Correlation of Secretory Activity of Neutrophils With Genotype in Patients With Familial Mediterranean Fever
Correlation of Secretory Activity of Neutrophils With Genotype in Patients With Familial Mediterranean Fever
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DOI：
10.1002/art.39784
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发表时间：
2016-12-01
影响因子：
13.3
通讯作者：
Wittkowski, Helmut
中科院分区：
文献类型：
--
作者：
Gohar, Faekah;Orak, Banu;Wittkowski, Helmut
目标。家族性地中海热(FMF)是一种由吡喃编码的MEFV突变引起的自身炎症性疾病。患者出现反复但自限性的急性炎症发作，并经常有持续性的亚临床炎症。其病理生理机制尚不完全清楚，但中性粒细胞过度激活是该病的一个特征。S100A12是一种中性粒细胞衍生的促炎危险信号，在活动期FMF中显著升高。本研究旨在研究FMF患者外周血中中性粒细胞的体外分泌活性，并探讨S100A12与疾病活动性及基因分型的关系。对携带P.M694V突变的FMF患者(1例为复合杂合子，5例为纯合子)患者的中性粒细胞和4例健康对照的中性粒细胞进行体外纯化和刺激。检测中性粒细胞分泌S100A12、IL-18、IL-1β和caspase-1。在这些体外分析的基础上，还对128例临床和遗传学特征的FMF患者的血清S100A12、IL-18和IL-1β浓度进行了分析。在体外，来自P.M694V阳性患者的未受刺激的中性粒细胞自发地比来自健康对照组的中性粒细胞自发地分泌更多的S100A12、IL-18和caspase 1。血清S100A12水平与疾病活动性和基因分型有关，纯合子患者血清S100A12水平最高，复合杂合子患者血清S100A12水平高于杂合子患者。与P.M694V突变阴性个体相比，杂合子、复合杂合子和纯合子P.M694V阳性患者在非活动期和亚临床疾病期间血清S100A12和IL-18水平较高。已知携带p.M694V突变的患者的FMF表型更为严重。本文报道了由非常规分泌途径分泌的两种分子S100A12和IL-18，它们的浓度与FMF患者的临床疾病活动性和基因相关。在这种临床和遗传上不同的疾病中，管理这些替代标记物可能有助于改善患者的护理和预后。
Objective. Familial Mediterranean fever (FMF) is an autoinflammatory disorder caused by pyrin-encoding MEFV mutations. Patients present with recurrent but self-limiting episodes of acute inflammation and often have persistent subclinical inflammation. The pathophysiology is only partially understood, but neutrophil overactivation is a hallmark of the disease. S100A12 is a neutrophil-derived proinflammatory danger signal that is strongly elevated in active FMF. This study was undertaken to characterize the secretory activity of neutrophils in vitro and investigate the association of S100A12 with disease activity and genotype in patients with FMF.Methods. Neutrophils from FMF patients carrying the p.M694V mutation (1 compound heterozygous and 5 homozygous) and neutrophils from 4 healthy control subjects were purified and stimulated in vitro. Neutrophil secretion of S100A12, interleukin-18 (IL-18), IL-1 beta, and caspase 1 was determined. Based on these in vitro analyses, serum concentrations of S100A12, IL-18, and IL-1 beta were also analyzed in 128 clinically and genetically characterized patients with FMF.Results. In vitro, unstimulated neutrophils from p.M694V-positive patients spontaneously secreted more S100A12, IL-18, and caspase 1 compared to neutrophils from healthy controls. Serum concentrations of S100A12 correlated with disease activity and genotype, with the levels being highest in homozygous patients and with compound heterozygotes displaying higher levels than heterozygotes. Compared to individuals negative for the p.M694V mutation, heterozygous, compound heterozygous, or homozygous p.M694V-positive patients had higher serum levels of S100A12 and IL-18 during inactive and subclinical disease.Conclusion. The FMF phenotype is known to be more severe in patients carrying the p.M694V mutation. This report describes 2 molecules secreted by unconventional secretory pathways, S100A12 and IL-18, whose concentrations correlated with clinical disease activity and genotype in patients with FMF. In this clinically and genetically heterogeneous disease, management of these surrogate markersmight help to improve patient care and outcomes.