Elucidation of regulation mechanism of ocular surface inflammation by IKZF1

• Project/Area Number: 16K11327
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Ophthalmology
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: UETA MAYUMI 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 ; Ohsako Seiko
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: IKZF1 / 皮膚粘膜炎症 / 眼表面炎症 / 上皮細胞 / 炎症制御 / 眼表面上皮 / 眼免疫学

Outline of Final Research Achievements

We found that human epidermis and conjunctival epithelium expressed IKZF1, and in PHCjECs and HEKa, the expression of IKZF1 mRNA was upregulated by stimulation with polyI:C, a TLR3 ligand. In Ikzf1 Tg, we observed dermatitis and mucosal inflammation including the ocular surface. In contact dermatitis model, inflammatory infiltrates in the skin of Ikzf1 Tg were significantly increased compared with wild type. Microarray analysis showed that Lcn2, Adh7, Epgn, Ifi202b, Cdo1, Gpr37, Duoxa1, Tnfrsf4, and Enpp5 genes were significantly upregulated in the epidermis of Ikzf1 Tg compared with wild type.

Academic Significance and Societal Importance of the Research Achievements

全ゲノム関連解析によりIKZF1遺伝子が皮膚粘膜炎症性疾患の発症に大きく関与していることが研究代表者の以前の研究で明らかとなっている。本研究は、生体において、IKZF1遺伝子が皮膚粘膜炎症を制御していることを世界で初めて発見した重要な研究である。本研究により、IKZF1は皮膚粘膜炎症疾患に対する新規治療薬の標的となると考えられる。

Research Products

• [Journal Article] Distinctly regulated functions and mobilization of CD11c-positive cells elicited by TLR3- and IPS-1 signaling in the cornea (2019)
  • Author(s): Ueta Mayumi、Hamuro Junji、Ohsako Suzuko、Kinoshita Shigeru
  • Journal Title: Immunology Letters Volume: 206 Pages: 49-53
  • DOI: 10.1016/j.imlet.2018.12.004
  • Peer Reviewed
• [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] 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] 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] 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] 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
• [Presentation] Regulation of Ikzf1 inducible genes in epidermis (2018)
  • Author(s): Mayumi Ueta, Hiromi Nishigaki, Suzuko Ohsako, Shigeru Kinoshita.
  • Organizer: The European Academy of Allergy and Clinical Immunology (EAACI) Congress 2018
  • Int'l Joint Research
• [Presentation] Regulation of Ikzf1 inducible genes by TLR3 and IPS-1 (2018)
  • Author(s): Mayumi Ueta, Hiromi Nishigaki, Kiyoko Oosako, Shigeru Kinoshita
  • Organizer: 2018 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO)
  • Int'l Joint Research
• [Presentation] Distinctly regulated functions and mobilization of CD11c-positive cells by TLR3- and IPS-1 signaling in the cornea (2018)
  • Author(s): Mayumi Ueta, Junji Hamuro, Shigeru Kinoshita
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] Ocular Surface inflammation is regulated by innate immunity ----- focusing on Stevens-Johnson syndrome ----- (2017)
  • Author(s): MAYUMI UETA
  • Organizer: 2017 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO)
  • Int'l Joint Research
• [Presentation] Elevated Expression of Ikaros Family Zinc Finger 1 (IKZF1) Exacerbates Mucocutaneous Inflammation (2017)
  • Author(s): Mayumi Ueta, Junji Hamuro, Naomi Nakamura,Risa Tamagawa-Mineoka, Norito Katoh, Shigeru Kinoshita.
  • Organizer: The European Academy of Allergy and Clinical Immunology (EAACI) Congress 2017
  • Int'l Joint Research
• [Presentation] Skin Inflammation of Ikzf1-EGFP Transgenic Mice (2017)
  • Author(s): MAYUMI Ueta, Junji Hamuro, Shigeru Kinoshita,
  • Organizer: The EAACI/ESCD Skin Allergy Meeting, SAM
  • Int'l Joint Research
• [Presentation] 感冒薬関連SJS疾患関連遺伝子IKZF1による皮膚粘膜炎症制御 (2017)
  • Author(s): 上田真由美、羽室淳爾、中村直美、峠岡理沙、加藤則人、人見祐基、徳永勝士、木下茂.
  • Organizer: 日本人類遺伝学会 第６１回大会
• [Presentation] HLA and Stevens Johnson Syndrome (2017)
  • Author(s): MAYUMI UETA
  • Organizer: I PANCORNEA CONGRESS
  • Place of Presentation: 米国、マイアミ
  • Int'l Joint Research / Invited
• [Presentation] Pathology of Stevens-Johnson Syndrome (2016)
  • Author(s): Mayumi Ueta
  • Organizer: 2nd Chulalongkorn Eye Center-Kyoto Prefectural University of Medicine Joint meeting
  • Place of Presentation: タイ、バンコク
  • Int'l Joint Research / Invited