Saito Megumu, Nishikomori Ryuta, Kambe Naotomo, Fujisawa Akihiro, Tanizaki Hideaki, Takeichi Kyoko, Imagawa Tomoyuki, Iehara Tomoko, Takada Hidetoshi, Matsubayashi Tadashi, Tanaka Hiroshi, Kawashima Hisashi, Kawakami Kiyoshi, Kagami Shinji, Okafuji Ikuo, Yoshioka Takakazu, Adachi Souichi, Heike Toshio, Miyachi Yoshiki, Nakahata Tatsutoshi
Departments of Pediatrics, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto, Japan.
Blood. 2008 Feb 15;111(4):2132-41. doi: 10.1182/blood-2007-06-094201. Epub 2007 Dec 6.
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 determine 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 "mutation-negative" 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.
冷吡啉相关周期性综合征（CAPS）是一类全身性自身炎症性疾病，大多数患者的冷诱导自身炎症综合征（CIAS）1基因存在突变。尽管具有难以区分的临床特征，但一些患者通过传统核苷酸测序未发现CIAS1突变。我们最近报道了一名患有突变型CIAS1嵌合体的CAPS患者，并提出由于嵌合体频率较低，CIAS1突变在“突变阴性”患者中被忽视的可能性。为了确定“突变阴性”患者中是否存在潜在的突变细胞，我们试图鉴定患者单核细胞的突变相关生物学表型。我们发现脂多糖选择性地诱导携带CIAS1突变的单核细胞发生坏死样细胞死亡。单核细胞死亡与CIAS1上调相关，依赖于组织蛋白酶B，且不依赖于半胱天冬酶-1。细胞死亡是CIAS1突变单核细胞所固有的，不是由炎症环境介导的，并且与疾病严重程度或抗IL-1治疗无关。通过在脂多糖处理后收集濒死的单核细胞，我们成功富集了CIAS1突变的单核细胞，并在4例“突变阴性”CAPS患者中的3例中鉴定出低水平的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CIAS1嵌合体在突变阴性CAPS患者中起重要作用。
