated with oxidative stress and characterized by anti-nuclear antibodies and the presence of the subset.
Lupus flare severity was quantitated using the Systemic Lupus Erythematosus Disease Activity Index, and Sjogren's flare severity using the European Sjogren's Syndrome Disease Activity Index. Subset size was determined by flow cytometry. Protein modifications were determined by ELISA.
Only protein nitration correlated with the size of the subset in lupus and Sjogren's syndrome.
These results support a role for protein nitration in subset size and lupus flare severity. Protein nitration may also contribute to autoantibody formation in Sjogren's syndrome.
狼疮发作由引起氧化应激的环境因素触发，但其中涉及的机制尚不清楚。狼疮发作的特征是蛋白质被4-羟基壬烯醛、丙二醛、羰基和硝化作用进行氧化修饰。这些修饰被认为通过“自身改变”机制诱导并维持狼疮发作。在活动性狼疮患者中发现了一种表观遗传改变的CD4+CD28+ T细胞亚群，至少部分是由T细胞信号分子的硝化作用引起的，并且硝化的T细胞足以在动物模型中引发狼疮样自身免疫。然而，蛋白质4-羟基壬烯醛、丙二醛、羰基和硝化作用与狼疮发作的关系尚不清楚。我们测试了表观遗传改变的亚群大小是否与狼疮患者的疾病活动以及这些氧化修饰中的一种或多种相关。我们还测试了干燥综合征（另一种也与氧化应激相关且以抗核抗体和该亚群的存在为特征的自身免疫性疾病）中该亚群大小、疾病活动与相同氧化修饰之间的关系。
使用系统性红斑狼疮疾病活动指数对狼疮发作的严重程度进行定量，使用欧洲干燥综合征疾病活动指数对干燥综合征发作的严重程度进行定量。通过流式细胞术确定亚群大小。通过酶联免疫吸附测定法确定蛋白质修饰。
在狼疮和干燥综合征中，只有蛋白质硝化作用与亚群大小相关。
这些结果支持蛋白质硝化作用在亚群大小和狼疮发作严重程度中起作用。蛋白质硝化作用也可能导致干燥综合征中自身抗体的形成。
