Katholieke University Leuven, Leuven, Belgium.
University Hospitals Leuven, Leuven, Belgium.
Arthritis Rheumatol. 2021 May;73(5):875-884. doi: 10.1002/art.41605. Epub 2021 Apr 1.
Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood. The predominant subtypes, oligoarticular and polyarticular JIA, are traditionally considered to be autoimmune diseases with a central role for T cells and autoantibodies. Mounting evidence suggests an important role for neutrophils in JIA pathogenesis. We undertook this study to investigate the phenotypic features of neutrophils present in the blood and inflamed joints of patients.
JIA synovial fluid (SF) and parallel blood samples from JIA patients and healthy children were collected. SF-treated neutrophils from healthy donors and pleural neutrophils from patients with pleural effusion were investigated as controls for SF exposure and extravasation. Multicolor flow cytometry panels allowed for in-depth phenotypic analysis of neutrophils, focusing on the expression of adhesion molecules, activation, and maturation markers and chemoattractant receptors. Multiplex technology was used to quantify cytokines in plasma and SF.
SF neutrophils displayed an activated, hypersegmented phenotype with decreased CD62L expression, up-regulation of adhesion molecules CD66b, CD11b, and CD15, and down-regulation of CXCR1/2. An elevated percentage of CXCR4-positive neutrophils was detected in SF from patients. Pleural neutrophils showed less pronounced maturation differences. Strikingly, significant percentages of SF neutrophils showed a profound up-regulation of atypical neutrophil markers, including CXCR3, intercellular adhesion molecule 1, and HLA-DR.
Our data show that neutrophils in inflamed joints of JIA patients have an activated phenotype. This detailed molecular analysis supports the notion that a complex intertwining between these innate immune cells and adaptive immune events drives JIA.
幼年特发性关节炎（JIA）是儿童中最常见的风湿性疾病。主要亚型寡关节型和多关节型 JIA 传统上被认为是自身免疫性疾病，以 T 细胞和自身抗体为中心。越来越多的证据表明中性粒细胞在 JIA 发病机制中起重要作用。我们进行这项研究是为了调查存在于患者血液和发炎关节中的中性粒细胞的表型特征。
收集 JIA 患者的关节液（SF）和血液以及健康儿童的平行血液样本。从健康供体的 SF 处理中性粒细胞和胸腔积液患者的胸腔中性粒细胞作为 SF 暴露和渗出的对照进行研究。多色流式细胞术面板允许对中性粒细胞进行深入的表型分析，重点是粘附分子、激活和成熟标志物以及趋化因子受体的表达。使用多重技术定量血浆和 SF 中的细胞因子。
SF 中性粒细胞表现出激活、过度分叶的表型，CD62L 表达降低，粘附分子 CD66b、CD11b 和 CD15 上调，CXCR1/2 下调。在患者的 SF 中检测到 CXCR4 阳性中性粒细胞的百分比升高。胸腔中性粒细胞显示出不那么明显的成熟差异。引人注目的是，SF 中性粒细胞中显著比例的中性粒细胞表现出非典型中性粒细胞标志物的明显上调，包括 CXCR3、细胞间粘附分子 1 和 HLA-DR。
我们的数据表明，JIA 患者炎症关节中的中性粒细胞具有激活的表型。这种详细的分子分析支持这样一种观点，即这些先天免疫细胞与适应性免疫事件之间的复杂交织驱动 JIA。
