OBJECTIVE Familial hemophagocytic lymphohistiocytosis (FHLH) is a complex cytokine storm syndrome caused by genetic abnormalities rendering CD8+ T cells and natural killer cells incapable of cytolytic killing. In murine models of FHLH, interferon-γ (IFNγ) produced by CD8+ T cells has been identified as a critical mediator of disease, and an IFNγ-blocking antibody (emapalumab) has recently been approved by the Food and Drug Administration. However, development of hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) in patients who are genetically unresponsive to IFNγ questions the absolute necessity of IFNγ in driving disease. This study was undertaken to determine the necessity of IFNγ in driving HLH. METHODS IFNγ-/- Prf1-/- mice were infected with lymphocytic choriomeningitis virus (LCMV), and HLH immunopathologic features, including survival, weight loss, cytopenias, cytokine profiles, and immune cell phenotypes, were assessed. Mixed bone marrow chimeras were created to determine the immune cell-intrinsic role of IFNγ receptor signaling. CD8+ T cell depletion and interleukin-33 (IL-33)/ST2 blockade were performed using monoclonal antibodies. RESULTS LCMV infection of IFNγ-/- Prf1-/- mice resulted in severe HLH-like disease. CD8+ T cells and the IL-33/ST2 axis remained essential mediators of disease; however, IFNγ-independent HLH immunopathology correlated with a 10-15-fold increase in neutrophilia (P < 0.001) and an altered cytokine milieu dominated by IL-6, IL-1β, and granulocyte-macrophage colony-stimulating factor (GM-CSF) (P < 0.05). Furthermore, IFNγ regulated CD8+ T cell expression of GM-CSF and neutrophil survival. CONCLUSION IFNγ is not necessary for the development of fulminant HLH, requiring physicians to consider case-by-case treatment strategies. Use of therapies that target upstream activators of CD8+ T cells, such as IL-33/ST2 signaling, may be more universally applicable treatment options that ameliorate both IFNγ-dependent and -independent manifestations of HLH/MAS.

中文翻译：

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干扰素-γ的遗传缺陷揭示了小鼠血噬细胞性淋巴细胞组织细胞增生症的干扰素-γ独立表现。

目的家族性噬血细胞淋巴组织细胞增生症（FHLH）是一种复杂的细胞因子风暴综合症，由遗传异常引起，致使CD8 + T细胞和自然杀伤细胞无法进行溶细胞杀伤。在FHLH的鼠模型中，已经确定了CD8 + T细胞产生的干扰素-γ（IFNγ）是疾病的关键介质，并且最近食品与药物管理局批准了IFNγ阻断抗体（emapalumab）。然而，遗传上对IFNγ无反应的患者的噬血细胞淋巴组织细胞增生症（HLH）/巨噬细胞活化综合征（MAS）的发展质疑了IFNγ在驱动疾病中的绝对必要性。进行该研究以确定IFNγ在驱动HLH中的必要性。方法用IFNγ-/-Prf1-/-小鼠感染淋巴细胞性脉络膜脑膜炎病毒（LCMV），并评估了HLH免疫病理学特征，包括生存率，体重减轻，血细胞减少症，细胞因子谱和免疫细胞表型。创建了混合的骨髓嵌合体，以确定IFNγ受体信号传导的免疫细胞内在作用。使用单克隆抗体进行CD8 + T细胞耗竭和白介素33（IL-33）/ ST2阻断。结果LCMV感染IFNγ-/-Prf1-/-小鼠导致了严重的HLH样疾病。CD8 + T细胞和IL-33 / ST2轴仍然是疾病的重要介质。然而，不依赖IFNγ的HLH免疫病理学与中性粒细胞增加10-15倍（P <0.001）和由IL-6，IL-1β和粒细胞巨噬细胞集落刺激因子（GM-CSF）主导的细胞因子环境改变相关）（P <0.05）。此外，IFNγ调节了GM-CSF的CD8 + T细胞表达和中性粒细胞存活。结论IFNγ对于暴发性HLH的形成不是必需的，需要医生考虑逐案治疗策略。使用靶向CD8 + T细胞上游激活剂的疗法（例如IL-33 / ST2信号传导）可能是更普遍适用的治疗选择，可减轻HLH / MAS的IFNγ依赖性和非依赖性。