IFN-γ and CD25 drive distinct pathologic features during hemophagocytic lymphohistiocytosis
IFN-γ and CD25 drive distinct pathologic features during hemophagocytic lymphohistiocytosis
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DOI：
10.1016/j.jaci.2018.10.068
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发表时间：
2019-06-01
影响因子：
14.2
通讯作者：
Liston, Adrian
中科院分区：
文献类型：
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作者：
Humblet-Baron, Stephanie;Franckaert, Dean;Liston, Adrian
背景：如果不加以控制，CD8(+) T 细胞的炎症激活可导致严重的免疫病理学变化。通过一系列广泛的触发信号过度刺激 CD8(+) T 细胞可引发噬血细胞性淋巴组织细胞增多症 (HLH)，这是一种危及生命的全身性炎症性疾病。 目的：将 CD8(+) T 细胞过度激活与病理学联系起来的机制存在争议，因为 IFN-γ 的过度产生，以及最近的 IL-2 的过度消耗，这被提出作为相互竞争的假设。我们在 HLH 小鼠模型中正式测试了每个通路的近端机制事件。 方法：除了报告具有 HLH 病理学多个方面的完全常染色体隐性 IFN-γ 受体 1 缺陷患者外，我们使用感染淋巴细胞脉络膜脑膜炎病毒的穿孔素 (Prf1)(KO) 小鼠模型从基因上消除 IFN-γ 产生或 CD25 表达，并评估免疫学、血液学、结果：我们发现 CD8(+) T 细胞介导的病理学的血液学和炎症成分的机制基础之间存在惊人的二分法。 HLH 的血液学特征完全依赖于 IFN-γ 的产生，在 IFN-γ 产生丧失后得到完全校正，对 CD8(+) T 细胞介导的 IL-2 消耗没有任何作用。相比之下，免疫学特征的机制贡献被逆转，对IFN-γ的产生没有作用，但在过度活化的CD8+T细胞减少IL-2消耗后得到实质性纠正。这些结果得到了患有 HLH 样疾病的 IFN-γ 受体 1 缺陷患者的表征的补充，在这些患者中，在缺乏 IFN-γ 信号传导的情况下观察到 HLH 病理学的多个方面。 结论：这些结果将 HLH 病理学的竞争机制模型合成为通过离散途径驱动的二分发病机制。整体模型为理解 HLH 以及更广泛地理解 CD8+ T 细胞过度激活的后果提供了新的范例，从而为基于个体患者 HLH 特征的临床干预铺平了道路。
Background: Inflammatory activation of CD8(+) T cells can, when left unchecked, drive severe immunopathology. Hyperstimulation of CD8(+) T cells through a broad set of triggering signals can precipitate hemophagocytic lymphohistiocytosis (HLH), a life-threatening systemic inflammatory disorder.Objective: The mechanism linking CD8(+) T-cell hyperactivation to pathology is controversial, with excessive production of IFN-gamma and, more recently, excessive consumption of IL-2, which are proposed as competing hypotheses. We formally tested the proximal mechanistic events of each pathway in a mouse model of HLH.Methods: In addition to reporting a complete autosomal recessive IFN-gamma receptor 1-deficient patient with multiple aspects of HLH pathology, we used the mouse model of perforin (Prf1)(KO) mice infected with lymphocytic choriomeningitis virus to genetically eliminate either IFN-gamma production or CD25 expression and assess the immunologic, hematologic, and physiologic disease measurement.Results: We found a striking dichotomy between the mechanistic basis of the hematologic and inflammatory components of CD8(+) T cell-mediated pathology. The hematologic features of HLH were completely dependent on IFN-gamma production, with complete correction after loss of IFN-gamma production without any role for CD8(+) T cell-mediated IL-2 consumption. By contrast, the mechanistic contribution of the immunologic features was reversed, with no role for IFN-gamma production but substantial correction after reduction of IL-2 consumption by hyperactivated CD8(+) T cells. These results were complemented by the characterization of an IFN-gamma receptor 1-deficient patients with HLH-like disease, in whom multiple aspects of HLH pathology were observed in the absence of IFN-gamma signaling.Conclusion: These results synthesize the competing mechanistic models of HLH pathology into a dichotomous pathogenesis driven through discrete pathways. A holistic model provides a new paradigm for understanding HLH and, more broadly, the consequences of CD8(+) T-cell hyperactivation, thereby paving the way for clinical intervention based on the features of HLH in individual patients.