Huang Xinfang, Li Jingjing, Dorta-Estremera Stephanie, Di Domizio Jeremy, Anthony Scott M, Watowich Stephanie S, Popkin Daniel, Liu Zheng, Brohawn Philip, Yao Yihong, Schluns Kimberly S, Lanier Lewis L, Cao Wei
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Rheumatology, Renji Hospital, Shanghai Institute of Rheumatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, China.
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cell Rep. 2015 Aug 18;12(7):1120-32. doi: 10.1016/j.celrep.2015.07.021. Epub 2015 Aug 6.
Here, we examine the mechanism by which plasmacytoid dendritic cells (pDCs) and type I interferons promote humoral autoimmunity. In an amyloid-induced experimental autoimmune model, neutrophil depletion enhanced anti-nuclear antibody development, which correlated with heightened IFN-γ production by natural killer (NK) cells. IFN-α/β produced by pDCs activated NK cells via IL-15 induction. Neutrophils released reactive oxygen species (ROS), which negatively modulated the levels of IL-15, thereby inhibiting IFN-γ production. Mice deficient in NADPH oxidase 2 produced increased amounts of IFN-γ and developed augmented titers of autoantibodies. Both the pDC-IFN-α/β pathway and IFN-γ were indispensable in stimulating humoral autoimmunity. Male NZB/W F1 mice expressed higher levels of superoxide than their female lupus-prone siblings, and depletion of neutrophils resulted in spontaneous NK cell and autoimmune B cell activation. Our findings suggest a regulatory role for neutrophils in vivo and highlight the importance of an NK-IFN-γ axis downstream of the pDC-IFN-α/β pathway in systemic autoimmunity.
在此，我们研究浆细胞样树突状细胞（pDCs）和I型干扰素促进体液自身免疫的机制。在淀粉样蛋白诱导的实验性自身免疫模型中，中性粒细胞耗竭增强了抗核抗体的产生，这与自然杀伤（NK）细胞产生的IFN-γ增加相关。pDCs产生的IFN-α/β通过诱导IL-15激活NK细胞。中性粒细胞释放活性氧（ROS），其负向调节IL-15水平，从而抑制IFN-γ的产生。缺乏NADPH氧化酶2的小鼠产生的IFN-γ量增加，自身抗体滴度升高。pDC-IFN-α/β途径和IFN-γ在刺激体液自身免疫中均不可或缺。雄性NZB/W F1小鼠比其易患狼疮的雌性同胞表达更高水平的超氧化物，中性粒细胞耗竭导致NK细胞和自身免疫B细胞自发激活。我们的研究结果表明中性粒细胞在体内具有调节作用，并突出了pDC-IFN-α/β途径下游的NK-IFN-γ轴在系统性自身免疫中的重要性。
