Key Points A COPA syndrome mouse model develops lung disease that mirrors that in patients. Mutant Copa in thymic epithelial cells impairs thymocyte selection. T cells are important drivers of lung disease in CopaE241K/+ mice. COPA syndrome is a recently described Mendelian autoimmune disorder caused by missense mutations in the coatomer protein complex subunit α (COPA) gene. Patients with COPA syndrome develop arthritis and lung disease that presents as pulmonary hemorrhage or interstitial lung disease (ILD). Immunosuppressive medications can stabilize the disease, but many patients develop progressive pulmonary fibrosis, which requires life-saving measures, such as lung transplantation. Because very little is understood about the pathogenesis of COPA syndrome, it has been difficult to devise effective treatments for patients. To date, it remains unknown which cell types are critical for mediating the disease as well as the mechanisms that lead to autoimmunity. To explore these issues, we generated a CopaE241K/+ germline knock-in mouse bearing one of the same Copa missense mutations in patients. Mutant mice spontaneously developed ILD that mirrors lung pathology in patients, as well as elevations of activated cytokine-secreting T cells. In this study, we show that mutant Copa in epithelial cells of the thymus impairs the thymic selection of T cells and results in both an increase in autoreactive T cells and decrease in regulatory T cells in peripheral tissues. We demonstrate that T cells from CopaE241K/+ mice are pathogenic and cause ILD through adoptive transfer experiments. In conclusion, to our knowledge, we establish a new mouse model of COPA syndrome to identify a previously unknown function for Copa in thymocyte selection and demonstrate that a defect in central tolerance is a putative mechanism by which COPA mutations lead to autoimmunity in patients.

中文翻译：

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胸腺耐受性缺陷导致 COPA 综合征小鼠模型中 T 细胞介导的自身免疫

关键点 COPA 综合征小鼠模型会发展出与患者相同的肺部疾病。胸腺上皮细胞中的突变型 Copa 会损害胸腺细胞的选择。T 细胞是 CopaE241K/+ 小鼠肺部疾病的重要驱动因素。COPA 综合征是最近描述的一种孟德尔自身免疫性疾病，由外壳蛋白复合物亚基 α (COPA) 基因中的错义突变引起。COPA 综合征患者会出现关节炎和肺部疾病，表现为肺出血或间质性肺病 (ILD)。免疫抑制药物可以稳定病情，但许多患者会出现进行性肺纤维化，这需要采取肺移植等挽救生命的措施。由于对 COPA 综合征的发病机制了解甚少，因此很难为患者设计有效的治疗方法。迄今为止，尚不清楚哪些细胞类型对介导疾病以及导致自身免疫的机制至关重要。为了探讨这些问题，我们生成了 CopaE241K/+ 种系基因敲入小鼠，其在患者中携带相同的 Copa 错义突变之一。突变小鼠自发发展 ILD，反映患者的肺部病理，以及激活的细胞因子分泌 T 细胞的升高。在这项研究中，我们表明胸腺上皮细胞中的突变 Copa 会损害 T 细胞的胸腺选择，并导致外周组织中自身反应性 T 细胞的增加和调节性 T 细胞的减少。我们通过过继转移实验证明来自 CopaE241K/+ 小鼠的 T 细胞具有致病性并导致 ILD。总之，据我们所知，