Lack of reactive oxygen species breaks T cell tolerance to collagen type II and allows development of arthritis in mice
Lack of reactive oxygen species breaks T cell tolerance to collagen type II and allows development of arthritis in mice
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DOI：
10.4049/jimmunol.179.3.1431
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发表时间：
2007-08-01
影响因子：
4.4
通讯作者：
Holmdahl, Rikard
中科院分区：
文献类型：
--
作者：
Hultqvist, Malin;Backlund, Johan;Holmdahl, Rikard
关于炎症中活性氧（ROS）的观点目前正在从被认为是破坏性的转变为在调节炎症反应中具有更复杂的作用。我们最近证明了ROS在调节自身免疫性疾病类风湿性关节炎动物模型中的作用。由于编码NADPH氧化酶复合物Ncf1（别名p47（Phox））亚基的Ncf1基因突变，ROS产生水平较低，显示与大鼠和小鼠自身免疫性增加和关节炎严重程度相关。为了进一步研究ROS在自身免疫中的作用，我们研究了表达II型胶原（CII）的转基因小鼠，所述CII在模拟大鼠和人CII的免疫显性表位中具有突变（D266E）（即，突变的小鼠胶原蛋白或MMC）。这种突变导致表位与MHC II类分子的更强结合，并导致对大鼠CII诱导的关节炎的更明显的耐受性和抗性。当Ncfl突变繁殖到这些小鼠中时，耐受性被打破，导致T细胞自身反应性增强，抗CII抗体滴度高，并发展为严重的关节炎。这些发现强调了足够的ROS产生在维持对自身抗原的耐受性中的重要性，这是自身免疫性疾病如类风湿性关节炎的中心机制。这很重要，因为我们第一次可以跟踪ROS对分子机制的影响，其中T细胞负责保护或促进关节炎，这取决于产生的氧物质水平。
The view on reactive oxygen species (ROS) in inflammation is currently shifting from being considered damaging toward having a more complex role in regulating inflammatory reactions. We recently demonstrated a role of ROS in regulation of animal models for the autoimmune disease rheumatoid arthritis. Low levels of ROS production, due to a mutation in the Ncf1 gene coding for the Ncf1 (alias p47(Phox)) subunit of the NADPH oxidase complex, was shown to be associated with increased autoimmunity and arthritis severity in both rats and mice. To further investigate the role of ROS in autoimmunity, we studied transgenic mice expressing collagen type II (CII) with a mutation (D266E) in the immunodominant epitope that mimics the rat and human CII (i.e., mutated mouse collagen or MMC). This mutation results in a stronger binding of the epitope to the MHC class II molecule and leads to more pronounced tolerance and resistance to arthritis induced with rat CII. When the Ncfl mutation was bred into these mice, tolerance was broken, resulting in enhanced T cell autoreactivity, high titers of anti-CII Abs, and development of severe arthritis. These findings highlight the importance of a sufficient ROS production in maintenance of tolerance to self-Ags, a central mechanism in autoimmune diseases such as rheumatoid arthritis. This is important as we, for the first time, can follow the effect of ROS on molecular mechanisms where T cells are responsible for either protection or promotion of arthritis depending on the level of oxygen species produced.