Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, USA.
Diabetes. 2011 Aug;60(8):2144-51. doi: 10.2337/db10-1222. Epub 2011 Jun 29.
The role of reactive oxygen species (ROS) and their dissipation in type 1 diabetes pathogenesis have garnered considerable controversy. Our recent work has demonstrated the importance of NADPH oxidase (NOX) activity for type 1 diabetes development and modulating T-cell autoreactivity. We previously linked decreased monocyte ROS with diabetes resistance in the alloxan-resistant mouse, and NOD-Ncf1(m1J) mice with a genetic ablation of NOX activity had reduced and delayed type 1 diabetes compared with NOD mice.
To determine the required cellular sources of ROS that are necessary for type 1 diabetes initiation, we used antibody depletion and adoptive transfer experiments into NOD and NOD-Scid females, respectively. After receiving treatment, female mice were monitored for hyperglycemia and overt diabetes.
Depletion of macrophages and neutrophils fully protected NOD mice from type 1 diabetes. However, elimination of neutrophils alone showed no significant reduction or delay. Type 1 diabetes induction in NOD-Scid mice by adoptive transfer with NOD-Ncf1(m1J) splenocytes was significantly delayed compared with NOD splenocytes, suggesting macrophage ROS and modulation of effector responses are critical for diabetes. The adaptive immune response was also altered by the absence of NOX activity, as purified T cells from NOD-Ncf1(m1J) mice exhibited delayed transfer kinetics. Cotransfer experiments demonstrated the defect was intrinsic to NOX-deficient CD8(+) T cells. After stimulation, cytotoxic T cells exhibited decreased effector function in the absence of superoxide production.
These data demonstrate that the impaired autoreactive response of NOX-deficient NOD-Ncf1(m1J) immune system results from an alteration in the antigen-presenting cell-T-cell axis rather than failure of neutrophils to act as effector cells and that ROS signaling is important for the initiation of β-cell-directed autoimmunity by T cells.
活性氧（ROS）及其在 1 型糖尿病发病机制中的耗散作用引起了相当大的争议。我们最近的工作表明 NADPH 氧化酶（NOX）活性对于 1 型糖尿病的发展和调节 T 细胞自身反应性非常重要。我们之前已经证明，在丙烯醛抗性小鼠中，单核细胞 ROS 的减少与糖尿病抗性有关，并且与 NOD 小鼠相比，NOX 活性遗传缺失的 NOD-Ncf1(m1J)小鼠的 1 型糖尿病减少且发病延迟。
为了确定启动 1 型糖尿病所必需的 ROS 的必需细胞来源，我们分别使用抗体耗竭和过继转移实验对 NOD 和 NOD-Scid 雌性小鼠进行了实验。接受治疗后，监测雌性小鼠的高血糖和显性糖尿病。
巨噬细胞和中性粒细胞的耗竭可使 NOD 小鼠完全免受 1 型糖尿病的侵害。然而，单独消除中性粒细胞并没有明显的减少或延迟。用 NOD-Ncf1(m1J)脾细胞过继转移到 NOD-Scid 小鼠中可显著延迟 1 型糖尿病的诱导，与 NOD 脾细胞相比，这表明巨噬细胞 ROS 和效应应答的调节对于糖尿病至关重要。NOX 活性的缺失也改变了适应性免疫应答，因为 NOD-Ncf1(m1J)小鼠的纯化 T 细胞表现出延迟的转移动力学。共转导实验表明该缺陷是 NCF1 缺陷 CD8(+)T 细胞固有的。刺激后，缺乏超氧化物产生的细胞毒性 T 细胞表现出效应功能降低。
这些数据表明，NOX 缺陷的 NOD-Ncf1(m1J)免疫系统的自身反应性受损是由于抗原呈递细胞-T 细胞轴的改变所致，而不是由于中性粒细胞无法作为效应细胞发挥作用，并且 ROS 信号对于 T 细胞启动β细胞定向自身免疫非常重要。
