Division of Rheumatology, Department of Medicine,University of Washington, Seattle, WA, USA.
Department of Public Health and Clinical Medicine, Umea University, Umea, Sweden.
Rheumatology (Oxford). 2023 Aug 1;62(8):2880-2886. doi: 10.1093/rheumatology/keac722.
Neutrophils are important in host defence. However, neutrophils are also linked to inflammation and organ damage. The purpose of this study was to assess whether markers of neutrophil activation are increased in PMR.
Levels of immune complexes (IC), calprotectin and neutrophil extracellular traps (NETs) were measured in plasma of healthy individuals (n = 30) and patients with PMR (n = 60), at flare and upon treatment with glucocorticoids using ELISA. Plasma-mediated neutrophil activation was assessed in presence of an FcγRIIA inhibitory antibody (IV.3).
Plasma levels of calprotectin and NETs were elevated in PMR (P < 0.001). Mechanistically, neutrophil activation was driven by ICs, present in plasma, able to up-regulate neutrophil activation markers CD66b and CD11b (P < 0.0001) in an FcγRIIA-dependent manner (P < 0.01). Of note, circulating levels of IC correlated with plasma induced CD66b and CD11b (r = 0.51, P = 0.004, and r = 0.46, P = 0.01, respectively) and decreased after glucocorticoid therapy. In contrast to NETs, calprotectin significantly decreased after glucocorticoid therapy (P < 0.001) and was higher in PMR without overlapping GCA compared with patients with overlapping disease (P = 0.014). Interestingly, musculoskeletal involvement was associated with elevated levels of calprotectin before initiation of glucocorticoid therapy (P = 0.036).
Neutrophil activation, including NET formation, is increased in PMR, through IC-mediated engagement of FcγRIIA. Clinically, neutrophil activation is associated with musculoskeletal involvement, with calprotectin, but not NETs, being a biomarker of treatment response in PMR patients. In all, IC-mediated neutrophil activation is a central process in PMR pathogenesis identifying potential novel therapeutic targets (FcγRIIA), as well as soluble markers for disease monitoring (calprotectin).
中性粒细胞在宿主防御中起重要作用。然而，中性粒细胞也与炎症和器官损伤有关。本研究旨在评估 PMR 中是否存在中性粒细胞活化标志物增加。
采用酶联免疫吸附试验（ELISA）检测健康个体（n=30）和 PMR 患者（n=60）在发作时和接受糖皮质激素治疗时血浆中的免疫复合物（IC）、钙卫蛋白和中性粒细胞胞外陷阱（NETs）水平。使用 FcγRIIA 抑制性抗体（IV.3）评估血浆介导的中性粒细胞活化。
PMR 患者血浆中钙卫蛋白和 NETs 水平升高（P<0.001）。在机制上，存在于血浆中的 IC 驱动中性粒细胞活化，上调中性粒细胞活化标志物 CD66b 和 CD11b（P<0.0001），呈 FcγRIIA 依赖性（P<0.01）。值得注意的是，循环 IC 水平与血浆诱导的 CD66b 和 CD11b 相关（r=0.51，P=0.004 和 r=0.46，P=0.01），且在糖皮质激素治疗后降低。与 NETs 不同，钙卫蛋白在糖皮质激素治疗后显著降低（P<0.001），且与重叠性 GCA 的 PMR 患者相比，无重叠性疾病的 PMR 患者的钙卫蛋白水平更高（P=0.014）。有趣的是，在开始糖皮质激素治疗前，肌肉骨骼受累与钙卫蛋白水平升高相关（P=0.036）。
PMR 中存在通过 IC 介导的 FcγRIIA 结合引起的中性粒细胞活化，包括 NET 形成。临床上，中性粒细胞活化与肌肉骨骼受累相关，钙卫蛋白而非 NETs 是 PMR 患者治疗反应的生物标志物。总之，IC 介导的中性粒细胞活化是 PMR 发病机制中的一个核心过程，确定了潜在的新型治疗靶点（FcγRIIA）以及疾病监测的可溶性标志物（钙卫蛋白）。
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