Department of Pediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Mo.
J Allergy Clin Immunol. 2019 Jul;144(1):254-266.e8. doi: 10.1016/j.jaci.2019.01.044. Epub 2019 Feb 14.
Monogenic interferonopathies are thought to be mediated by type I interferon. For example, a gain-of-function mutation in stimulator of interferon genes (STING; N153S) upregulates type I interferon-stimulated genes and causes perivascular inflammatory lung disease in mice. The equivalent mutation in human subjects also causes lung disease, which is thought to require signaling through the cyclic GMP-AMP synthase (cGAS)-STING pathway and subsequent activation of interferon regulatory factors (IRFs) 3 and 7, type I interferon, and interferon-stimulated genes.
We set out to define the roles of cGAS, IRF3, IRF7, the type I interferon receptor (IFN-α and IFN-β receptor subunit 1 [IFNAR1]), T cells, and B cells in spontaneous lung disease in STING N153S mice.
STING N153S mice were crossed to animals lacking cGAS, IRF3/IRF7, IFNAR1, adaptive immunity, αβ T cells, and mature B cells. Mice were evaluated for spontaneous lung disease. Additionally, bone marrow chimeric mice were assessed for lung disease severity and survival.
Lung disease in STING N153S mice developed independently of cGAS, IRF3/IRF7, and IFNAR1. Bone marrow transplantation revealed that certain features of STING N153S-associated disease are intrinsic to the hematopoietic compartment. Recombination-activating gene 1 (Rag1) STING N153S mice that lack adaptive immunity had no lung disease, and T-cell receptor β chain (Tcrb) STING N153S animals only had mild disease. STING N153S led to a reduction in percentages and numbers of naive and regulatory T cells, as well as an increased frequency of cytokine-producing effector T cells.
Spontaneous lung disease in STING N153S mice develops independently of type I interferon signaling and cGAS. STING N153S relies primarily on T cells to promote lung disease in mice.
单基因干扰素病被认为是由 I 型干扰素介导的。例如，刺激干扰素基因（STING；N153S）的功能获得性突变上调 I 型干扰素刺激基因，并导致小鼠血管周围炎症性肺疾病。人类受试者中相同的突变也会导致肺部疾病，这被认为需要通过环鸟苷酸-腺苷酸合酶（cGAS）-STING 途径和随后激活干扰素调节因子（IRFs）3 和 7、I 型干扰素和干扰素刺激基因来实现。
我们旨在确定 cGAS、IRF3、IRF7、I 型干扰素受体（IFN-α 和 IFN-β 受体亚单位 1 [IFNAR1]）、T 细胞和 B 细胞在 STING N153S 小鼠自发性肺疾病中的作用。
将 STING N153S 小鼠与缺乏 cGAS、IRF3/IRF7、IFNAR1、适应性免疫、αβ T 细胞和成熟 B 细胞的动物进行杂交。评估自发性肺疾病。此外，还评估了骨髓嵌合小鼠的肺疾病严重程度和存活率。
STING N153S 小鼠的肺疾病独立于 cGAS、IRF3/IRF7 和 IFNAR1 发生。骨髓移植显示，STING N153S 相关疾病的某些特征是造血细胞固有存在的。缺乏适应性免疫的重组激活基因 1（Rag1）STING N153S 小鼠没有肺部疾病，而 T 细胞受体 β 链（Tcrb）STING N153S 动物只有轻度疾病。STING N153S 导致幼稚和调节性 T 细胞的百分比和数量减少，以及细胞因子产生效应 T 细胞的频率增加。
STING N153S 小鼠的自发性肺疾病独立于 I 型干扰素信号和 cGAS 发生。STING N153S 主要依赖 T 细胞促进小鼠的肺部疾病。
