Invetigation of pathogensis of SJS/TEN

• Project/Area Number: 16H05488
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Ophthalmology
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: SOTOZONO CHIE 京都府立医科大学, 医学(系)研究科(研究院), 教授 (30216585)
• Co-Investigator(Kenkyū-buntansha): 木下 茂 京都府立医科大学, 医学(系)研究科(研究院), 教授 (30116024) ; 上田 真由美 京都府立医科大学, 医学(系)研究科(研究院), 准教授 (60398386)
• Research Collaborator: NISHIGAKI HIROMI
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2018: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2016: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: Stevens-Johnson症候群 / SJS/TEN / Stevens-Johnson症候群（SJS） / 中毒性表皮壊死融解症（TEN） / 視力障害 / 遺伝素因 / 病態解明 / 薬疹 / 病態 / 微生物感染 / 臨床サンプル / 遺伝子 / プロテオミクス / 中毒性表皮壊死症 / 臨床研究

Outline of Final Research Achievements

Analysis of lipid mediators of SJS / TEN patients with severe ocular complications showed that there were less glycerine lipids and higher in oxidized PC in the SJS / TEN patients. In proteomics analysis of tears of the SJS / TEN patients, IL-6, IL-8, IFN-g, eotaxin, RANTES, and MIP-1b were elevated in the SJS / TEN patients. In exhaustive protein expression analysis in ocular surface tissues , expression of PIGR, HEPACAM2 and ADH1C decreased significantly and ODZ2 (teneurin-2) increased significantly. In genetic analysis, REC114 and several new related genes were able to identify.

Academic Significance and Societal Importance of the Research Achievements

新規の疾患関連遺伝子REC114の発見や、患者組織・細胞や涙液の遺伝子ならびにタンパクの変化の発見は、病態把握につながり、今後の治療方針の決定や、新規治療法の開発に役立つものと期待される

Research Products

• [Journal Article] Expression of prostaglandin E2 receptor 3 in the eyelid epidermis of patients with Stevens-Johnson syndrome/toxic epidermal necrolysis (2019)
  • Author(s): Mieno Hiroki、Ueta Mayumi、Yamada Keiko、Yamanaka Yukito、Nakayama Tomomichi、Watanabe Akihide、Kinoshita Shigeru、Sotozono Chie
  • Journal Title: British Journal of Ophthalmology Volume: - Issue: 7 Pages: 1022-1027
  • DOI: 10.1136/bjophthalmol-2018-313587
  • Peer Reviewed
• [Journal Article] Association of human antigen class I genes with cold medicine-related Stevens-Johnson syndrome with severe ocular complications in a Korean population (2019)
  • Author(s): Jun Ikhyun、Rim John Hoon、Kim Mee Kum、Yoon Kyung-Chul、Joo Choun-Ki、Kinoshita Shigeru、Seo Kyoung Yul、Ueta Mayumi
  • Journal Title: British Journal of Ophthalmology Volume: 103 Issue: 4 Pages: 573-576
  • DOI: 10.1136/bjophthalmol-2018-313263
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mucocutaneous inflammation in the Ikaros Family Zinc Finger 1-keratin 5-specific transgenic mice (2018)
  • Author(s): Ueta M, Hamuro J, Nishigaki H, Nakamura N, Shinomiya K, Mizushima K, Hitomi Y, Tamagawa-Mineoka R, Yokoi N, Naito Y, Tokunaga K, Katoh N, Sotozono C, Kinoshita S.
  • Journal Title: Allergy Volume: 73 Issue: 2 Pages: 395-404
  • DOI: 10.1111/all.13308
  • Peer Reviewed / Open Access
• [Journal Article] 急性期に川崎病との鑑別を要したStevens-Johnson症候群の1例 (2018)
  • Author(s): 松本佳保里、福岡秀記、富田晃正、峠岡理沙、稲富 勉、上田真由美、外園千恵
  • Journal Title: 日眼会誌 Volume: 122（9) Pages: 705-710
  • Peer Reviewed / Open Access
• [Journal Article] 白内障手術後の前嚢縁白色塊から術後真菌性眼内炎の診断に至ったStevens-Johnson症候群の1例 (2018)
  • Author(s): 吉岡 誇、福岡秀記、米田一仁、外園千恵
  • Journal Title: 日眼会誌 Volume: 122(12) Pages: 928-933
  • Peer Reviewed / Open Access
• [Journal Article] Results of Detailed Investigations Into Stevens-Johnson Syndrome With Severe Ocular Complications (2018)
  • Author(s): Ueta Mayumi
  • Journal Title: Investigative Opthalmology & Visual Science Volume: 59 Issue: 14 Pages: DES183-DES183
  • DOI: 10.1167/iovs.17-23537
  • Peer Reviewed / Open Access
• [Journal Article] Severe Dry Eye With Combined Mechanisms is Involved in the Ocular Sequelae of SJS/TEN at the Chronic Stage (2018)
  • Author(s): Sotozono Chie、Ueta Mayumi、Yokoi Norihiko
  • Journal Title: Investigative Opthalmology & Visual Science Volume: 59 Issue: 14 Pages: DES80-DES80
  • DOI: 10.1167/iovs.18-24019
  • Peer Reviewed / Open Access
• [Journal Article] HLA Alleles and CYP 2C9*3 as Predictors of Phenytoin Hypersensitivity in East Asians (2018)
  • Author(s): Su Shih‐Chi、Chen Chun‐Bing、Chang Wan‐Chun、Wang Chuang‐Wei、Fan Wen‐Lang、Lu Lai‐Ying、Nakamura Ryosuke、Saito Yoshiro、Ueta Mayumi、Kinoshita Shigeru、Sukasem Chonlaphat、et al
  • Journal Title: Clinical Pharmacology & Therapeutics Volume: 105 Issue: 2 Pages: 476-485
  • DOI: 10.1002/cpt.1190
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Association between HLA-B*44:03-HLA-C*07:01 haplotype and cold medicine-related Stevens-Johnson syndrome with severe ocular complications in Thailand (2018)
  • Author(s): Jongkhajornpong Passara、Lekhanont Kaevalin、Pisuchpen Phattrawan、Chantaren Patchima、Puangsricharern Vilavun、Prabhasawat Pinnita、Suphapeetiporn Kanya、Kinoshita Shigeru、Ueta Mayumi
  • Journal Title: British Journal of Ophthalmology Volume: 102 Issue: 9 Pages: 1303-1307
  • DOI: 10.1136/bjophthalmol-2017-311823
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Downregulation of interferon-γ-induced protein 10 in the tears of patients with Stevens-Johnson syndrome with severe ocular complications in the chronic stage (2017)
  • Author(s): Ueta Mayumi、Nishigaki Hiromi、Sotozono Chie、Kinoshita Shigeru
  • Journal Title: BMJ Open Ophthalmology Volume: 1 Issue: 1 Pages: e000073-e000073
  • DOI: 10.1136/bmjophth-2017-000073
  • Peer Reviewed
• [Journal Article] Human Leukocyte Antigen Class I Genes Associated With Stevens-Johnson Syndrome and Severe Ocular Complications Following Use of Cold Medicine in a Brazilian Population. (2017)
  • Author(s): 1.Wakamatsu TH, Ueta M, Tokunaga K, Okada Y, Loureiro RR, Costa KA, Sallum JM, Milhomens JA, Inoue C, Sotozono C, Gomes JÁ, Kinoshita S
  • Journal Title: JAMA Ophthalmol. Volume: in press Issue: 4 Pages: 355-355
  • DOI: 10.1001/jamaophthalmol.2017.0074
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Genome-wide association study using the ethnicity-specific Japonica array: identification of new susceptibility loci for cold medicine-related Stevens-Johnson syndrome with severe ocular complications (2017)
  • Author(s): Mayumi Ueta , Hiromi Sawai*, Ryosei Shingaki, Yusuke Kawai, Chie Sotozono, Kaname Kojima, Kyung-Chul Yoon, Mee Kum Kim, Kyoung Yul Seo, Choun-Ki Joo, et al. *Contributed equally with the first author
  • Journal Title: Journal of Human Genetics Volume: 62 Issue: 4 Pages: 485-489
  • DOI: 10.1038/jhg.2016.160
  • NAID: 40021158280
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reply: amniotic membrane transplantation in Stevens-Johnson syndrome (2017)
  • Author(s): Jain Rajat、Sharma Namrata、Basu Sayan、Iyer Geetha、Ueta Mayumi、Sotozono Chie、Kannibiran Chitra、Rathi Varsha M.、Gupta Nidhi、Kinoshita Shigeru、Gomes Jos? A.P.、Chodosh James、Sangwan Virender S.
  • Journal Title: Survey of Ophthalmology Volume: 62 Issue: 2 Pages: 249-250
  • DOI: 10.1016/j.survophthal.2016.10.005
  • Peer Reviewed
• [Journal Article] 重症多形滲出性紅斑 スティーヴンス・ジョンソン症候群・中毒性表皮壊死症 診療ガイドライン (2017)
  • Author(s): 塩原哲夫、狩野葉子、水川良子、佐山浩二、 橋本公二、藤山幹子、 相原道子、池澤善郎、松倉節子、末木博彦、飯島正文、 渡辺秀晃、 森田栄伸、新原寛之、 浅田秀夫、小豆澤宏明、宮川史、椛島健治、中島沙恵子、野村尚史、 橋爪秀夫、阿部理一郎、 高橋勇人、 青山裕美、黒沢美智子、莚田泰誠、外園千恵、木下茂、上田真由美
  • Journal Title: 日眼会誌 Volume: 121 Pages: 42-86
  • NAID: 130007040223
  • Peer Reviewed
• [Journal Article] 難治性眼表面疾患に対する新規治療とその実用化 (2017)
  • Author(s): 外園千恵
  • Journal Title: 京都府立医科大学雑誌 Volume: 126 Pages: 145-155
  • NAID: 40021168804
  • Peer Reviewed
• [Journal Article] Stevens-Johnson症候群の治療 (2017)
  • Author(s): 吉川大和、外園千恵
  • Journal Title: Frontiers in Dry Eye 涙液から見たオキュラ―サーフェス 別刷 Volume: 12 Pages: 51-54
  • Peer Reviewed
• [Journal Article] Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis - A Comprehensive Review and Guide to Therapy. I. Systemic Disease. (2016)
  • Author(s): 4.Kohanim S, Palioura S, Saeed HN, Akpek EK, Amescua G, Basu S, Blomquist PH, Bouchard CS, Dart JK, Gai X, Gomes JA, Gregory DG, Iyer G, Jacobs DS, Johnson AJ, Kinoshita S, Mantagos IS, Mehta JS, Perez VL, Pflugfelder SC, Sangwan VS, Sippel KC, Sotozono C, Srinivasan B, Tan DT, Tandon R, Tseng SC, Ueta M, Chodosh J.
  • Journal Title: Ocul Surf Volume: 14(1) Issue: 1 Pages: 2-19
  • DOI: 10.1016/j.jtos.2015.10.002
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Acute and Chronic Ophthalmic Involvement in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis - A Comprehensive Review and Guide to Therapy. II. Ophthalmic Disease. (2016)
  • Author(s): 2.Kohanim S, Palioura S, Saeed HN, Akpek EK, Amescua G, Basu S, Blomquist PH, Bouchard CS, Dart JK, Gai X, Gomes JA, Gregory DG, Iyer G, Jacobs DS, Johnson AJ, Kinoshita S, Mantagos IS, Mehta JS, Perez VL, Pflugfelder SC, Sangwan VS, Sippel KC, Sotozono C, Srinivasan B, Tan DT, Tandon R, Tseng SC, Ueta M, Chodosh J.
  • Journal Title: Ocul Surf. Volume: 14(2) Issue: 2 Pages: 00011-2
  • DOI: 10.1016/j.jtos.2016.02.001
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Analysis of Ocular Manifestation and Genetic Association of Allopurinol-Induced Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in South Korea. (2016)
  • Author(s): Lee HS, Ueta M, Kim MK, Seo KY, Sotozono C, Kinoshita S, Yoon KC
  • Journal Title: Cornea Volume: 35(2) Issue: 2 Pages: 199-204
  • DOI: 10.1097/ico.0000000000000708
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Stevens Johnsons Syndrome: The Role of an Ophthalmologist. (2016)
  • Author(s): 3.Jain R, Sharma N, Basu S, Iyer G, Ueta M, Sotozono C, Kannibiran C, Rathi VM, Gupta N, Kinoshita S, Gomes JA, Chodosh J, Sangwan VS.
  • Journal Title: Surv Ophthalmol Volume: - Issue: 4 Pages: 168-88
  • DOI: 10.1016/j.survophthal.2016.01.004
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Plasma Lipid Profiling of Patients with Chronic Ocular Complications Caused by Stevens Johnson Syndrome/Toxic Epidermal Necrolysis (2016)
  • Author(s): Saito K, Ueta M, Maekawa K, Sotozono C, Kinoshita S, Saito Y
  • Journal Title: PLoS One Volume: 11 Issue: 11 Pages: e0167402-e0167402
  • DOI: 10.1371/journal.pone.0167402
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 重症多形滲出性紅斑 スティーヴンス・ジョンソン症候群・中毒性表皮壊死症 診療ガイドライン (2016)
  • Author(s): 塩原哲夫、狩野葉子、水川良子、佐山浩二、 橋本公二、藤山幹子、 相原道子、池澤善郎、松倉節子、末木博彦、飯島正文、 渡辺秀晃、 森田栄伸、新原寛之、 浅田秀夫、小豆澤宏明、宮川史、椛島健治、中島沙恵子、野村尚史、 橋爪秀夫、阿部理一郎、 高橋勇人、 青山裕美、黒沢美智子、莚田泰誠、外園千恵、木下茂、上田真由美
  • Journal Title: 日皮会誌 Volume: 126 Pages: 1637-1685
  • NAID: 130007040223
  • Open Access
• [Journal Article] Ocular surface reconstruction using stem cell and tissue engineering. (2015)
  • Author(s): Nakamura T, Inatomi T, Sotozono C, Koizumi N, Kinoshita S
  • Journal Title: Prog Retin Eye Res Volume: 51 Pages: 187-207
  • DOI: 10.1016/j.preteyeres.2015.07.003
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Treatment strategies of chronic SJS patients in Japan (2019)
  • Author(s): Sotozono C
  • Organizer: The 4th international Stevens-Johnson syndrome symposium
  • Int'l Joint Research
• [Presentation] HLA types associated with Stevens-Johnson Syndrome with Severe Ocular Complications (2019)
  • Author(s): Ueta M
  • Organizer: The 4th international Stevens-Johnson syndrome symposium
• [Presentation] Significant Association between HLA-B*44:03 and Cold medicine related Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) with Severe Ocular complications in various ethnic populations. (2018)
  • Author(s): Ueta M，Jongkhajornpong P，Wakamatsu TH，Kannabiran C，Lekhanont K，Gomes JAP，SaV，Sotozono C，Kinoshita Sngwan
  • Organizer: Drug Hypersensitivitiy Meeing 2018
  • Int'l Joint Research
• [Presentation] Gene Expression Analysis of conjunctival epithelium of Stevens-Johnson syndrome patients in the chronic stage. (2018)
  • Author(s): Ueta M，Nishigaki H，Sotozono C，Ohsako S，Yokoi N，Kinoshita S
  • Organizer: Biennial Meeting of the International Society for Eye Research(ISER 2018)
  • Int'l Joint Research
• [Presentation] Cold medicine related Stevens-Johnson syndrome associated with Hla-B*44:03 in various ethnic populations. (2018)
  • Author(s): Ueta M，Jongkhajornpong P，Wakamatsu TH，Kannabiran C，Lekhanont K，Gomes JA，Sangwan VS，Sotozono C，Kinoshita S
  • Organizer: AAO 2018
  • Int'l Joint Research
• [Presentation] 慢性期Stevens-Johnson症候群の特徴的所見と診断基準 (2018)
  • Author(s): 外園千恵、三重野洋喜、上田真由美、小川葉子、佐竹良之、島﨑 潤、森田栄伸
  • Organizer: 第124回京都眼科学会
• [Presentation] 前眼部所見からみた慢性期Stevens-Johnson症候群の悪化・非悪化に関する検討 (2018)
  • Author(s): 吉川大和、上田真由美、福岡秀記、田尻健介、稲富 勉、横田 勲、横井則彦、木下 茂、池田恒彦、外園千恵
  • Organizer: 第72回日本臨床眼科学会
• [Presentation] Pharmacogenomics「HLA class I & II analysis of Acetaminophen related Stevens-Johnson Syndrome」． (2018)
  • Author(s): Ueta M，Tokunaga K，Sotozono C，Yabe T，Kinoshita S
  • Organizer: 日本人類遺伝学会 第63回大会
• [Presentation] Pterygium, MMP, SJS, and Chemical Injury・Treatment of Stevens-Johnson Syndrome (2017)
  • Author(s): Sotozono Chie
  • Organizer: 32nd Asia-Pacific Academy of Ophthalmology (APAO2017)
  • Int'l Joint Research
• [Presentation] The expression of prostaglandin E2 receptor 3 in the eyelid epidermis of patients with Stevens-Johnson syndrome/toxic epidermal necrolysis (2017)
  • Author(s): Hiroki Mieno,Mayumi Ueta,Keiko Yamada,Yukito Yamanaka,Tomomichi Nakayama,Akihide Watanabe,Shigeru Kinoshita,Chie Sotozono
  • Organizer: ARVO 2017 Annual Meeting
  • Int'l Joint Research
• [Presentation] Extended removal of continuous curvilinear capsulorrhexis, including fungal lesions, in a Stevens-Johnson patient after cataract surgery (2017)
  • Author(s): Hideki Fukuoka,Hokoru Yoshioka,Kazuhito Yoneda,Chie Sotozono
  • Organizer: 35th Congress of the European Society of Cataract and Refractive Surgeons
  • Int'l Joint Research
• [Presentation] Long-term Clinical Course of Stevens-Johnson Syndrome with Ocular Sequelae (2017)
  • Author(s): Yamato Yoshikawa,Mayumi Ueta,Tsutomu Inatomi,Norihiko Yokoi,Tsunehiko Ikeda,Chie Sotozono
  • Organizer: AAO 2017
  • Int'l Joint Research
• [Presentation] 瘢痕性角結膜上皮症 up to date (2017)
  • Author(s): 外園千恵
  • Organizer: 第121回日本眼科学会総会
• [Presentation] 前嚢縁の真菌塊形成により白内障術後眼内炎と判明したStevens-Johnson症候群の一例 (2017)
  • Author(s): 福岡秀記、吉岡誇、米田一仁、外園千恵.
  • Organizer: フォーサム2017大阪・第54回日本眼感染症学会
• [Presentation] 付加価値使用コンタクトレンズの可能性輪部支持ハードコンタクトレンズの可能性 (2017)
  • Author(s): 外園千恵
  • Organizer: フォーサム2017大阪・第60回日本コンタクトレンズ学会総会
• [Presentation] 近未来の組織・細胞治療羊膜移植および培養自家口腔粘膜上皮シート移植 (2017)
  • Author(s): 外園千恵
  • Organizer: 第16回日本組織移植学会総会・学術集会
• [Presentation] 慢性期Stevens-Johnson症候群の涙液中IP-10の低下 (2017)
  • Author(s): 上田真由美、西垣裕美、外園千恵、木下 茂
  • Organizer: 角膜カンファランス2017/第41回日本角膜学会総会/第33回日本角膜移植会
• [Presentation] Stevens-Johnson症候群に対する培養自家口腔粘膜上皮移植と輪部支持HCL装用 (2017)
  • Author(s): 富田有佳、上田真由美、中村隆宏、稲富 勉、木下 茂、外園千恵
  • Organizer: 角膜カンファランス2017/第41回日本角膜学会総会/第33回日本角膜移植会
• [Presentation] 慢性期Stevens-Johnson症候群の長期経過 (2017)
  • Author(s): 吉川大和、上田真由美、稲富 勉、横井則彦、木下 茂、田尻健介、池田恒彦、外園千恵
  • Organizer: 角膜カンファランス2017/第41回日本角膜学会総会/第33回日本角膜移植会
• [Presentation] Stevens-Johnson症候群および中毒性表皮壊死症の初期治療と予後 (2017)
  • Author(s): 松本佳保里、稲富 勉、上田真由美、外園千恵、木下 茂
  • Organizer: 角膜カンファランス2017/第41回日本角膜学会総会/第33回日本角膜移植会
• [Presentation] 保存的治療が奏功した中毒性表皮壊死症による重篤な角膜上皮欠損の1例 (2017)
  • Author(s): 森川恵輔、稲富 勉、近藤衣里、稲垣香代子、外園千恵
  • Organizer: 角膜カンファランス2017/第41回日本角膜学会総会/第33回日本角膜移植会
• [Presentation] 睫毛乱生症を合併したSJS患者の眼瞼皮膚表皮におけるEP3の発現の検討 (2017)
  • Author(s): 三重野洋喜、上田真由美、山田桂子、山中行人、中山知倫、渡辺彰英、木下 茂、外園千恵
  • Organizer: 第121回日本眼科学会総会
• [Presentation] 川崎病との鑑別を要したStevens-Johnson症候群の一例 (2017)
  • Author(s): 松本佳保里、福岡秀記、富田晃正、峠岡理沙、稲富 勉、上田真由美、外園千恵
  • Organizer: 第73回日本弱視斜視学会総会(JASA)・第42回小児眼科学会総会(JAPO)合同学会