Department of Ophthalmology, National Defense Medical College, Saitama, Japan; Division of Traumatology, Research Institute, National Defense Medical College, Saitama, Japan.
Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.
Am J Pathol. 2021 Jun;191(6):1077-1093. doi: 10.1016/j.ajpath.2021.02.014. Epub 2021 Mar 8.
Programmed cell death protein (PD)-1 is a coinhibitory molecule that suppresses immune response and maintains immune homeostasis. Moreover, the PD-1 pathway blocks cancers from being attacked by immune cells. Anti-PD-1 antibody therapy such as nivolumab improves survival in cancer patients. However, the occurrence of autoimmune inflammatory disorders in various organs has been increasingly reported as an adverse effect of nivolumab. Of the disorders associated with nivolumab, Sicca syndrome occurs in 3% to 11% of cases and has unknown pathologic mechanisms. Whether the absence of the PD-1 pathway causes functional and morphologic disorders in lacrimal glands was determined by analyzing PD-1 gene-knockout (Pdcd1) mice. Histopathologic analysis showed that Pdcd1 mice developed dacryoadenitis beginning at 3 to 4 months of age, and deteriorated with age. Flow-cytometric analysis confirmed that cells infiltrating the affected lacrimal glands consisted mainly of CD3 T cells and only a small proportion of CD19 B cells. Among infiltrating T cells, the CD4 Th-cell subset consisted of Th1 cells producing interferon-γ in an early stage of dacryoadenitis in Pdcd1 mice. Experiments of lymphocyte transfer from Pdcd1 into irradiated wild-type mice confirmed that CD4 T cells from Pdcd1 mice induced dacryoadenitis. These results indicate that PD-1 plays an important role in the prevention of autoimmune inflammatory disorders in lacrimal glands caused by activated CD4 Th1 cells.
程序性细胞死亡蛋白 1（PD-1）是一种抑制性分子，可抑制免疫反应并维持免疫稳态。此外，PD-1 通路阻止癌症被免疫细胞攻击。抗 PD-1 抗体疗法，如纳武单抗，可改善癌症患者的生存率。然而，越来越多的报道称，纳武单抗会导致各种器官的自身免疫性炎症性疾病的发生，这是其不良反应之一。在与纳武单抗相关的疾病中，干燥综合征在 3%至 11%的病例中发生，其病理机制尚不清楚。通过分析 PD-1 基因敲除（Pdcd1）小鼠，确定 PD-1 通路的缺失是否导致泪腺的功能和形态异常。组织病理学分析表明，Pdcd1 小鼠从 3 到 4 月龄开始出现泪腺炎，且随着年龄的增长而恶化。流式细胞术分析证实，浸润受影响泪腺的细胞主要由 CD3 T 细胞组成，而只有一小部分 CD19 B 细胞。在浸润的 T 细胞中，CD4 Th 细胞亚群在 Pdcd1 小鼠的泪腺炎早期产生干扰素-γ的 Th1 细胞。从 Pdcd1 向照射野生型小鼠转移淋巴细胞的实验证实，来自 Pdcd1 小鼠的 CD4 T 细胞可诱导泪腺炎。这些结果表明，PD-1 在预防由激活的 CD4 Th1 细胞引起的自身免疫性炎症性泪腺疾病中发挥重要作用。
