From the Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center, Heidelberg; Department of Rheumatology and Clinical Immunology, University of Giessen, Giessen; Internal Medicine I, Division of Rheumatology, University of Mainz, Mainz; Internal Medicine V, Division of Rheumatology, University of Heidelberg, Heidelberg; Department of Dermatology, University of Münster, Münster, Germany.
J Rheumatol. 2013 Oct;40(10):1683-96. doi: 10.3899/jrheum.121299. Epub 2013 Sep 15.
An increased incidence of apoptotic cells and an increased activation of dendritic cells (DC) may be involved in the pathogenesis of systemic lupus erythematosus (SLE). We investigated the characteristics of apoptotic neutrophils and monocyte-derived DC of patients with SLE, their interaction, and the influence of autoantibodies and inflammatory cytokines on this interaction.
Kinetics of neutrophil apoptosis and DC activation were studied by flow cytometry. To analyze the interaction of apoptotic cells with phagocytes, crossover coculture experiments were performed with DC from patients with SLE and apoptotic Jurkat T cells as well as with apoptotic neutrophils from patients with SLE and the monocytic cell line U937. SLE serum and cytokines were added to this coculture, and activation and suppression of DC were quantified by levels of inflammatory cytokine secretion.
Apoptotic neutrophils and DC from patients with SLE showed no inherent defects compared to healthy controls, and the suppressive nature of their interaction was not affected. Autoantibodies as well as the inflammatory cytokines interleukin 17 (IL-17) and IL-1β had no influence on the interaction in this setup. Interferon (IFN)-α, however, substantially reduced the suppressive effect of apoptotic cells on DC.
The data suggest that aberrant immune reactivity in SLE is not generally due to an intrinsic defect in apoptotic cells, their processing, or their interaction with DC, but likely arises from the milieu in which this interaction takes place. Our study highlights the importance of IFN-α during early stages of SLE and its potential as a therapeutic target.
凋亡细胞的增加和树突状细胞（DC）的激活增加可能与系统性红斑狼疮（SLE）的发病机制有关。我们研究了 SLE 患者凋亡中性粒细胞和单核细胞衍生的 DC 的特征、它们之间的相互作用以及自身抗体和炎症细胞因子对这种相互作用的影响。
通过流式细胞术研究中性粒细胞凋亡和 DC 激活的动力学。为了分析凋亡细胞与吞噬细胞的相互作用，进行了交叉共培养实验，用来自 SLE 患者的 DC 和凋亡 Jurkat T 细胞以及来自 SLE 患者的凋亡中性粒细胞和单核细胞系 U937 进行共培养。将 SLE 血清和细胞因子添加到共培养物中，并通过炎症细胞因子分泌水平来量化 DC 的激活和抑制。
与健康对照组相比，SLE 患者的凋亡中性粒细胞和 DC 没有内在缺陷，并且它们相互作用的抑制性质不受影响。自身抗体以及炎症细胞因子白细胞介素 17（IL-17）和 IL-1β 对这种共培养中的相互作用没有影响。然而，干扰素（IFN）-α 大大降低了凋亡细胞对 DC 的抑制作用。
这些数据表明，SLE 中的异常免疫反应不是由于凋亡细胞、其处理或与 DC 的相互作用的内在缺陷引起的，而是可能源于这种相互作用发生的环境。我们的研究强调了 IFN-α 在 SLE 早期的重要性及其作为治疗靶点的潜力。
