OBJECTIVE Patients with hypomorphic mutations in DNase II develop a severe and debilitating autoinflammatory disease. This study was undertaken to compare the disease parameters in these patients to those in a murine model of DNase II deficiency, and to evaluate the role of specific nucleic acid sensors and identify the cell types responsible for driving the autoinflammatory response. METHODS To avoid embryonic death, Dnase2-/- mice were intercrossed with mice that lacked the type I interferon (IFN) receptor (Ifnar-/- ). The hematologic changes and immune status of these mice were evaluated using complete blood cell counts, flow cytometry, serum cytokine enzyme-linked immunosorbent assays, and liver histology. Effector cell activity was determined by transferring T cells from Dnase2-/- × Ifnar-/- double-knockout (DKO) mice into Rag1-/- mice, and 4 weeks after cell transfer, induced changes were assessed in the recipient mice. RESULTS In Dnase2-/- × Ifnar-/- DKO mice, many of the disease features found in DNase II-deficient patients were recapitulated, including cytopenia, extramedullary hematopoiesis, and liver fibrosis. Dnase2+/+ × Rag1-/- mice (n > 22) developed a hematologic disorder that was attributed to the transfer of an unusual IFNγ-producing T cell subset from the spleens of donor Dnase2-/- × Ifnar-/- DKO mice. Autoinflammation in this murine model did not depend on the stimulator of IFN genes (STING) pathway but was highly dependent on the chaperone protein Unc93B1. CONCLUSION Dnase2-/- × Ifnar-/- DKO mice may be a valid model for exploring the innate and adaptive immune mechanisms responsible for the autoinflammation similar to that seen in DNASE2-hypomorphic patients. In this murine model, IFNγ is required for T cell activation and the development of clinical manifestations. The role of IFNγ in DNASE2-deficient patient populations remains to be determined, but the ability of Dnase2-/- mouse T cells to transfer disease to Rag1-/- mice suggests that T cells may be a relevant therapeutic target in patients with IFN-related systemic autoinflammatory diseases.

中文翻译：

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产生γ-干扰素的Th1细胞在DNase II缺乏导致的I型干扰素独立性自发炎症小鼠模型中的作用。

目的DNase II基因亚型突变的患者会发展为严重的使人衰弱的自身炎症性疾病。进行这项研究的目的是将这些患者的疾病参数与DNase II缺乏小鼠模型中的疾病参数进行比较，并评估特定核酸传感器的作用并确定引起自身炎症反应的细胞类型。方法为了避免胚胎死亡，将Dnase2-/-小鼠与缺乏I型干扰素（IFN）受体（Ifnar-/-）的小鼠进行了杂交。使用全血细胞计数，流式细胞仪，血清细胞因子酶联免疫吸附试验和肝脏组织学评估了这些小鼠的血液学变化和免疫状态。通过将T细胞从Dnase2-/-×Ifnar-/-双敲除（DKO）小鼠转移到Rag1-/-小鼠中来确定效应细胞的活性，细胞转移后4周，评估受体小鼠的诱导变化。结果在Dnase2-/-×Ifnar-/-DKO小鼠中，DNase II缺陷患者发现的许多疾病特征都得到了概括，包括血细胞减少，髓外造血和肝纤维化。Dnase2 + / +×Rag1-/-小鼠（n> 22）发生了血液学疾病，这归因于从供体Dnase2-/-×Ifnar-/-DKO小鼠脾脏转移了一个异常的产生IFNγ的T细胞亚群。该鼠模型中的自发炎症并不依赖于IFN基因（STING）途径的刺激物，而高度依赖于伴侣蛋白Unc93B1。结论Dnase2-/-×Ifnar-/-DKO小鼠可能是探索与DNASE2亚型患者相似的导致自身炎症的先天性和适应性免疫机制的有效模型。在这种鼠模型中，IFNγ是T细胞活化和临床表现发展所必需的。IFNγ在缺乏DNASE2的患者群体中的作用尚待确定，但是Dnase2-/-小鼠T细胞将疾病转移至Rag1-/-小鼠的能力表明T细胞可能是IFN-α患者的相关治疗靶标相关的全身性自身炎性疾病。