Department of Medicine, University of California, San Francisco, San Francisco, CA 94143.
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143.
J Immunol. 2020 May 1;204(9):2360-2373. doi: 10.4049/jimmunol.2000028. Epub 2020 Mar 20.
COPA syndrome is a recently described Mendelian autoimmune disorder caused by missense mutations in the () 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 germline knock-in mouse bearing one of the same 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 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 mutations lead to autoimmunity in patients.
COPA 综合征是一种新近描述的孟德尔自身免疫性疾病，由 () 基因的错义突变引起。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，但许多患者会发展为进行性肺纤维化，这需要进行挽救生命的治疗措施，如肺移植。由于对 COPA 综合征的发病机制了解甚少，因此很难为患者制定有效的治疗方法。迄今为止，尚不清楚哪些细胞类型对于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，我们生成了一种携带患者相同错义突变的 () 基因种系敲入小鼠。突变小鼠自发地发展为ILD，类似于患者的肺部病理学，以及激活的细胞因子分泌 T 细胞的升高。在这项研究中，我们表明突变的 Copa 在胸腺上皮细胞中损害了 T 细胞的胸腺选择，导致外周组织中自身反应性 T 细胞增加和调节性 T 细胞减少。我们证明来自 () 小鼠的 T 细胞是致病性的，并通过过继转移实验导致 ILD。总之，据我们所知，我们建立了一种新的 COPA 综合征小鼠模型，以确定 Copa 在胸腺细胞选择中的一个先前未知的功能，并证明中枢耐受缺陷是 () 突变导致患者自身免疫的一个潜在机制。
