Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice
Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice
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DOI：
10.1172/jci43157
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发表时间：
2011-06-01
影响因子：
15.9
通讯作者：
Koretzky, Gary A.
中科院分区：
文献类型：
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作者：
Behrens, Edward M.;Canna, Scott W.;Koretzky, Gary A.
噬血细胞性淋巴组织细胞增生症（HLH）和巨噬细胞活化综合征（MAS）是2种相似的疾病，其特征是细胞因子风暴、压倒性炎症、多器官功能障碍和死亡。HLH的动物模型表明，疾病是由持续抗原暴露刺激的CD 8（+）淋巴细胞产生的IFN-γ驱动的。在这些模型和“原发性”HLH患者中，由于遗传缺陷，抗原持续存在，导致CD 8（+）T细胞的无效细胞毒性反应和病原体清除不良。然而，在MAS患者中通常无法识别感染性触发因素，并且一些HLH或MAS患者缺乏细胞毒性T细胞杀伤缺陷。在此，我们表明，重复刺激TLR 9产生HLH/MAS样综合征的正常遗传背景下，没有外源性抗原。与以前的HLH模型一样，TLR 9诱导的MAS是IFN-γ依赖性的;然而，与其他模型不同，疾病不需要淋巴细胞。我们进一步表明，IL-10在该模型中起保护作用，阻断IL-10信号传导导致噬血细胞作用的发展。因此，IL-10可能是开发MAS有效疗法的重要靶点。我们的数据提供了对炎症性疾病患者MAS样综合征的深入了解，其中存在慢性先天免疫激活，但细胞毒性细胞功能没有遗传缺陷。
Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are 2 similar diseases characterized by a cytokine storm, overwhelming inflammation, multiorgan dysfunction, and death. Animal models of HLH suggest that disease is driven by IFN-gamma produced by CD8(+) lymphocytes stimulated by persistent antigen exposure. In these models and patients with "primary" HLH, the antigen persists due to genetic defects, resulting in ineffective cytotoxic responses by CD8(+) T cells and poor pathogen clearance. However, infectious triggers are often not identified in patients with MAS, and some patients with HLH or MAS lack defects in cytotoxic T cell killing. Herein, we show that repeated stimulation of TLR9 produced an HLH/MAS-like syndrome on a normal genetic background, without exogenous antigen. Like previous HLH models, TLR9-induced MAS was IFN-gamma dependent; however, unlike other models, disease did not require lymphocytes. We further showed that IL-10 played a protective role in this model and that blocking IL-10 signaling led to the development of hemophagocytosis. IL-10 may therefore be an important target for the development of effective therapeutics for MAS. Our data provide insight into MAS-like syndromes in patients with inflammatory diseases in which there is chronic innate immune activation but no genetic defects in cytotoxic cell function.