Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Rd., Cambridge, United Kingdom.
Circulation. 2012 Aug 28;126(9):1099-109. doi: 10.1161/CIRCULATIONAHA.112.110619. Epub 2012 Jul 25.
Beyond their role as innate immune effectors, natural killer (NK) cells are emerging as important regulators of angiogenesis and vascular remodeling. Pulmonary arterial hypertension (PAH) is characterized by severe pulmonary vascular remodeling and has long been associated with immune dysfunction. Despite this association, a role for NK cells in disease pathology has not yet been described.
Analysis of whole blood lymphocytes and isolated NK cells from PAH patients revealed an expansion of the functionally defective CD56(-)/CD16(+) NK subset that was not observed in patients with chronic thromboembolic pulmonary hypertension. NK cells from PAH patients also displayed decreased levels of the activating receptor NKp46 and the killer immunoglobulin-like receptors 2DL1/S1 and 3DL1, reduced secretion of the cytokine macrophage inflammatory protein-1β, and a significant impairment in cytolytic function associated with decreased killer immunoglobulin-like receptor 3DL1 expression. Genotyping patients (n=222) and controls (n=191) for killer immunoglobulin-like receptor gene polymorphisms did not explain these observations. Rather, we show that NK cells from PAH patients exhibit increased responsiveness to transforming growth factor-β, which specifically downregulates disease-associated killer immunoglobulin-like receptors. NK cell number and cytotoxicity were similarly decreased in the monocrotaline rat and chronic hypoxia mouse models of PAH, accompanied by reduced production of interferon-γ in NK cells from hypoxic mice. NK cells from PAH patients also produced elevated quantities of matrix metalloproteinase 9, consistent with a capacity to influence vascular remodeling.
Our work is the first to identify an impairment of NK cells in PAH and suggests a novel and substantive role for innate immunity in the pathobiology of this disease.
自然杀伤 (NK) 细胞除了作为先天免疫效应细胞外，还正在成为血管生成和血管重塑的重要调节因子。肺动脉高压 (PAH) 的特征是严重的肺血管重塑，长期以来一直与免疫功能障碍有关。尽管存在这种关联，但 NK 细胞在疾病发病机制中的作用尚未得到描述。
对 PAH 患者的全血淋巴细胞和分离的 NK 细胞进行分析，显示功能缺陷的 CD56(-)/CD16(+) NK 亚群扩张，而在慢性血栓栓塞性肺动脉高压患者中未观察到这种情况。PAH 患者的 NK 细胞还表现出激活受体 NKp46 和杀伤免疫球蛋白样受体 2DL1/S1 和 3DL1 的水平降低，细胞因子巨噬细胞炎症蛋白-1β 的分泌减少，以及与杀伤免疫球蛋白样受体 3DL1 表达减少相关的细胞毒性功能显著受损。对 222 名患者（n=222）和 191 名对照（n=191）进行杀伤免疫球蛋白样受体基因多态性基因分型并未解释这些观察结果。相反，我们表明 PAH 患者的 NK 细胞对转化生长因子-β的反应性增加，这特异性地下调与疾病相关的杀伤免疫球蛋白样受体。在 PAH 的单克隆大鼠和慢性低氧小鼠模型中，NK 细胞数量和细胞毒性均降低，低氧小鼠 NK 细胞中干扰素-γ的产生减少。PAH 患者的 NK 细胞也产生了更高数量的基质金属蛋白酶 9，这与影响血管重塑的能力一致。
我们的工作首次在 PAH 中鉴定出 NK 细胞的损伤，并表明先天免疫在这种疾病的病理生物学中具有新的实质性作用。
