Jordan Michael B, Hildeman David, Kappler John, Marrack Philippa
Integrated Department of Immunology, University of Colorado Health Sciences Center, Denver, USA.
Blood. 2004 Aug 1;104(3):735-43. doi: 10.1182/blood-2003-10-3413. Epub 2004 Apr 6.
Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder with familial and acquired forms. The familial form is associated with mutations in the perforin gene and both forms are associated with severe defects in lymphocyte cytotoxic function. We examined perforin-deficient mice as a model of HLH in order to gain insight into this poorly understood disorder. While these mice do not spontaneously develop HLH-like symptoms, we found that they manifest all of the features of HLH after infection with lymphocytic choriomeningitic virus (LCMV). Following LCMV infection, perforin-deficient mice develop fever, splenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, and elevation of multiple serum cytokine levels, and hemophagocytosis is evident in many tissues. Investigation into how this phenotype develops has revealed that CD8+ T cells, but not natural killer (NK) cells, are necessary for the development of this disorder. Cytokine neutralization studies have revealed that interferon gamma (IFNgamma) is uniquely essential as well. Finally, the excessive amount of IFNgamma seen in affected mice appears to be driven by increased antigen presentation to CD8+ T cells. These studies provide insight into the pathophysiology of HLH, and provide new targets for specific therapeutic intervention in this fatal disorder.
噬血细胞性淋巴组织细胞增生症（HLH）是一种罕见的疾病，有家族性和获得性两种形式。家族性形式与穿孔素基因突变有关，两种形式均与淋巴细胞细胞毒性功能的严重缺陷有关。我们研究了穿孔素缺陷小鼠作为HLH的模型，以便深入了解这种了解甚少的疾病。虽然这些小鼠不会自发出现HLH样症状，但我们发现它们在感染淋巴细胞性脉络丛脑膜炎病毒（LCMV）后会表现出HLH的所有特征。LCMV感染后，穿孔素缺陷小鼠会出现发热、脾肿大、全血细胞减少、高甘油三酯血症、低纤维蛋白原血症以及多种血清细胞因子水平升高，并且在许多组织中可见噬血细胞现象。对这种表型如何发展进行的研究表明，CD8 + T细胞而非自然杀伤（NK）细胞是这种疾病发展所必需的。细胞因子中和研究表明，γ干扰素（IFNγ）同样具有独特的必要性。最后，在受影响小鼠中观察到的过量IFNγ似乎是由向CD8 + T细胞的抗原呈递增加所驱动。这些研究为HLH的病理生理学提供了见解，并为这种致命疾病的特异性治疗干预提供了新的靶点。
