Disease-associated CIAS1 mutations induce monocyte death, revealing low-level mosaicism in mutation-negative cryopyrin-associated periodic syndrome patients
Disease-associated CIAS1 mutations induce monocyte death, revealing low-level mosaicism in mutation-negative cryopyrin-associated periodic syndrome patients
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DOI：
10.1182/blood-2007-06-094201
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发表时间：
2008-02-15
期刊：
影响因子：
20.3
通讯作者：
Nakahata, Tatsutoshi
中科院分区：
文献类型：
--
作者：
Saito, Megumu;Nishikomori, Ryuta;Nakahata, Tatsutoshi
低温比林相关周期性综合征(CAPS)是一种全身性自身炎症性疾病，其中大多数患者的冷诱导自体炎症综合征(CIAS)1基因发生突变。尽管有难以区分的临床特征，但通过传统的核苷酸测序，一些患者缺乏CIAS1突变。我们最近报道了一例CAPS患者患有突变的CIAS1嵌合体，并提出了由于嵌合体频率较低，“突变阴性”患者中CIAS1突变被忽视的可能性。为了确定在“突变阴性”患者中是否存在潜在突变细胞，我们试图鉴定患者单核细胞突变相关的生物学表型。我们发现，在携带CIAS1突变的单核细胞中，脂多糖选择性地诱导坏死样细胞死亡。单核细胞死亡与CIAS1上调相关，依赖于组织蛋白酶B，不依赖于caspase-1。细胞死亡是CIAS1突变的单核细胞固有的，不受炎症环境的调节，与疾病严重程度或抗IL-1治疗无关。通过收集脂多糖处理后死亡的单核细胞，我们成功地在4例“突变阴性”CAPS患者中的3例中富集了CIAS1突变的单核细胞，并鉴定出低水平的CIAS1嵌合体。我们的发现揭示了CIAS1突变在促进坏死样细胞死亡方面的新作用，并证明了CIAS1嵌合体在突变阴性的CAPS患者中发挥着重要作用。
Cryopyrin-associated periodic syndrome (CAPS) is a spectrum of systemic autoinflammatory disorders in which the majority of patients have mutations in the cold-induced autoinflammatory syndrome (CIAS)1 gene. Despite having indistinguishable clinical features, some patients lack CIAS1 mutations by conventional nucleotide sequencing. We recently reported a CAPS patient with mosaicism of mutant CIAS1, and raised the possibility that CIAS1 mutations were overlooked in,"mutation-negative" patients, due to a low frequency of mosaicism. To deter-mine whether there were latent mutant cells in "mutation-negative" patients, we sought to identify mutation-associated biologic phenotypes of patients' monocytes. We found that lipopolysaccharide selectively induced necrosis-like cell death in monocytes bearing CIAS1 mutations. Monocyte death correlated with CIAS1 up-regulation, was dependent on cathepsin B, and was independent of caspase-1. Cell death was intrinsic to CIAS1-mutated monocytes, was not mediated by the inflammatory milieu, and was independent of disease severity or anti-IL-1 therapy. By collecting dying monocytes after lipopolysaccharide treatment, we succeeded in enriching CIAS1-mutant monocytes and identifying low-level CIAS1-mosaicism in 3 of 4 "mutationnegative" CAPS patients. Our findings reveal a novel effect of CIAS1 mutations in promoting necrosis-like cell death, and demonstrate that CIAS1 mosaicism plays an important role in mutation-negative CAPS patients.