Development of CINCA syndrome therapy based upon the pathophysiology of CINCA syndrome elucidated by cytoengineering.

• Project/Area Number: 21390310
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Kyoto University
• Principal Investigator: NISHIKOMORI Ryuta 京都大学, 医学研究科, 准教授 (70359800)
• Co-Investigator(Kenkyū-buntansha): HEIKE Toshio 京都大学, 医学研究科, 教授 (90190173)
• Co-Investigator(Renkei-kenkyūsha): OHARA Osamu かずさDNA研究所, ヒトゲノム究部 (20370926) ; KAMBE Naotomo 千葉大学, 医学研究院, 准教授 (50335254)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2011: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2010: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2009: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: 小児免疫 / アレルギー / 膠原病 / CINCA症候群 / NLRP3 / 体細胞モザイク / iPS細胞

Research Abstract

CINCA syndrome is an autoinflammatory disease with fever, urticarial rash, aseptic meningitis, and arthritis caused by NLRP3 gene mutations. It has been known that 40% of the CINCA syndrome patients lack NLRP3 mutations by Sanger sequencing. Recently we have reported"mutation-negative"CINCA syndrome can be caused by NLRP3 somatic mosaicism. In this study, we have collected"mutation-negative"CINCA patients worldwide and demonstrated that 69% of the"mutation-negative"CINCA patients are caused by NLRP3 mosaicism. We also developed an easier and less labor-intensive method to identify NLRP3 mosaicism by next-generation sequencing. Furthermore, we created induced pluripotent stem cells(iPSC) derived from CINCA syndrome and developed methods to differentiate the iPSC to macrophages and chondrocytes, which can be utilized for research on the elucidation of the pathophysiology of the CINCA syndrome.

Research Products

• [Journal Article] Detection of Base Substitution-Type Somatic Mosaicism of the NLRP3 Gene with> 99. 9% Statistical Confidence by Massively Parallel Sequencing (2012)
  • Author(s): Izawa, K., A. Hijikata, N. Tanaka, T. Kawai, M. K. Saito, R. Goldbach-Mansky, I. Aksentijevich, T. Yasumi, T. Nakahata, T. Heike, R. Nishikomori, and O. Ohara
  • Journal Title: DNA Res Volume: 19 Issue: 2 Pages: 143-52
  • DOI: 10.1093/dnares/dsr047
  • Peer Reviewed
• [Journal Article] Cryopyrin-associated Periodic Syndrome (2012)
  • Author(s): Aoyama, K., H. Amano, Y. Takaoka, R. Nishikomori, and O. Ishikawa
  • Journal Title: ACase Report and Review of the Japanese Literature. Acta Derm Venereol Volume: 92 Issue: 4 Pages: 395-398
  • DOI: 10.2340/00015555-1322
  • NAID: 40017399781
  • Peer Reviewed
• [Journal Article] Characterization of NLRP3 variants in Japanese cryopyrin-associated periodic syndrome patients (2012)
  • Author(s): Ohnishi, H., T. Teramoto, H. Iwata, Z. Kato, T. Kimura, K. Kubota, R. Nishikomori, H. Kaneko, M. Seishima, and N. Kondo
  • Journal Title: J Clin Immunol Volume: 32 Issue: 2 Pages: 221-9
  • DOI: 10.1007/s10875-011-9629-0
  • Peer Reviewed
• [Journal Article] High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome (2011)
  • Author(s): Tanaka N, Izawa K, Saito MK, Sakuma M, Oshima K, Ohara O, Nishikomori R, Morimoto T, Kambe N, Goldbach-Mansky R, Aksentijevich I, de Saint Basile G, Neven B, van Gijn M, Frenkel J, Arostegui JI, Yague J, Merino R, Ibanez M, Pontillo A, Takada H, Imagawa T
  • Journal Title: Arthritis Rheum Volume: 63 Issue: 11 Pages: 3625-32
  • DOI: 10.1002/art.30512
  • Peer Reviewed
• [Journal Article] Familial cases of periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis syndrome (2011)
  • Author(s): Adachi, M., A. Watanabe, A. Nishiyama, Y. Oyazato, I. Kamioka, M. Murase, A. Ishida, H. Sakai, R. Nishikomori, and T. Heike
  • Journal Title: The Journal of pediatrics Volume: 158 Issue: 1 Pages: 155-9
  • DOI: 10.1016/j.jpeds.2010.09.054
  • Peer Reviewed
• [Journal Article] Patient with neonatal-onset chronic hepatitis presenting with mevalonate kinase deficiency with a novel MVK gene mutation (2011)
  • Author(s): Tahara, M., H. Sakai, R. Nishikomori, T. Yasumi, T. Heike, I. Nagata, A. Inui, T. Fujisawa, Y. Shigematsu, K. Nishijima, K. Kuwakado, S. Watabe, and J. Kameyama
  • Journal Title: Modern rheumatology the Japan Rheumatism Association Volume: 21 Issue: 6 Pages: 641-645
  • DOI: 10.1007/s10165-011-0442-7
  • NAID: 10030206205
  • Peer Reviewed
• [Journal Article] Novel mutations of MVK gene in Japanese family members affected with hyperimmunog lobulinemia D and periodic fever syndrome (2011)
  • Author(s): Mizuno, T., H. Sakai, R. Nishikomori, K. Oshima, O. Ohara, I. Hata, Y. Shigematsu, T. Ishige, K. Tamura, and H. Arakawa
  • Journal Title: Rheumatol Int Volume: (in press) Issue: 12 Pages: 3761-3764
  • DOI: 10.1007/s00296-011-2225-z
  • Peer Reviewed
• [Journal Article] Nationwide Survey of Patients with Primary Immunodeficiency Diseases in Japan (2011)
  • Author(s): Ishimura M, 他
  • Journal Title: Journal of clinical immunology Volume: (in press) Issue: 6 Pages: 968-976
  • DOI: 10.1007/s10875-011-9594-7
  • Peer Reviewed
• [Journal Article] Enhanced NF-kappa activation with aninflammasome activator correlates with activity of auto inflammatory disease associated with NLRP3 mutations outside of exon 3 (2010)
  • Author(s): Kambe, N., Satoh, T., Tanizaki, H., Fujisawa, A., Saito, M. K. & Nishikomori, R
  • Journal Title: Arthritis Rheum Volume: 62 Issue: 10 Pages: 3124-3125
  • DOI: 10.1002/art.27619
  • Peer Reviewed
• [Journal Article] Enhanced NF-kappaB activation with an inflammasome activator correlates with activity of autoinflammatory disease associated with NLRP3 mutations outside of exon 3 : comment on the article by Jeru et al. (2010)
  • Author(s): Kambe, N., T.Satoh, H.Tanizaki, A.Fujisawa, M.K.Saito, R.Nishikomori
  • Journal Title: Arthritis Rheum Volume: 62 Pages: 3124-3125
  • Peer Reviewed
• [Journal Article] The inflammasome, an innate immunity guardian, participates in skin urticarial reactions and contact hypersensitivity. (2010)
  • Author(s): Kambe, N., Y Nakamura, M.Saito, R.Nishikomori
  • Journal Title: Allergol Int Volume: 59 Pages: 105-113
  • NAID: 10029669779
• [Journal Article] Role of the NOD2 genotype in the clinical phenotype of Blau syndrome and early-onset sarcoidosis (2009)
  • Author(s): Okafuji, I., Nishikomori, R., Kanazawa, N., Kambe, N., Fujisawa, A., Yamazaki, S., Saito, M., Yoshioka, T., Kawai, T., Sakai, H., Tanizaki, H., Heike, T., Miyachi, Y. & Nakahata, T.
  • Journal Title: Arthritis Rheum Volume: 60 Issue: 1 Pages: 242-250
  • DOI: 10.1002/art.24134
  • Peer Reviewed
• [Journal Article] Cardiac infiltration in early-on setsarcoi dosis associated with a novel heterozygous mutation (2009)
  • Author(s): Okada, S., Konishi, N., Tsumura, M., Shirao, K., Yasunaga, S., Sakai, H., Nishikomori, R., Takihara, Y. & Kobayashi M
  • Journal Title: CARD15 Rheumatology(Oxford) Volume: 48 Issue: 6 Pages: 706-707
  • DOI: 10.1093/rheumatology/kep061
  • Peer Reviewed
• [Journal Article] Mast cells mediate neutrophil recruitment and vascular leakage through the NLRP3 inflammasome in histamine-independent urticaria (2009)
  • Author(s): Nakamura, Y., Kambe, N., Saito, M., Nishikomori, R., Kim, Y. G., Murakami, M., Nunez, G. & Matsue, H.
  • Journal Title: J Exp Med Volume: 206 Issue: 5 Pages: 1037-1046
  • DOI: 10.1084/jem.20082179
  • Peer Reviewed
• [Journal Article] Role of the NOD2 genotype in the clinical phenotype of Blau syndrome and early-onset sarcoidosis (2009)
  • Author(s): Okafuji I, 他
  • Journal Title: Arthritis Rheum 60 Pages: 242-250
  • Peer Reviewed
• [Journal Article] Mast cells mediate neutrophil recruitment and vascular leakage through the NLRP3 inflammasome in histamine-independent urticaria (2009)
  • Author(s): Nakamura Y, 他
  • Journal Title: J Exp Med 206 Pages: 1037-1042
  • Peer Reviewed
• [Journal Article] A case of early-onset sarcoidosis with a six-base deletion in the NOD2 gene (2009)
  • Author(s): Sakai H, 他
  • Journal Title: Rheumatology 49 Pages: 194-196
  • Peer Reviewed
• [Presentation] Diagnosis of NLRP3 somatic mosaicism in CINCA/NOMID patients using next-generation sequencing (2011)
  • Author(s): Izawa K, 他
  • Organizer: PReS 2011 18th
  • Place of Presentation: Bruges, Belgium
  • Year and Date: 2011-09-17
• [Presentation] NLRP3体細胞モザイクはCINCA症候群の25%以上に認められる (2011)
  • Author(s): 田中尚子, 他
  • Organizer: 日本リウマチ学会総会
  • Place of Presentation: ポートピアホテル、神戸
  • Year and Date: 2011-07-20
• [Presentation] 原発性免疫不全症における臨床遺伝学日本における自己炎症疾患における遺伝子診断について (2011)
  • Author(s): 西小森隆太, 他
  • Organizer: 遺伝医学合同学術集会2011
  • Place of Presentation: 京都大学百周年時計台記念館、京都(招待講演)
  • Year and Date: 2011-06-17
• [Presentation] Rapid detection ofNLRP3 somatic mosaicism using next-generation sequencing (2011)
  • Author(s): 井澤和司、西小森隆太、八角高裕、平家俊男、土方敦司、小原收
  • Organizer: 第56回日本人類遺伝学会・第11回東アジア人類遺伝学会共同大会
  • Place of Presentation: 千葉
• [Presentation] Diagnosis of nlrp3 somatic mosaicism incinca/nomid patients using next-generation sequencing : Poster Session, Board P292 : 18thEuropean Pediatric Rheumatology Congress (2011)
  • Author(s): K. Izawa, A. Hijikata, R. Nishikomori, O. Ohara, J. Abe, N. Tanaka, M. K. Saito, R. Goldbach-Mansky, I. Aksentijevich, T. Kawai, T. Yasumi, T. Nakahata, T. Heike
  • Organizer: September
  • Place of Presentation: Bruges, Belgium
• [Presentation] NLRP3体細胞モザイクはCINCA症候群の25%以上に認められる (2011)
  • Author(s): 田中尚子、井澤和司、斎藤潤、作間未織、大嶋宏一、小原収、西小森隆太、森本剛、中畑龍俊、平家俊男
  • Organizer: 第114回日本小児科学会学術集会
  • Place of Presentation: 東京
• [Presentation] High incidence of nlrp3 somatic mosaicism in chronic infantile neurological cutaneous andarticular syndrome patients : a report from an international multicenter collaborative study (2011)
  • Author(s): R. Nishikomori, N. Tanikaze, K. Izawa, M. K. Saito, R. Goldbach-ManskyI. Aksentijevich, G. de Saint Basile, B. Neven, J. Frenkel, M. Van Gijn, J. I. Arostegui, J. Yague, T. Morimoto, M. Sakuma, N. Kambe, T. Yasumi, T. Kawai, A. Pontillo, K. Oshima, H. Tak
  • Organizer: OP0142 : Annual European Congress of Rheumatology EULAR
  • Place of Presentation: London, United Kingdom
• [Presentation] サイトカインを標的にした病態の制御の可能性抗IL-1療法 (2010)
  • Author(s): 西小森隆太
  • Organizer: 第30回日本炎症・再生医学会
  • Place of Presentation: 東京
• [Presentation] 炎症病態の観点から見た小児疾患自己炎症疾患における炎症病態NLRP3遺伝子を中心にして (2010)
  • Author(s): 西小森隆太
  • Organizer: 第113回日本小児科学会総会
  • Place of Presentation: 盛岡
• [Presentation] サイトカインを標的とした病態制御の可能性抗IL-1療法 (2010)
  • Author(s): 西小森隆太
  • Organizer: 第30回日本炎症・再生医学会
  • Place of Presentation: 東京(招待講演)
• [Presentation] "炎症"病態の観点から見た小児疾患 自己炎症性疾患における炎症病態 NLRP3遺伝子を中心にして (2010)
  • Author(s): 西小森隆太
  • Organizer: 第113回日本小児科学会総会
  • Place of Presentation: 盛岡(招待講演)
• [Presentation] 自己炎症症候群の新しい展開"NLRP3変異陰性"CINCA症候群/NOMIDにおけるNLRP3モザイシズムについて (2010)
  • Author(s): 西小森隆太
  • Organizer: 第55回日本リウマチ学会総会
  • Place of Presentation: 神戸(招待講演)
• [Presentation] 自己炎症性疾患の病態とシグナル伝達 (2009)
  • Author(s): 西小森隆太
  • Organizer: 第41回日本小児感染症学会
  • Place of Presentation: 福井
  • Year and Date: 2009-11-14
• [Presentation] 小児リウマチ疾患に対する分子標的治療薬の適応CINCA症候群に対する抗IL-1療法について (2009)
  • Author(s): 西小森隆太
  • Organizer: 第53回日本リウマチ学会総会
  • Place of Presentation: 東京
  • Year and Date: 2009-04-24
• [Presentation] 小児リウマチ性疾患に対する分子標的治療薬の適応CINCA症候群に対する抗IL-1療法について (2009)
  • Author(s): 西小森隆太
  • Organizer: 第53回日本リウマチ学会総会
  • Place of Presentation: 東京
  • Year and Date: 2009-04-24