Division of Rheumatology, Department of Medicine, College of Medicine, Upstate Medical University, State University of New York, Syracuse, NY 13210, USA.
J Immunol. 2013 Sep 1;191(5):2236-46. doi: 10.4049/jimmunol.1301005. Epub 2013 Aug 2.
The mechanistic target of rapamycin (mTOR) is recognized as a sensor of mitochondrial dysfunction and effector of T cell lineage development; however, its role in autoimmunity, including systemic lupus erythematosus, remains unclear. In this study, we prospectively evaluated mitochondrial dysfunction and mTOR activation in PBLs relative to the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) during 274 visits of 59 patients and 54 matched healthy subjects. Partial least square-discriminant analysis identified 15 of 212 parameters that accounted for 70.2% of the total variance and discriminated lupus and control samples (p < 0.0005); increased mitochondrial mass of CD3(+)/CD4(-)/CD8(-) double-negative (DN) T cells (p = 1.1 × 10(-22)) and FOXP3 depletion in CD4(+)/CD25(+) T cells were top contributors (p = 6.7 × 10(-7)). Prominent necrosis and mTOR activation were noted in DN T cells during 15 visits characterized by flares (SLEDAI increase ≥ 4) relative to 61 visits of remission (SLEDAI decrease ≥ 4). mTOR activation in DN T cells was also noted at preflare visits of SLE patients relative to those with stable disease or healthy controls. DN lupus T cells showed increased production of IL-4, which correlated with depletion of CD25(+)/CD19(+) B cells. Rapamycin treatment in vivo blocked the IL-4 production and necrosis of DN T cells, increased the expression of FOXP3 in CD25(+)/CD4(+) T cells, and expanded CD25(+)/CD19(+) B cells. These results identify mTOR activation to be a trigger of IL-4 production and necrotic death of DN T cells in patients with SLE.
雷帕霉素的作用靶点（mTOR）被认为是线粒体功能障碍的传感器和 T 细胞谱系发育的效应器；然而，其在自身免疫中的作用，包括系统性红斑狼疮，仍然不清楚。在这项研究中，我们前瞻性地评估了 59 名患者和 54 名匹配的健康对照者的 274 次就诊中相对系统性红斑狼疮疾病活动指数（SLEDAI）的 PBLs 中线粒体功能障碍和 mTOR 激活。偏最小二乘判别分析从 212 个参数中识别出 15 个，占总方差的 70.2%，可区分狼疮和对照样本（p<0.0005）；CD3(+)/CD4(-)/CD8(-)双阴性（DN）T 细胞中线粒体质量增加（p=1.1×10(-22))和 CD4(+)/CD25(+)T 细胞中 FOXP3 耗竭是主要贡献者（p=6.7×10(-7))。在 15 次以发作为特征的就诊中（SLEDAI 增加≥4），与 61 次缓解就诊（SLEDAI 降低≥4）相比，DN T 细胞中出现明显的坏死和 mTOR 激活。与疾病稳定或健康对照组相比，SLE 患者在发作用就诊前也观察到 DN T 细胞中的 mTOR 激活。DN 狼疮 T 细胞表现出增加的 IL-4 产生，这与 CD25(+)/CD19(+)B 细胞耗竭相关。体内给予雷帕霉素可阻断 DN T 细胞的 IL-4 产生和坏死，增加 CD25(+)/CD4(+)T 细胞中 FOXP3 的表达，并扩增 CD25(+)/CD19(+)B 细胞。这些结果表明，mTOR 激活是 SLE 患者中 IL-4 产生和 DN T 细胞坏死性死亡的触发因素。
