Impaired endotoxin tolerance induction in patients with familial Mediterranean fever
Impaired endotoxin tolerance induction in patients with familial Mediterranean fever
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DOI：
10.1159/000093089
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发表时间：
2006-01-01
期刊：
影响因子：
5
通讯作者：
Mkrtchyan, Nana R.
中科院分区：
文献类型：
--
作者：
Davtyan, Tigran K.;Hakopyan, Gagik S.;Mkrtchyan, Nana R.
目的：探讨家族性地中海热（FMF）患者在发作期和缓解期中性粒细胞和单核细胞促炎性激活的周期性紊乱。研究方法：20名未经秋水仙碱治疗且未患有淀粉样变性的FMF患者和10名患有Behget病（BID）的患者入组本研究。流式细胞术检测吞噬功能、呼吸爆发、CD 11 a/CD 18表达和细胞内细胞因子合成。内毒素耐受性诱导定义为单核细胞在首次暴露于LPS后对脂多糖（LPS）活化的反应能力降低。结果如下：在FMF患者中，我们观察到中性粒细胞和单核细胞的吞噬活性和氧化爆发在缓解和下调的吞噬活性和刺激依赖的氧化爆发在攻击过程中的上调。对氧化爆发的比较分析表明，虽然中性粒细胞群体在自发和诱导性呼吸爆发的增加（缓解期间）和减少（发作期间）中显示出一定的周期性，但单核细胞群体的周期性非常差。此外，与缓解期患者相比，发作期患者中LPS诱导的氧化爆发和CID 11 a/CD 18整合素表面表达更高。在FMF患者发作期间，正常供体和BID患者中观察到单核细胞对LPS重复作用的同源耐受性的诱导，而缓解期患者的单核细胞未能诱导LPS同源耐受性，并表现出对细菌内毒素的敏感性增加。我们发现，秋水仙碱能够恢复受损的LPS同源耐受诱导FMF患者在缓解后，在FMF患者单核细胞中的IL-4的合成增加。结论：FMF期间的慢性炎症的特征在于单核细胞和中性粒细胞活化的周期性变化以及对内毒素的高度敏感性，这与FMF的发作性性质相关。在缓解期内增加的内毒素敏感性可能是由于单核细胞活化程序从“交替”变为“经典”活化的单核细胞，这可能对FMF的治疗具有重要意义。版权所有（c）2006 S. Karger AG，巴塞尔。
Objective:To investigate periodic disturbances in proinflammatory activation of neutrophils and monocytes in patients with familial Mediterranean fever (FMF) both during an attack and in remission. Methods: 20 FMF patients, who were naive to colchicine treatment and did not have amyloidosis, and 10 patients with Behget's disease (BID) were enrolled in this study. Phagocytosis, respiratory burst, CD11a/CD18 expression and intracellular cytokine synthesis were determined by flow cytometry. Endotoxin tolerance induction was defined by a reduced capacity of monocytes to respond to lipopolysaccharide (LPS) activation following a first exposure to LPS. Results: In FMF patients, we observed upregulation of neutrophil and monocyte phagocytic activity and oxidative burst during remission and downregulation of phagocytic activity and stimulus-dependent oxidative burst during an attack. A comparative analysis of oxidative burst has revealed that while the neutrophil population shows a certain periodicity in the increase (during remission) and decrease (during attacks) in the spontaneous and inducible respiratory burst, periodicity in the monocyte population is very poor. In addition, LPS-induced oxidative burst and CID11a/CD18 integrin surface expression is higher in patients during an attack compared to patients in remission. The induction of homologous tolerance of monocytes to the repeated action of LPS is observed in FMF patients during an attack, normal donors and patients with BID, whereas monocytes from patients in remission failed to induce LPS homologous tolerance and exhibited heightened sensitivity to bacterial endotoxin. We found that colchicine is able to restore impaired LPS homologous tolerance induction in FMF patients in remission upon increased synthesis of IL-4 in FMF patient monocytes. Conclusion: Chronic inflammation during FMF is characterized by periodic changes in monocyte and neutrophil activation and heightened sensitivity to endotoxin, which is associated with the episodic nature of FMF. Increased endotoxin sensitivity in the period of remission could result from a shift in the monocyte activation program from 'alternatively' into 'classically' activated monocytes, which may have important implications for the treatment of FMF. Copyright (c) 2006 S. Karger AG, Basel.