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Blood, 15 February 2008, Vol. 111, No. 4, pp. 2132-2141.
Prepublished online as a Blood First Edition Paper on December 6, 2007; DOI 10.1182/blood-2007-06-094201.
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Submitted June 6, 2007
Accepted November 29, 2007
Disease-associated CIAS1 mutations induce monocyte death, revealing low-level mosaicism in mutation-negative cryopyrin-associated periodic syndrome patients
Megumu Saito, Ryuta Nishikomori*, Naotomo Kambe, Akihiro Fujisawa, Hideaki Tanizaki, Kyoko Takeichi, Tomoyuki Imagawa, Tomoko Iehara, Hidetoshi Takada, Tadashi Matsubayashi, Hiroshi Tanaka, Hisashi Kawashima, Kiyoshi Kawakami, Shinji Kagami, Ikuo Okafuji, Takakazu Yoshioka, Souichi Adachi, Toshio Heike, Yoshiki Miyachi, and Tatsutoshi Nakahata
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
Department of Dermatology, Chiba University Graduate School of Medicine, Chiba, Japan
Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
Department of Pediatrics, Ehime Prefectural Central Hospital, Matsuyama, Japan
Department of Pediatrics, Yokohama City University School of Medicine, Yokohama, Japan
Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
Department of Pediatrics, Kyushu University Graduate School of Medicine, Fukuoka, Japan
Department of Pediatrics, Seirei Hamamatsu Hospital, Hamamatsu, Japan
Department of Pediatrics, School of Medicine, Hirosaki University, Hirosaki, Japan
Department of Pediatrics, Tokyo Medical University, Tokyo, Japan
Department of Pediatrics, Kagoshima City Hospital, Kagoshima, Japan
Department of Dermatology, University of Tokyo, Tokyo, Japan
* Corresponding author; email: rnishiko{at}kuhp.kyoto-u.ac.jp.
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 biological phenotypes of patients' monocytes. We found that lipopolysaccharide selectively induced necrosis-like cell death in monocytes bearing CIAS1 mutations. Monocyte death correlated with CIAS1 upregulation, 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 out 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.
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