Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
JCI Insight. 2016 Oct 6;1(16):e87270. doi: 10.1172/jci.insight.87270.
Lymphangioleiomyomatosis (LAM) is a rare lung disease of women that leads to progressive cyst formation and accelerated loss of pulmonary function. Neoplastic smooth muscle cells from an unknown source metastasize to the lung and drive destructive remodeling. Given the role of NK cells in immune surveillance, we postulated that NK cell activating receptors and their cognate ligands are involved in LAM pathogenesis. We found that ligands for the NKG2D activating receptor UL-16 binding protein 2 (ULBP2) and ULBP3 are localized in cystic LAM lesions and pulmonary nodules. We found elevated soluble serum ULBP2 (mean = 575 pg/ml ± 142) in 50 of 100 subjects and ULBP3 in 30 of 100 (mean = 8,300 pg/ml ± 1,515) subjects. LAM patients had fewer circulating NKG2D NK cells and decreased NKG2D surface expression. Lung function decline was associated with soluble NKG2D ligand (sNKG2DL) detection. The greatest rate of decline forced expiratory volume in 1 second (FEV, -124 ± 30 ml/year) in the 48 months after enrollment (NHLBI LAM Registry) occurred in patients expressing both ULBP2 and ULBP3, whereas patients with undetectable sNKG2DL levels had the lowest rate of FEV decline (-32.7 ± 10 ml/year). These data suggest a role for NK cells, sNKG2DL, and the innate immune system in LAM pathogenesis.
淋巴管平滑肌瘤病（LAM）是一种罕见的女性肺部疾病，导致进行性囊形成和肺功能加速丧失。来源不明的肿瘤平滑肌细胞转移到肺部并驱动破坏性重塑。鉴于 NK 细胞在免疫监视中的作用，我们推测 NK 细胞激活受体及其同源配体参与 LAM 的发病机制。我们发现 NKG2D 激活受体 UL-16 结合蛋白 2（ULBP2）和 ULBP3 的配体定位于囊性 LAM 病变和肺结节中。我们发现 100 名受试者中的 50 名（平均=575 pg/ml ± 142）和 30 名（平均=8300 pg/ml ± 1515）患有 ULBP2 和 ULBP3 的可溶性血清 ULBP2 和 ULBP3 升高。LAM 患者循环中的 NKG2D NK 细胞较少，NKG2D 表面表达减少。肺功能下降与可溶性 NKG2D 配体（sNKG2DL）检测相关。在登记后的 48 个月（NHLBI LAM 登记处），FEV 下降最快的是同时表达 ULBP2 和 ULBP3 的患者（-124 ± 30 ml/年），而 sNKG2DL 水平不可检测的患者 FEV 下降率最低（-32.7 ± 10 ml/年）。这些数据表明 NK 细胞、sNKG2DL 和先天免疫系统在 LAM 发病机制中起作用。
