Monocytes From Patients With Macrophage Activation Syndrome and Secondary Hemophagocytic Lymphohistiocytosis Are Hyperresponsive to Interferon Gamma.
Monocytes From Patients With Macrophage Activation Syndrome and Secondary Hemophagocytic Lymphohistiocytosis Are Hyperresponsive to Interferon Gamma.
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DOI：
10.3389/fimmu.2021.663329
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发表时间：
2021
影响因子：
7.3
通讯作者：
Prencipe G
中科院分区：
文献类型：
--
作者：
Pascarella A;Bracaglia C;Caiello I;Arduini A;Moneta GM;Rossi MN;Matteo V;Pardeo M;De Benedetti F;Prencipe G
目的：研究继发性噬血细胞淋巴组织细胞增多症/巨噬细胞激活综合征患者单核细胞干扰素γ信号通路的激活情况，探讨磷酸化STAT1水平是否可作为疾病早期识别的生物标志物。前瞻性采集sHLH/MAS活动期、未接受糖皮质激素治疗(n=10)和接受糖皮质激素治疗(n=14)患儿的新鲜全血标本。以活动期无MAS的系统性幼年特发性关节炎(SJIA)患者、缓解期sHLH/MAS患者和其他风湿性疾病患者为疾病对照组。用不同浓度的干扰素γ刺激全血细胞10min，用流式细胞仪检测单核细胞内酪氨酸磷酸化信号转导通路(PSTAT1)水平。未经治疗的sHLH/MAS患者的单核细胞pSTAT1的基础水平显著高于糖皮质激素治疗的sHLH/MAS患者和所有其他疾病对照组的单核细胞。此外，观察到未经治疗的单核细胞对干扰素γ的反应性显著增加，这是通过体外刺激后pSTAT1水平的增加来评估的。单核细胞中的pSTAT1水平区分了未接受糖皮质激素治疗的sHLH/MAS患者和活动期sJIA或其他风湿病患者[AuC0.93；95%可信区间0.85-1.00，p<；0.001]。全血细胞IFNG mRNA水平、外周血单核细胞干扰素γ水平和单核细胞pSTAT1水平之间存在显著的相关性。我们的数据显示，sHLH/MAS患者单核细胞中pSTAT1的基础水平较高，且对干扰素γ刺激具有高反应性，这表明下游干扰素γ信号通路的激活受到干扰，是导致这些患者发生过度炎症的因素之一。最后，观察到糖皮质激素在体内影响PSTAT1水平，这使得在临床实践中很难考虑将PSTAT1水平的测量作为识别早期sHLH/MAS患者的生物标志物。
To investigate the activation of the IFNγ signaling pathway in monocytes of patients with secondary hemophagocytic lymphohistiocytosis (sHLH)/macrophage activation syndrome (MAS) and to evaluate whether levels of phosphorylated STAT1 represent a biomarker for the identification of patients at early stages of the disease. Fresh whole blood samples from pediatric patients with active sHLH/MAS, not receiving (n=10) and receiving glucocorticoids (n=14) at time of sampling, were prospectively collected. As disease control groups, patients with active systemic juvenile idiopathic arthritis (sJIA) without MAS, patients with sHLH/MAS in remission and patients with other rheumatic diseases were also sampled. Whole blood cells were left unstimulated or stimulated with increasing concentrations of IFNγ for 10 minutes and the intracellular Tyrosine (701)-phosphorylated STAT1 (pSTAT1) levels were evaluated in monocytes by flow cytometry. Monocytes from untreated sHLH/MAS patients showed significantly higher basal levels of pSTAT1 compared to those observed in monocytes from glucocorticoid-treated sHLH/MAS patients and from all the other disease controls. In addition, a significant increase in responsiveness to IFNγ, as assessed by increased levels of pSTAT1 following ex vivo stimulation, was observed in monocytes from untreated sHLH/MAS patients. pSTAT1 levels in monocytes distinguished patients with sHLH/MAS not treated with glucocorticoids from patients with active sJIA or with other rheumatic diseases [AUC, 0.93; 95% confidence interval 0.85-1.00, p<0.001]. Statistically significant correlations between IFNG mRNA levels in whole blood cells, circulating IFNγ levels and pSTAT1 levels in sHLH/MAS monocytes were found. Our data demonstrating higher basal levels of pSTAT1 as well as a hyperreactivity to IFNγ stimulation in monocytes from patients with sHLH/MAS point to perturbations in the activation of downstream IFNγ signaling pathway as a contributor to the hyperinflammation occurring in these patients. Finally, the observation that glucocorticoids affect pSTAT1 levels in vivo, makes it difficult to consider the measurement of pSTAT1 levels as a biomarker to identify patients at early stages of sHLH/MAS in clinical practice.
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影响因子：
30.5
作者：
Hu, XY;Herrero, C;Ivashkiv, LB
通讯作者：
Ivashkiv, LB
影响因子：
3.7
作者：
Prencipe, Giusi;Bracaglia, Claudia;De Benedetti, Fabrizio
通讯作者：
De Benedetti, Fabrizio
影响因子：
158.5
作者：
Locatelli, F.;Jordan, M. B.;de Min, C.
通讯作者：
de Min, C.
影响因子：
4.4
作者：
Hu, XY;Li, WP;Ivashkiv, LB
通讯作者：
Ivashkiv, LB
DOI：
10.1084/jem.20102538
发表时间：
2011-06-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Zoller EE;Lykens JE;Terrell CE;Aliberti J;Filipovich AH;Henson PM;Jordan MB
通讯作者：
Jordan MB