Severe combined immunodeficiency in stimulator of interferon genes (STING) V154M/wild-type mice
Severe combined immunodeficiency in stimulator of interferon genes (STING) V154M/wild-type mice
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DOI：
10.1016/j.jaci.2018.04.034
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发表时间：
2019-02-01
影响因子：
14.2
通讯作者：
Soulas-Sprauel, Pauline
中科院分区：
文献类型：
--
作者：
Bouis, Delphine;Kirstetter, Peggy;Soulas-Sprauel, Pauline
背景：人类干扰素基因刺激物(STING)的常染色体显性功能获得突变可导致一种严重的自身炎症性疾病，称为婴儿期STING相关血管病变，与干扰素刺激基因转录增强有关。目的：本研究的目的是分析一种新的STING过度激活的小鼠模型的表型以及I型干扰素在该系统中的作用。方法：我们在小鼠STING中建立了一种带有氨基酸替代(V154M)的敲入模型，对应于人类STING相关性血管病婴儿起病患者中的一个反复突变。对造血细胞发育和组织学进行分析。在体外检测淋巴细胞的活化和增殖。将STING V154M/野生型(WT)小鼠与干扰素-α/β受体(IFNAR)基因敲除小鼠杂交，以评估突变的Sting表型对I型干扰素的依赖性。结果：在STING V154M/WT小鼠中，我们在肺和肾脏检测到不同程度的炎性浸润物表达。这些小鼠的存活率显著下降，并患上了严重的联合免疫缺陷病(SCID)，影响B、T和自然杀伤细胞，几乎完全缺乏抗体，单核细胞和粒细胞显著扩张。B细胞和T细胞的发育受阻始于骨髓和胸腺的早期未成熟阶段。此外，体外实验揭示了成熟T细胞固有的增殖缺陷。虽然V154M/WT突变体显示干扰素刺激的基因表达增加，但在STING V154M/WT IFNAR基因敲除小鼠中，SCID表型没有逆转。然而，T细胞中的抗增殖缺陷可以通过IFNAR缺陷得到部分挽救。结论：STING功能获得小鼠出现了一种非干扰素依赖的SCID表型，具有T细胞、B细胞和自然杀伤细胞发育缺陷和低丙种球蛋白血症，这与肺和肾脏的炎症迹象有关。只有T细胞固有的增殖缺陷部分依赖于干扰素。
Background: Autosomal dominant gain-of-function mutations in human stimulator of interferon genes (STING) lead to a severe autoinflammatory disease called STING-associated vasculopathy with onset in infancy that is associated with enhanced expression of interferon-stimulated gene transcripts.Objective: The goal of this study was to analyze the phenotype of a new mouse model of STING hyperactivation and the role of type I interferons in this system.Methods: We generated a knock-in model carrying an amino acid substitution (V154M) in mouse STING, corresponding to a recurrent mutation seen in human patients with STING-associated vasculopathy with onset in infancy. Hematopoietic development and tissue histology were analyzed. Lymphocyte activation and proliferation were assessed in vitro. STING V154M/wild-type (WT) mice were crossed to IFN-alpha/beta receptor (IFNAR) knockout mice to evaluate the type I interferon dependence of the mutant Sting phenotype recorded.Results: In STING V154M/WT mice we detected variable expression of inflammatory infiltrates in the lungs and kidneys. These mice showed a marked decrease in survival and developed a severe combined immunodeficiency disease (SCID) affecting B, T, and natural killer cells, with an almost complete lack of antibodies and a significant expansion of monocytes and granulocytes. The blockade in B-and T-cell development was present from early immature stages in bone marrow and thymus. In addition, in vitro experiments revealed an intrinsic proliferative defect of mature T cells. Although the V154M/WT mutant demonstrated increased expression of interferon-stimulated genes, the SCID phenotype was not reversed in STING V154M/WT IFNAR knockout mice. However, the antiproliferative defect in T cells was rescued partially by IFNAR deficiency.Conclusions: STING gain-of-function mice developed an interferon-independent SCID phenotype with a T-cell, B-cell, and natural killer cell developmental defect and hypogammaglobulinemia that is associated with signs of inflammation in lungs and kidneys. Only the intrinsic proliferative defect of T cells was partially interferon dependent.