University of Leuven, Leuven, Belgium.
University Hospitals Leuven, Leuven, Belgium.
Arthritis Rheumatol. 2017 Jan;69(1):213-224. doi: 10.1002/art.39933.
Systemic juvenile idiopathic arthritis (JIA) is an immunoinflammatory disease characterized by arthritis and systemic manifestations. The role of natural killer (NK) cells in the pathogenesis of systemic JIA remains unclear. The purpose of this study was to perform a comprehensive analysis of NK cell phenotype and functionality in patients with systemic JIA.
Transcriptional alterations specific to NK cells were investigated by RNA sequencing of highly purified NK cells from 6 patients with active systemic JIA and 6 age-matched healthy controls. Cytokines (NK cell-stimulating and others) were quantified in plasma samples (n = 18). NK cell phenotype and cytotoxic activity against tumor cells were determined (n = 10), together with their interferon-γ (IFNγ)-producing function (n = 8).
NK cells from the systemic JIA patients showed an altered gene expression profile compared to cells from the healthy controls, with enrichment of immunoinflammatory pathways, increased expression of innate genes including TLR4 and S100A9, and decreased expression of immune-regulating genes such as IL10RA and GZMK. In the patients' plasma, interleukin-18 (IL-18) levels were increased, and a decreased ratio of IFNγ to IL-18 was observed. NK cells from the patients exhibited specific alterations in the balance of inhibitory and activating receptors, with decreased killer cell lectin-like receptor G1 and increased NKp44 expression. Although NK cells from the patients showed increased granzyme B expression, consistent with intact cytotoxicity and degranulation against a tumor cell line, decreased granzyme K expression in CD56 NK cells and defective IL-18-induced IFNγ production and signaling were demonstrated.
NK cells are active players in the inflammatory environment typical of systemic JIA. Although their cytotoxic function is globally intact, subtle defects in NK-related pathways, such as granzyme K expression and IL-18-driven IFNγ production, may contribute to the immunoinflammatory dysregulation in this disease.
全身型幼年特发性关节炎（JIA）是一种以关节炎和全身表现为特征的免疫炎症性疾病。自然杀伤（NK）细胞在全身型 JIA 发病机制中的作用尚不清楚。本研究旨在对活动期全身型 JIA 患者的 NK 细胞表型和功能进行全面分析。
通过对 6 例活动期全身型 JIA 患者和 6 名年龄匹配的健康对照者的高度纯化 NK 细胞进行 RNA 测序，研究 NK 细胞的转录变化。检测了（刺激 NK 细胞的和其他的）细胞因子在血浆样本中的含量（n=18）。测定了 NK 细胞的表型和对肿瘤细胞的细胞毒性（n=10），并测定了其干扰素-γ（IFNγ）产生功能（n=8）。
与健康对照组相比，全身型 JIA 患者的 NK 细胞表现出改变的基因表达谱，免疫炎症途径富集，包括 TLR4 和 S100A9 在内的固有基因表达增加，免疫调节基因如 IL10RA 和 GZMK 表达降低。在患者的血浆中，白细胞介素-18（IL-18）水平升高，观察到 IFNγ与 IL-18 的比值降低。患者的 NK 细胞在抑制性和激活性受体的平衡方面表现出特定的改变，表现为杀伤细胞凝集素样受体 G1 减少和 NKp44 表达增加。尽管患者的 NK 细胞显示颗粒酶 B 表达增加，与对肿瘤细胞系的完整细胞毒性和脱颗粒作用一致，但在 CD56 NK 细胞中观察到颗粒酶 K 表达降低以及 IL-18 诱导的 IFNγ产生和信号传导缺陷。
NK 细胞是全身型 JIA 典型炎症环境中的活跃参与者。尽管它们的细胞毒性功能总体上是完整的，但 NK 相关途径的细微缺陷，如颗粒酶 K 表达和 IL-18 驱动的 IFNγ产生，可能导致该疾病的免疫炎症失调。
