Division of Rheumatology, Bambino Gesù Children's Hospital IRCCS, Rome, Italy.
Division of Rheumatology, Bambino Gesù Children's Hospital IRCCS, Rome, Italy.
J Allergy Clin Immunol. 2018 Apr;141(4):1439-1449. doi: 10.1016/j.jaci.2017.07.021. Epub 2017 Aug 12.
The pathogenesis of macrophage activation syndrome (MAS) is not clearly understood: a large body of evidence supports the involvement of mechanisms similar to those implicated in the setting of primary hemophagocytic lymphohistiocytosis.
We sought to investigate the pathogenic role of IFN-γ and the therapeutic efficacy of IFN-γ neutralization in an animal model of MAS.
We used an MAS model established in mice transgenic for human IL-6 (IL-6TG mice) challenged with LPS (MAS mice). Levels of IFN-γ and IFN-γ-inducible chemokines were evaluated by using real-time PCR in the liver and spleen and by means of ELISA in plasma. IFN-γ neutralization was achieved by using the anti-IFN-γ antibody XMG1.2 in vivo.
Mice with MAS showed a significant upregulation of the IFN-γ pathway, as demonstrated by increased mRNA levels of Ifng and higher levels of phospho-signal transducer and activator of transcription 1 in the liver and spleen and increased expression of the IFN-γ-inducible chemokines Cxcl9 and Cxcl10 in the liver and spleen, as well as in plasma. A marked increase in Il12a and Il12b expression was also found in livers and spleens of mice with MAS. In addition, mice with MAS had a significant increase in numbers of liver CD68 macrophages. Mice with MAS treated with an anti-IFN-γ antibody showed a significant improvement in survival and body weight recovery associated with a significant amelioration of ferritin, fibrinogen, and alanine aminotransferase levels. In mice with MAS, treatment with the anti-IFN-γ antibody significantly decreased circulating levels of CXCL9, CXCL10, and downstream proinflammatory cytokines. The decrease in CXCL9 and CXCL10 levels paralleled the decrease in serum levels of proinflammatory cytokines and ferritin.
These results provide evidence for a pathogenic role of IFN-γ in the setting of MAS.
巨噬细胞活化综合征（MAS）的发病机制尚不清楚：大量证据支持涉及类似于原发性噬血细胞性淋巴组织细胞增生症的机制。
我们旨在研究 IFN-γ 在 MAS 动物模型中的致病作用和 IFN-γ 中和的治疗效果。
我们使用了转人白细胞介素 6（IL-6）的小鼠（IL-6TG 小鼠）用 LPS 建立的 MAS 模型（MAS 小鼠）。通过实时 PCR 在肝和脾中评估 IFN-γ 和 IFN-γ 诱导的趋化因子的水平，并通过 ELISA 在血浆中评估。通过体内使用抗 IFN-γ 抗体 XMG1.2 来中和 IFN-γ。
MAS 小鼠表现出 IFN-γ 途径的显著上调，这表现在肝和脾中 Ifng 的 mRNA 水平升高，磷酸信号转导和转录激活因子 1 的水平升高，肝和脾中 IFN-γ 诱导的趋化因子 Cxcl9 和 Cxcl10 的表达增加，以及在血浆中。在 MAS 小鼠的肝和脾中还发现 Il12a 和 Il12b 的表达明显增加。此外，MAS 小鼠的肝 CD68 巨噬细胞数量显著增加。用抗 IFN-γ 抗体治疗的 MAS 小鼠的生存率和体重恢复明显改善，铁蛋白、纤维蛋白原和丙氨酸氨基转移酶水平明显改善。在 MAS 小鼠中，用抗 IFN-γ 抗体治疗显著降低了循环中的 CXCL9、CXCL10 和下游促炎细胞因子的水平。CXCL9 和 CXCL10 水平的降低与血清中促炎细胞因子和铁蛋白水平的降低平行。
这些结果为 IFN-γ 在 MAS 中的致病作用提供了证据。
