Division of Immunology, University Children's Hospital Zurich, Zurich, Switzerland.
Faculty of Medicine, University of Zurich, Zurich, Switzerland.
Adv Exp Med Biol. 2024;1448:481-496. doi: 10.1007/978-3-031-59815-9_33.
Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disease caused by mutations in effectors and regulators of cytotoxicity in cytotoxic T cells (CTL) and natural killer (NK) cells. The complexity of the immune system means that in vivo models are needed to efficiently study diseases like HLH. Mice with defects in the genes known to cause primary HLH (pHLH) are available. However, these mice only develop the characteristic features of HLH after the induction of an immune response (typically through infection with lymphocytic choriomeningitis virus). Nevertheless, murine models have been invaluable for understanding the mechanisms that lead to HLH. For example, the cytotoxic machinery (e.g., the transport of cytotoxic vesicles and the release of granzymes and perforin after membrane fusion) was first characterized in the mouse. Experiments in murine models of pHLH have emphasized the importance of cytotoxic cells, antigen-presenting cells (APC), and cytokines in hyperinflammatory positive feedback loops (e.g., cytokine storms). This knowledge has facilitated the development of treatments for human HLH, some of which are now being tested in the clinic.
噬血细胞性淋巴组织细胞增生症（HLH）是一种由细胞毒性 T 细胞（CTL）和自然杀伤（NK）细胞中细胞毒性效应器和调节剂的突变引起的过度炎症性疾病。免疫系统的复杂性意味着需要体内模型来有效地研究 HLH 等疾病。存在已知导致原发性 HLH（pHLH）的基因缺陷的小鼠。然而，这些小鼠只有在诱导免疫反应后（通常通过感染淋巴细胞脉络丛脑膜炎病毒）才会发展为 HLH 的特征性特征。尽管如此，鼠模型对于理解导致 HLH 的机制仍然非常有价值。例如，细胞毒性机制（例如，细胞毒性囊泡的转运以及膜融合后颗粒酶和穿孔素的释放）首先在小鼠中得到了表征。pHLH 的鼠模型实验强调了细胞毒性细胞、抗原呈递细胞（APC）和细胞因子在过度炎症性正反馈回路（例如细胞因子风暴）中的重要性。这些知识促进了针对人类 HLH 的治疗方法的发展，其中一些目前正在临床试验中进行测试。
