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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. This Article Full Text Full Text (PDF) Supplemental Table and Figures All Versions of this Article: blood-2007-06-094201v1 111/4/2132    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Saito, M. Articles by Nakahata, T. Search for Related Content PubMed PubMed Citation Articles by Saito, M. Articles by Nakahata, T. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Disease-associated CIAS1 mutations induce monocyte death, revealing low-level mosaicism in mutation-negative cryopyrin-associated periodic syndrome patients Megumu Saito1, Ryuta Nishikomori1, Naotomo Kambe2,3, Akihiro Fujisawa2, Hideaki Tanizaki2, Kyoko Takeichi4, Tomoyuki Imagawa5, Tomoko Iehara6, Hidetoshi Takada7, Tadashi Matsubayashi8, Hiroshi Tanaka9, Hisashi Kawashima10, Kiyoshi Kawakami11, Shinji Kagami12, Ikuo Okafuji1, Takakazu Yoshioka1, Souichi Adachi1, Toshio Heike1, Yoshiki Miyachi2, and Tatsutoshi Nakahata1 Departments of1 Pediatrics and 2 Dermatology, Kyoto University Graduate School of Medicine, Kyoto; 3 Department of Dermatology, Chiba University Graduate School of Medicine, Chiba; 4 Department of Pediatrics, Ehime Prefectural Central Hospital, Matsuyama; 5 Department of Pediatrics, Yokohama City University School of Medicine, Yokohama; 6 Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto; 7 Department of Pediatrics, Kyushu University Graduate School of Medicine, Fukuoka; 8 Department of Pediatrics, Seirei Hamamatsu Hospital, Hamamatsu; 9 Department of Pediatrics, School of Medicine, Hirosaki University, Hirosaki; 10 Department of Pediatrics, Tokyo Medical University, Tokyo; 11 Department of Pediatrics, Kagoshima City Hospital, Kagoshima; and 12 Department of Dermatology, University of Tokyo, Tokyo, Japan 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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