English

Profile

Mayumi Ueta, M.D., Ph.D.,
Associate Professor
Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan

Name,Family name: UETA
Forename: MAYUMI
Sex: Female
Nationality: Japanese

Present address (Mailing address):
Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine,
465 Kajiicho, Hirokoji, Kawaramachi, Kamigyoku, Kyoto 602-0841, Japan
Phone: 81-75-251-5578, Fax: 81-75-251-5663, e-mail: mueta@koto.kpu-m.ac.jp

Education and Research Experience

1990 M.D., Graduated from Kochi Medical School
1999 Graduate student, Kyoto Prefectural University of Medicine
2000 Reseach fellow, Research Institute for Microbial Diseases, Osaka University
2003 Ph.D., Kyoto Prefectural University of Medicine
2004 Department of Ophthalmology, Kyoto Prefectural University of Medicine
2008~2011 Assistant Professor, Research Center for Inflammation and Regenerative Medicine, Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan.
2010~ guest lecturer of Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
2010 Guest Researcher, NIH, USA
2011~2015 Associate Professor, Research Center for Inflammation and Regenerative Medicine, Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan.
2011~2014 Visiting Teacher, Osaka University, Kyoto, Japan.
2012~ Visiting Reseacher, Graduate School of Medicine, University of Tokyo, Japan
2015.4 ~ Associate Professor, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Publicaiton

Book

  1. Mayumi Ueta: Stevens-Johnson syndrome with ocular complication. biopharmaceutics and drug hypersensitivity. Paul Mossillo & John Pinzini editors, p129-150. Nova Science Publishers, Inc, NY, 2010.
  2. Mayumi Ueta: Ethnic differences in the association of HLA and SJS. European Ophthalmic Review vol3 issue 1, p15-18. Touch Briefings, London, 2009.

Paper

  1. Ueta M, Sawai H, Sotozono C, Hitomi Y, Kaniwa N, Kim MK, Seo KY, Yoon KC, Joo CK, Kannabiran C, Wakamatsu TH, Sangwan V, Rathi V, Basu S, Ozeki T, Mushiroda T, Sugiyama E, Maekawa K, Nakamura R, Aihara M, Matsunaga K, Sekine A, Gomes JAP, Hamuro J, Saito Y, Kubo M, Kinoshita S, Tokunaga K. New Susceptibility Gene, IKZF1, for Cold Medicine–Related Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis with Severe Mucosal Involvements. J Allergy Clin Immunol. In press[Epub ahead of print]
  2. Ueta M, Shoji J, Sotozono C, Kinoshita K. Downregulation of IL-8, ECP, and total IgE in the tears of patients with atopic keratoconjunctivitis treated with rebamipide eyedrops. Clinical and Translational Allergy, 2014 Oct 30;4:40.
  3. Nakamura N, Tamagawa-Mineoka R, Ueta M, Kinoshita S, Katoh N. Toll-Like Receptor 3 Increases Allergic and Irritant Contact Dermatitis. J Invest Dermatol. 2015 Feb;135(2):411-7.
  4. Kim DH, Yoon KC, Seo KY, Lee HS, Yoon SC, Sotozono C, Ueta M, Kim MK. The Role of Systemic Immunomodulatory Treatment and Prognostic Factors on Chronic Ocular Complications in Stevens-Johnson Syndrome. Ophthalmology. 2015 Feb;122(2):254-64..
  5. Ueta M, Kannabiran C, Wakamatsu TH, Kim MK,Yoon KC, Seo KY, Joo CK, Sangwan V, Rathi V, Basu S, Shamaila A, Lee HS, Yoon S, Sotozono C, Gomes JAP, Tokunaga K, Kinoshita S. Trans-ethnic study confirmed independent associations of HLA-A*02:06 and HLA-B*44:03 with cold medicine-related Stevens-Johnson syndrome with severe ocular surface complications. Sci Rep. 2014 ;4:5981.
  6. Sotozono C, Inatomi T, Nakamura T, Koizumi N, Yokoi N, Ueta M, Matsuyama K, Kaneda H, Fukushima M, Kinoshita S. Cultivated oral mucosal epithelial transplantation for persistent epithelial defect in severe ocular surface diseases with acute inflammatory activity. Acta Ophthalmol. 2014 ; 92(6):e447-53.
  7. Yamada K, Ueta M, Sotozono C, Yokoi N, Inatomi T, Kinoshita S. Upregulation of Toll-like receptor 5 expression in the conjunctival epithelium of various human ocular surface diseases. Br J Ophthalmol. 2014 ;. 98(8):1116-9.
  8. Ueta M, Kaniwa N, Sotozono C, Tokunaga K, Saito Y, Sawai H, Miyadera H, Sugiyama E, Maekawa K, Nakamura R, Nagato M, Aihara M, Matsunaga K, Takahashi Y, Furuya H, Muramatsu M, Ikezawa Z, Kinoshita S.Independent strong association of HLA-A*02:06 and HLA-B*44:03 with cold medicine-related Stevens-Johnson syndrome with severe mucosal involvement. Sci Rep. 2014;4:4862.
  9. Ueta M, Sotozono C, Koga A, Yokoi N, Kinoshita S. Usefulness of a New Therapy Using Rebamipide Eyedrops in Patients with VKC/AKC Refractory to Conventional Anti-Allergic Treatments. Allergol Int. 2014 63:75-81
  10. Isogai H, Miyadera H, Ueta M, Sotozono C, Kinoshita S, Tokunaga K, Hirayama N. In Silico Risk Assessment of HLA-A*02:06-Associated Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Caused by Cold Medicine Ingredients. J Toxicol. 2013;2013:514068. doi: 10.1155/2013/514068.
  11. Kaniwa N, Sugiyama E, Saito Y, Kurose K, Maekawa K, Hasegawa R, Furuya H, Ikeda H, Takahashi Y, Muramatsu M, Tohkin M, Ozeki T, Mushiroda T, Kubo M, Kamatani N, Abe M, Yagami A, Ueta M, Sotozono C, Kinoshita S, Ikezawa Z, Matsunaga K, Aihara M. Specific HLA types are associated with antiepileptic drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Japanese subjects. Pharmacogenomics. 2013. 14:1821-31
  12. Ueta M, Mizushima K, Naito Y, Narumiya S, Shinomiya K,1 Kinoshita S. Suppression of polyI:C-inducible gene expression by EP3 in murine conjunctival epithelium. Immunol Lett. 2013 Sep 12. pii: S0165-2478(13)00121-1.
  13. Watanabe A, Sotozono C, Ueta M, Katsuhiko Shinomiya, Kinoshita S, Kakizaki H, Selva D, FRANZCO F. Folliculitis in Clinically “Quiet” Chronic Stevens-Johnson syndrome. Ophthal Plast Reconstr Surg. 2014, 30:80-2.
  14. Ueta M, Sotozono C, Yokoi N, Kinoshita S: Rebamipide Suppresses PolyI:C-Stimulated Cytokine Production in Human Conjunctival Epithelial Cells. J Ocul Pharmacol Ther. 2013 Sep;29(7):688-93.
  15. Shinomiya K, Ueta M, Sotozono C, Inatomi T, Yokoi N, Koizumi N, Kinoshita S: Immunohistochemical analysis of inflammatory limbal conjunctiva adjacent to Mooren's ulcer. Br J Ophthalmol. 2013; 97(3):362-6
  16. Sotozono C, Inatomi T, Nakamura T, Koizumi N, Yokoi N, Ueta M, Matsuyama K, Miyakoda K, Kaneda H, Fukushima M, Kinoshita S: Visual Improvement after Cultivated Oral Mucosal Epithelial Transplantation. Ophthalmology. 2013; 120(1): 193-200.
  17. Ueta M: Epistatic interactions associated with stevens-johnson syndrome. Cornea. 2012; Suppl 1:S57-62
  18. Ueta M, Sotozono C, Yamada K, Yokoi N, Inatomi T, Kinoshita S: Expression of prostaglandin E receptor subtype EP4 in conjunctival epithelium of patients with ocular surface disorders: case-control study. BMJ Open. 2012; 2(5): pii: e001330. doi: 10.1136/bmjopen-2012-001330. Print 2012.
  19. Ueta M, Tokunaga K, Sotozono C, Sawai H, Tamiya G, Inatomi T, Kinoshita S: HLA-A*0206 with TLR3 Polymorphisms Exerts More than Additive Effects in Stevens-Johnson Syndrome with Severe Ocular Surface Complications. PLoS One. 2012; 7(8):e43650.
  20. Ueta M, Kinoshita S: Ocular surface inflammation is regulated by innate immunity. Prog Retin Eye Res. 2012; 31(6): 551-575.
  21. Imai K, Ueta M, Mori K, Ueno M, Ikeda Y, Oga T, Yokoi N, Shinomiya K, Narumiya S, Kinoshita S: Expression of prostaglandin F receptor in scleral and subconjunctival tissue. Br J Ophthalmol. 2012; 96(8): 1148-1149.
  22. Ueta M, Matsuoka T, Sotozono C, Kinoshita S: Prostaglandin E2 Suppresses Poly I: C-Stimulated Cytokine Production Via EP2 and EP3 in Immortalized Human Corneal Epithelial Cells. Cornea. 2012; 31(11): 1294-1298.
  23. Ueta M, Tamiya G, Tokunaga K, Sotozono C, Ueki M, Sawai H, Inatomi T, Matsuoka T, Akira S, Narumiya S, Tashiro K, Kinoshita S: Epistatic interaction between Toll-like receptor 3 (TLR3) and prostaglandin E receptor 3 (PTGER3) genes. J Allergy Clin Immunol. 2012; 129(5): 1413-1416.e11.
  24. Ueta M, Sotozono C, Yokoi N, Kinoshita S: Downregulation of monocyte chemoattractant protein 1 expression by prostaglandin e2 in human ocular surface epithelium. Arch Ophthalmol. 2012; 130(2): 249-251.
  25. Ueta M, Yokoi N, Kinoshita S: Endothelin-1 production upon polyI:C stimulation of human conjunctival epithelium. Br J Ophthalmol. 2011; 95(12):1760-1761.
  26. Ueta M, Sotozono C, Yokoi N, Inatomi T, Kinoshita S: Prostaglandin E Receptor Subtype EP3 Expression in Human Conjunctival Epithelium and Its Changes in Various Ocular Surface Disorders. PLoS One. 2011; 6(9): e25209.
  27. Tohkin M, Kaniwa N, Saito Y, Sugiyama E, Kurose K, Nishikawa J, Hasegawa R, Aihara M, Matsunaga K, Abe M, Furuya H, Takahashi Y, Ikeda H, Muramatsu M, Ueta M, Sotozono C, Kinoshita S, Ikezawa Z: A whole-genome association study of major determinants for allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis in Japanese patients. Pharmacogenomics J. 2013 ;13(1):60-9.
  28. Ueta M, Sotozono C, Kinoshita S: Expression of interleukin-4 receptor α in human corneal epithelial cells. Jpn J Ophthalmol. 2011; 55(4): 405-410.
  29. Yagi T, Sotozono C, Tanaka M, Fuwa M, Sekiyama E, Ueta M, Tashiro K, Kinoshita S: Cytokine storm arising on the ocular surface in a patient with Stevens-Johnson syndrome. Br J Ophthalmol. 2011; 95(7): 1030-1031.
  30. Ueta M, Matsuoka T, Yokoi N, Kinoshita S: Prostaglandin E2 suppresses polyinosine-polycytidylic acid (polyI:C)-stimulated cytokine production via prostaglandin (EP) 2 and 3 in human conjunctival epithelial cells. Br J Ophthalmol. 2011; 95(6): 859-863.
  31. Ueta M, Matsuoka T, Yokoi N, Kinoshita S: Prostaglandin E receptor subtype EP3 downregulates TSLP expression in human conjunctival epithelium. Br J Ophthalmol. 2011; 95(5): 742-743.
  32. Ueta M, Kawai T, Yokoi N, Akira S, Kinoshita S: Contribution of IPS-1 to polyI:C-induced cytokine production in conjunctival epithelial cells. Biochem Biophys Res Commun. 2011; 404(1): 419-423.
  33. Kaniwa N, Saito Y, Aihara M, Matsunaga K, Tohkin M, Kurose K, Furuya H, Takahashi Y, Muramatsu M, Kinoshita S, Abe M, Ikeda H, Kashiwagi M, Song Y, Ueta M, Sotozono C, Ikezawa Z, Hasegawa R: JSAR research group. HLA-B*1511 is a risk factor for carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Japanese patients. Epilepsia. 2010; 51(12): 2461-2465.
  34. Ueta M: Regulation of ocular surface inflammation by prostaglandin E receptor subtype EP3. Cornea. 2010; 29(11): S57-61.
  35. Ueta M, Sotozono C, Nakano M, Taniguchi T, Yagi T, Tokuda Y, Fuwa M, Inatomi T, Yokoi N, Tashiro K, Kinoshita S: Association between prostaglandin E receptor 3 polymorphisms and Stevens-Johnson syndrome identified by means of a genome-wide association study. J Allergy Clin Immunol. 2010; 126(6): 1218-1225.
  36. Ueta M, Sotozono C, Yokoi N, Inatomi T, Kinoshita S: Prostaglandin E receptor 4 expression in human conjunctival epithelium and its downregulation in devastating ocular surface inflammatory disorders. Arch Ophthalmol. 2010; 128(10): 1369-1371.
  37. Ueta M, Hamuro J, Kinoshita S: Spatio-temporal dual effects of IκBζ dictates the caution on visual disturbance resulting from IκBζ deficiency. Immunol Lett. 2010; 133(2): 115.
  38. Ueta M, Kinoshita S: Ocular surface inflammation mediated by innate immunity. Eye Contact Lens. 2010; 36(5): 269-281.
  39. Ueta M, Mizushima K, Yokoi N, Naito Y, Kinoshita S: Gene-expression analysis of polyI:C-stimulated primary human conjunctival epithelial cells. Br J Ophthalmol. 2010; 94(11): 1528-1532.
  40. Ueta M, Mizushima K, Yokoi N, Naito Y, Kinoshita S: Expression of the interleukin-4 receptor alpha in human conjunctival epithelial cells. Br J Ophthalmol. 2010; 94(9): 1239-1243.
  41. Kinoshita S, Ueta M: Innate immunity of the ocular surface. Jpn J Ophthalmol. 2010; 54(3): 194-198.
  42. Sotozono C, Ueta M, Kinoshita S: Systemic and local management at the onset of Stevens-Johnson syndrome and toxic epidermal necrolysis with ocular complications. Am J Ophthalmol, 2010; 149(2): 354.
  43. Ueta M, Kinoshita S: Innate immunity of the ocular surface. Brain Res Bull. 2010; 81(2-3): 219-228.
  44. Sotozono C, Ueta M, Kinoshita S: The management of severe ocular complications of stevens-johnson syndrome and toxic epidermal necrolysis. Arch Dermatol, 2009; 145(11): 1336-1337.
  45. Honda T, Matsuoka T, Ueta M, Kabashima K, Miyachi Y, Narumiya S: Prostaglandin E(2)-EP(3) signaling suppresses skin inflammation in murine contact hypersensitivity. J Allergy Clin Immunol. 2009; 124(4): 809-818.
  46. Ueta M, Uematsu S, Akira S, Kinoshita S: Toll-like receptor 3 enhances late-phase reaction of experimental allergic conjunctivitis. J Allergy Clin Immunol. 2009; 123(5): 1187-1189.
  47. Ueta M, Matsushita M, Sotozono C, Kinoshita S, Tokunaga K: Identification of a novel HLA-B allele, HLA-B*5904. Tissue Antigens. 2009; 73(6): 612-614.
  48. Ueta M, Sotozono C, Takahashi J, Kojima K, Kinoshita S: Examination of Staphylococcus aureus on the ocular surface of patients with catarrhal ulcers. Cornea. 2009; 28(7): 780-782.
  49. Araki Y, Sotozono C, Inatomi T, Ueta M, Yokoi N, Ueda E, Kishimoto S, Kinoshita S: Successful treatment of Stevens-Johnson syndrome with steroid pulse therapy at disease onset. Am J Ophthalmol. 2009; 147(6): 1004-1011.
  50. Sotozono C, Ueta M, Koizumi N, Inatomi T, Shirakata Y, Ikezawa Z, Hashimoto K, Kinoshita S: Diagnosis and treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis with ocular complications. Ophthalmology. 2009; 116(4): 685-690.
  51. Ueta M, Matsuoka T, Narumiya S, Kinoshita S: Prostaglandin E receptor subtype EP3 in conjunctival epithelium regulates late-phase reaction of experimental allergic conjunctivitis. J Allergy Clin Immunol. 2009; 123(2): 466-471.
  52. Kaniwa N, Saito Y, Aihara M, Matsunaga K, Tohkin M, Kurose K, Sawada J, Furuya H, Takahashi Y, Muramatsu M, Kinoshita S, Abe M, Ikeda H, Kashiwagi M, Song Y, Ueta M, Sotozono C, Ikezawa Z, Hasegawa R: JSAR research group. HLA-B locus in Japanese patients with anti-epileptics and allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis. Pharmacogenomics. 2008; 9(11): 1617-1622.
  53. Ueta M: Innate immunity of the ocular surface and ocular surface inflammatory disorders. Cornea. 2008; 27(Suppl 1):S31-40.
  54. Ueta M, Sotozono C, Inatomi T, Kojima K, Hamuro J, Kinoshita S: Association of Fas Ligand gene polymorphism with Stevens-Johnson syndrome. Br J Ophthalmol. 2008; 92(7): 989-991.
  55. Ueta M, Hamuro J, Ueda E, Katoh N, Yamamoto M, Takeda K, Akira S, Kinoshita S: Stat6-independent tissue inflammation occurs selectively on the ocular surface and perioral skin of IkappaBzeta-/- mice. Invest Ophthalmol Vis Sci. 2008; 49(8): 3387-3394.
  56. Ueta M, Tokunaga K, Sotozono C, Inatomi T, Yabe T, Matsushita M, Mitsuishi Y, Kinoshita S: HLA class I and II gene polymorphisms in Stevens-Johnson syndrome with ocular complications in Japanese. Mol Vis. 2008; 14: 550-555.
  57. Ueta M, Sotozono C, Inatomi T, Kojima K, Hamuro J, Kinoshita S: Association of combined IL-13/IL-4R signaling pathway gene polymorphism with Stevens-Johnson syndrome accompanied by ocular surface complications. Invest Ophthalmol Vis Sci. 2008; 49(5): 1809-1813.
  58. Kojima K, Ueta M, Hamuro J, Hozono Y, Kawasaki S, Yokoi N, Kinoshita S: Human conjunctival epithelial cells express functional Toll-like receptor 5. Br J Ophthalmol. 2008; 92(3): 411-416.
  59. Ueta M, Sotozono C, Inatomi T, Kojima K, Hamuro J, Kinoshita S: Association of IL4R polymorphisms with Stevens-Johnson syndrome. J Allergy Clin Immunol. 2007; 120(6): 1457-1459.
  60. Ueta M, Nakamura T, Tanaka S, Kojima K, Kinoshita S: Development of eosinophilic conjunctival inflammation at late-phase reaction in mast cell-deficient mice. J Allergy Clin Immunol. 2007; 120(2): 476-478.
  61. Ueta M, Sotozono C, Inatomi T, Kojima K, Tashiro K, Hamuro J, Kinoshita S: Toll like receptor 3 gene polymorphisms in Japanese patients with Stevens-Johnson syndrome. Br J Ophthalmol.  2007; 91(7): 962-965.
  62. Sotozono C, Ang LP, Koizumi N, Higashihara H, Ueta M, Inatomi T, Yokoi N, Kaido M, Dogru M, Shimazaki J, Tsubota K, Yamada M, Kinoshita S: New grading system for the evaluation of chronic ocular manifestations in patients with Stevens-Johnson syndrome. Opthalmology. 2007; 114(7): 1294-1302.
  63. Ueta M, Sotozono C, Tokunaga K, Yabe T, Kinoshita S: Strong association between HLA-A*0206 and Stevens-Johnson syndrome in the Japanese. Am J Ophthalmol. 2007; 143(2): 367-368.
  64. Ueta M, Iida T, Sakamoto M, Sotozono C, Takahashi J, Kojima K, Okada K, Chen X, Kinoshita S, Honda T: Polyclonality of Staphylococcus epidermidis residing on the healthy ocular surface. J Med Microbiol. 2007; 56(Pt 1): 77-82.
  65. Hozono Y, Ueta M, Hamuro J, Kojima K, Kawasaki S, Yamazaki K, Kinoshita S: Human corneal epithelial cells respond to ocular-pathogenic, but not to nonpathogenic-flagellin. Biochem Biophys Res Commun 2006; 347(1): 238-247.
  66. Naito Y, Takagi T, Mizushima K, Ueta M, Kinoshita S, Handa O, Kokura S, Ichikawa H, Yoshida N, Yoshikawa T: Gene expression clusters of a lipopolysaccharide-stimulated pathway in peripheral blood monocytes of Japanese patients with Crohn's disease. Aliment Pharmacol Ther. 2006; 24(Suppl 4): 256-265.
  67. Ono T, Park KS, Ueta M, Iida T, Honda T: Identification of proteins secreted via Vibrio parahaemolyticus type III secretion system 1.Infect Immun. 2006; 74(2): 1032-1042.
  68. Ueta M, Hamuro J, Kiyono H, Kinoshita S: Triggering of TLR3 by polyI:C in human corneal epithelial cells to induce inflammatory cytokines. Biochem Biophys Res Commun. 2005; 331(1): 285-294.
  69. Ueta M, Hamuro J, Yamamoto M, Kaseda K, Akira S, Kinoshita S: Spontaneous ocular surface inflammation and goblet cell disappearance in I kappa B zeta gene-disrupted mice. Invest Ophthalmol Vis Sci. 2005; 46(2): 579-588.
  70. Ueta M, Nochi T, Jang MH, Park EJ, Igarashi O, Hino A, Kawasaki S, Shikina T, Hiroi T, Kinoshita S, Kiyono H: Intracellularly expressed TLR2s and TLR4s contribution to an immunosilent environment at the ocular mucosal epithelium. J Immunol. 2004; 173(5): 3337-3347.
  71. Ueta M, Kweon MN, Sano Y, Sotozono C, Yamada J, Koizumi N, Kiyono H, Kinoshita S: Immunosuppressive properties of human amniotic membrane for mixed lymphocyte reaction. Clin Exp Immunol, 2002; 129(3): 464-470.

International Conference

Invited:

  1. Ueta M, Clinical finding of Stevens-Johnson Syndrome with severe ocular complications. 38 SIMASP, SaoPaulo, Brazil, 2015.3.5
  2. Ueta M, Suppressive effects of IL-8, ECP and total IgE in the tear of atopic keratoconjunctivitis by rebamipide eye drops. 38 SIMASP, SaoPaulo, Brazil, 2015.3.5
  3. Ueta M, Tokunaga K, Sotozono C, Sawai H, Kinoshita K. HLA-A*0206 with TLR3 Polymorphism Exerts more than Additive Effects in Cold medicine related Stevens-Johnson Syndrome with Severe Ocular Complications. 2014 ISER (The International Society for Eye Research) XXI Biennial Meeting, San Francisco, CA, USA, July 21, 2014
  4. Ueta M: Ocular Surface Inflammation and Ocular Surface Epithelial Cells. Biology & Pathobiology of the Cornea, Gordon Conference, Ventura, CA, USA, February 19, 2014
  5. Ueta M: Genetic Predisposition of Stevens-Johnson Syndrome with Ocular Complications. APAO/SOE Busan 2012, Busan, Korea, 2012.4.16.
  6. Ueta M: Earlier is Better for the Treatment of Stevens-Johnson Syndrom. APAO/SOE Busan 2012 , Busan, Korea, 2012.4.13.
  7. Ueta M: Regulation of Ocular Surface Inflammation by Prostaglandin E Receptor Subtype EP3. ESF-JSPS Frontier Science Conference for Young Researchers Cutting Edge Immunology and its Clinical Application(日本欧州先端科学セミナー), Hulshort, Netherlands, 2011.3.5.
  8. Ueta M: The importance of commensal bacteria on the ocular surface. APAO Sydney 2011 Congress, Sydney, Australia, 2011. 3. 22.
  9. Ueta M: Innate Immunity of the Ocular Surface. The 2nd Asia Cornea Society Biennial Scientific Meeting. Symposium 5. Basic Research (1) Angiogenesis and Immunoregulation, Kyoto, JAPAN, 2010.12.1.
  10. Ueta M: Downregulation of TSLP expression by Prostaglandin E Receptor Subtype EP3 in human conjunctival epithelium. 2010 Korea-Japan Joint Allergy Symposium and KAAACI (the Korean Academy & Asthma, Allergy and Clinical Immunology) Spring Congress, Soul, Korea, 2010. 5. 28.

General:

  1. Mayumi Ueta, Jun Shoji, Chie Sotozono, Shigeru Kinoshita. Downregulation of IL-8, ECP, and total IgE in the tears of patients with atopic keratoconjunctivitis treated with rebamipide eyedrops. 2015 Asia-ARVO, Yokohama, Japan, Feb 18, 2015.
  2. Mayumi Ueta, Hiromi Sawai, Chie Sotozono, Yuki Hitomi, Nahoko Kaniwa, Mee Kum Kim, Kyoung Yul Seo, Kyung-Chul Yoon, Choun-Ki Joo, Chitra Kannabiran, Tais Hitomi Wakamatsu, Virender Sangwan, Varsha Rathi, Sayan Basu, Takeshi Ozeki, Taisei Mushiroda, Emiko Sugiyama, Keiko Maekawa, Ryosuke Nakamura, Michiko Aihara, Kayoko Matsunaga, Akihiro Sekine, José Álvaro Pereira Gomes , Junji Hamuro, Yoshiro Saito, Michiaki Kubo, Shigeru Kinoshita, Katsushi Tokunaga. New Susceptibility Gene IKZF1 for Cold Medicine–Related Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis with Severe Mucosal Involvement. The American Society of Human Genetics (ASHG) 2014, San Diego, CA, USA. Oct 21, 2014.
  3. Hitomi Y, Khor SS, Ueta M, Sotozono C, Kinoshita S, Tokunaga K. Whole exome sequencing of Cold Medicine–Related Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (CM-SJS/TEN) with Severe Mucosal Involvement. The American Society of Human Genetics (ASHG) 2014, San Diego, CA, USA. Oct 20, 2014.
  4. Hiromi Sawai, Mayumi Ueta, Yuki Hitomi, Chie Sotozono, Shigeru Kinoshita, Katsushi Tokunaga. Search for new risk gene for Stevens-Johnson Syndrome independent of HLA risk allele. The American Society of Human Genetics (ASHG) 2014, San Diego, CA, USA. Oct 21, 2014.
  5. Mayumi Ueta, Jun Shoji, Chie Sotozono, Norihiko Yokoi, Shigeru Kinoshita. Suppressive effects of IL-8, ECP and total IgE in the tear of atopic keratoconjunctivitis by rebamipide eye drops. The European Academy of Allergy and Clinical Immunology  Congress 2014(EAACI 2014), Copenhagen, Denmark, June 10, 2014.
  6. Mayumi Ueta, Chie Sotozono, Shigeru Kinoshita. HLA markers of   cold medicine-related  Stevens-Johnson syndrome with severe mucosal involvements in the Japanese. 2014 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Orland, FL, USA, 2014.5.7.
  7. Mayumi Ueta, Ayaka Koga, Masaru Ishii, Shigeru Kinoshita. Analysis of the Cellular Dynamics of LysM-Positive Cells in a Corneal Suture Mouse Model using Intravital Imaging. Imaging Conference 2014 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Orland, FL, USA, 2014.5.3.
  8. Mayumi Ueta, Chie Sotozono, Hiromi Sawai, Katsushi Tokunaga, Shigeru Kinoshita. Strong association between HLA-A*02:06 and Acetaminophen-related Stevens-Johnson syndrome with severe mucosal involvements in the Japanese. The 6th International Drug Hypersensitivity Meeting, Bern, Switzerland 10 April 2014.
  9. Ryosuke Nakamura, Nahoko Kaniwa, Mayumi Ueta, Chie Sotozono, Emiko Sugiyama, Keiko Maekawa, Akiko Yagami, Setsuko Matsukura, Zenro Ikezawa, Kayoko Matsunaga, Tokunaga Katsushi, Michiko Aihara, Shigeru Kinoshita, Yoshiro Saito. HLA association with antipyretic analgesics-induced Stevens-Johnson syndrome / toxic epidermal necrolysis with severe ocular surface complications in Japanese patients. The 6th International Drug Hypersensitivity Meeting, Bern, Switzerland 10 April 2014.
  10. Nahoko Kaniwa, Mayumi Ueta, Ryosuke Nakamura, Emiko Sugiyama, Keiko Maekawa, Yukitoshi Takahashi, Hirokazu Furuya, Akiko Yagami, Setsuko Matsukura, Zenro Ikezawa, Kayoko Matsunaga, Chie Sotozono, Michiko Aihara, Shigeru Kinoshita, Yoshiro Saito. Medication tendencies for inducing severe ocular surface symptoms in Japanese Stevens-Johnson syndrome / toxic epidermal necrolysis patients. The 6th International Drug Hypersensitivity Meeting, Bern, Switzerland 10 April 2014.
  11. Mayumi Ueta, Jun Shoji, Chie Sotozono, Norihiko Yokoi, Shigeru Kinoshita. Anti-inflammatory effects of rebamipide eye drops on allergic conjunctivitis with and without giant papillae. 2014 World Ophthalmology Congress of the International Council of Ophthalmology. Tokyo, Japan, 2 April 2014.
  12. Yuriko Ban, Junko Tsujimoto, Keiko Yamada, Mayumi Ueta, Shigeru Kinoshita. The Change of the Barrier Function in hTERT Immortalized Corneal and Conjunctival Epithelia by Poly(I:C) Challenge. 2014 World Ophthalmology Congress of the International Council of Ophthalmology. Tokyo, Japan, 2 April 2014.
  13. Ueta M, Mizushima K,Naito Y, Narumiya S, Kinoshita S. Suppression of polyI:C-inducible gene expression by EP3 in murine conjunctival epithelium. ISMA  International Symposium on Molecular Allergology (ISMA) 2013, Vienna、Austria, 2013.12.5.
  14. Ueta M, Sotozono C, Tokunaga K, Kinoshita S: HLA MARKERS OF COLD MEDICINE RELATED STEVENS-JOHNSON SYNDROME. 8th International Cutaneous ADR Congress (ISCAR 2013), 桃園、台湾、2013. 11.17.
  15. Ueta M, Sotozono C, Kinoshita S: HLA analysis of cold medicine related Stevens-Johnson syndrome with ocular complication in Japan. 2013 Annual Meeting of the Asian Association for Research in Vision and Ophthalmology (Asian ARVO), New Delhi, India,2013.10.29.
  16. Ueta M, Sotozono C, Koga A, Yokoi N, Kinoshita S: Anti-inflammatory effects of rebamipide eye drops on allergic conjunctivitis. 2013 TFOS (7th International Conference on the Tear Film & Ocular Surface) Taormina, Sicily、Italy 2013.9.20
  17. Ueta M, Sotozono C, Yokoi N, Kinoshita K. The effect of rebamipide eye drops on allergic conjunctivitis with giant papilla. The EAACI (European Academy of Allergy and Clinical Immunology)-WAO (World Allergy Organization)  Congress 2013, Milano, Italy 2013.6.25
  18. Ueta M, Narumiya S, Kinoshita S: Suppression of TLR3-Inducible Gene Expression by EP3 in Conjunctival Epithelium. 2013 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Seattle, Washington, USA, 2013.5.6.
  19. Koga A, Ueta M, Ishii M, Minamiyama R, Koizumi N, Kinoshita S: Kinetic analysis of neutrophils in a corneal-alkali-injury mouse model. 2013 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Seattle, Washington, USA, 2013.5.6.
  20. Ueta M, Sotozono C, Yokoi N, Kinoshita S: Anti-inflammatory effect of rebamipide on the ocular surface. XX Biennial Meeting of the International Society for Eye Research, Leuven, Belgium, 2013.3.21.
  21. Koga A, Ueta M, Ishii M, Koizumi N, Kinoshita S: Kinetic analysis of neutrophils in a corneal-alkali-injury mouse model. The 28th Asia-Pacific Academy of Ophthalmology Congress held in conjunction with the 71th Annual Conference of All India Ophthalmological Society (APAO-AIOS 2013), Hyderabad, India. 2013.1.18.
  22. Shinomiya K, Ueta M, Sotozono C, Inatomi T, Yokoi N, Koizumi N, Kinoshita K: Immunohistochemical analysis of inflammatory limbal conjunctiva adjacent to Mooren’s ulcer. The 28th Asia-Pacific Academy of Ophthalmology Congress held in conjunction with the 71th Annual Conference of All India Ophthalmological Society (APAO-AIOS 2013), Hyderabad, India. 2013.1.17.
  23. Ueta M, Sotozono C, Yokoi N, Kinoshita S: Rebamipide Suppresses PolyI:C-Stimulated Cytokine Production in Human Conjunctival Epithelial Cells. XX Biennial Meeting of the International Society for Eye Research, Berlin, Gemany, 2012.7.23.
  24. Ueta M, Matsuoka T, Narumiya S, Akira S, Kinoshita S: EP3 Negatively Regulates TLR3 dependent eosinophilic infiltration of allergic conjunctivitis. European Academy of Allergy and Clinical Immunology Congress 2012, Geneva, Switzerland, 2012.6.17.
  25. Ueta M, Tokunaga K, Sotozono C, Sawai H, Tamiya G, Inatomi T, Kinoshita S: HLA-A*0206 and TLR3 SNPs are jointly predisposed with more than an additive effect to stevens-johnson syndrome with severe ocular complications. 16th International HLA and Immunogenetics Workshop, Liverpool, U.K. 2012.6.1.
  26. Ueta M, Matsuoka T, Narumiya S, Akira S, Kinoshita S: Epistatic interaction between TLR3 and ptger3 genes in experimental allergic conjunctivitis. 2012 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, Florida, USA, 2012.5.8.
  27. Yamada K, Ueta M, Sotozono C, Yokoi N, Inatomi T, Kinoshita S: Toll-like receptor subtype Tlr5 expression in human conjunctival epithelium in various cicatricial corneal conjunctival disorders. 2012 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, Florida, USA, 2012.5.8.
  28. Koga A, Ueta M, Ishii M, Koizumi N, Kinoshita S: Analysis of neutrophil dynamics in the cornea after alkali injury using lysm-gfp mice. 2012 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, Florida, USA, 2012.5.8.
  29. Shinomiya K, Ueta M, Kobori M, Nakanishi K, Yokoi N, Kinoshita S: Usefulness of a dry-eye mouse model produced by exorbital lacrimal gland excision and analysis of the increase of caspase-1 independent IL-1 β in the tear fluid of those mice. 2012 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, Florida, USA, 2012.5.7.
  30. Ueta M, Tamiya G, Tokunaga K, Sotozono C, Ueki M,Sawai H, Inatomi T, Matsuoka T, Akira S, Narumiya S, Kinoshita S: Epistatic interaction between TLR3 and PTGER3 confers an increased risk for Stevens-Johnson syndrome with ocular complications. 2012 Gordon Research Conference:Biology & Pathobiology of the Cornea, Ventura, California, USA, 2012.3.28.
  31. Ueta M: Up-regulation of RIG-I and MDA5 by polyI:C stimulation in human ocular surface epithelial cells. EAACI/GA2LEN Allergy School Clinical Impact and Mechanisms of Infections in Allergy, Edinburgh, UK, 2011.9.17.
  32. Ueta M, Yokoi N, Kinoshita S: Prostaglandin E2 suppresses polyI:C-stimulated cytokine production via EP2 and EP3 in human ocular surface epithelial cells. The European Academy of Allergy and Clinical Immunology (EAACI), Istanbul, Turkey, 2011.6.12.
  33. Yamada K, Ueta M, Sotozono C, Yokoi N, Inatomi T, Koizumi N, Kinoshita S: Prostaglandin E receptor subtype Ep4 expression in human conjunctival epithelium and its changes in various ocular surface disorders. 2011 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, Florida, USA, 2011.5.4.
  34. Imai K, Ueta M, Mori K, Ikeda Y, Ueno M, Yokoi N, Koga T, Narumiya S, Kinoshita S: FP localization and expression in ocular tissue. 2011 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, Florida, USA, 2011.5.4.
  35. Ueta M, Matsuoka T, Yokoi N, Kinoshita S: Prostaglandin E2 suppresses polyi:c-stimulated cytokine production via EP2 and EP3 in human conjunctival epithelial cells. 2011 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, Florida, USA, 2011.5.3.
  36. Ueta M, Sotozono C, Tokunaga K, Tamiya, Nakaji S, Inatomi T, Kinoshita S: HLA-A*0206 and the TLR3 polymorphism jointly predispose to Stevens-Johnson syndrome with ocular complications. The 2nd Asia Cornea Society Biennial Scientific Meeting, Kyoto, JAPAN, 2010.12.2.
  37. Ueta M, Yokoi N, Uematsu S, Kawai T, Akira S, Kinoshita S: The expression and function of RIG-I and MDA-5 in human ocular surface epithelium. the 6th International Conference on the Tear Film & Ocular Surface: Basic Science and Clinical Relevance, Florence, Italy, 2010.9.23.
  38. Ueta M, Sotozono C, Nakano M, Taniguchi T, Yagi T, Tokuda Y, Fuwa M, Inatomi T, Yokoi N,  Tashiro K, Kinoshita S: Association between prostaglandin E receptor 3 polymorphisms and Stevens-Johnson syndrome with ocular involvement identified by genome-wide association study in a Japanese population. Keystone Symposia, Bioactive Lipids, Biochemistry and Diseases, Kyoto, JAPAN, 2010.6.9.
  39. Ban Y, Tsujimoto J, Ueta M, Yokoi N, Kinoshita S: Poly(I:C) challenge strengthens the barrier function in hTERT immortalized corneal and conjunctival epithelia. 2010 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, Florida, USA, 2010.5.3.
  40. Sotozono C, Ueta M, Inatomi T, Kinoshita S: Chronic ocular complications in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis 4th International Drug Hypersensitivity Meeting, Roma, Italy, 2010.4.22.
  41. Ueta M, Sotozono C, Inatomi T, Kinoshita S: Genetic factors of Stevens-Johnson syndrome with ocular complications in Japanese. 4th International Drug Hypersensitivity Meeting. Roma, Italy, 2010.4.22.
  42. Ueta M, Mizushima K, Yokoi N, Naito Y, Kinoshita S: Gene expression analysis of polyI:C-stimulated primary human conjunctival epithelial cells. Gordon Research Conferences, Biology & Pathobiology of the Cornea, Ventura, California, USA, 2010. 3. 10.
  43. Ueta M, Uematsu S,Akira S, Kinoshita S: Toll-like receptor 3 regulates late-phase reaction of experimental allergic conjunctivitis. 14th international congress of mucosal immunology (ICMI2009) Boston, Massachusetts, USA. 2009.7.7.
  44. Ueta M, Sotozono C, Yokoi N, Inatomi T, Kinoshita S: EP3 expression and functions in human ocular surface epithelium. 2009 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, Florida, USA, 2009.5.6.
  45. Kinoshita S, Ueta M, Sotozono C, Inatomi T, Nakano M, Yagi T, Taniguchi T, Fuwa M, Tokuda Y, Tashiro K: EP3 gene polymorphisms in Japanese patients with Stevens-Johnson syndrome. 2009 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, Florida, USA, 2009.5.6.
  46. Ueta M, Sotozono C, Inatomi T, Kinoshita S: Association of Toll-like receptor 3 gene polymorphisms with Stevens-Johnson syndrome. Keystone Symposia, Pattern Recognition Molecules and Immune Sensors of Pathogens, Banff, Alberta, Canada. 2009. 4. 2.
  47. Ueta M, Matsuoka T, Narumiya S, Kinoshita S: Prostaglandin E receptor subtype EP3 in mouse conjunctival epithelium regulates late-phase reaction of experimental allergic conjunctivitis. Keystone Symposia, allergy and asthma. Keystone, Colorado, USA. 2009. 1. 24.
  48. Sotozono C, Ueta M, Koizumi N, Inatomi T, Kinoshita S: Importance of ocular findings for the early diagnosis of Stevens-Johnson syndrome. 2008 American Academy of Ophthalmology, Atlanta, USA. 2008. 11. 10.
  49. Ueta M, Sotozono C, Inatomi T, Kinoshita S: Genetic factors of Stevens-Johnson syndrome in Japanese. 2008 American Academy of Ophthalmology, Atlanta, USA, 2008. 11. 10.
  50. Ueta M, Matsuoka T, Narumiya S, Kinoshita S: Regulation of murine experimental allergic conjunctivitis late-phase reaction by prostaglandin E receptor subtype EP3. ISOCB Conference 2008, San Diego, California, USA, 2008.9.2-5.
  51. Ueta M, Sotozono C, Inatomi T, Hamuro J, Kinoshita S: Association of Fas Ligand gene polymorphism with Stevens-Johnson syndrome. World Ophthalmology Congress (WOC) 2008, Hong Kong, 2008. 7.29.
  52. Sotozono C, Araki Y, Inatomi T, Ueta M, Yokoi N, Kinoshita S: Successful treatment of Stevens-Johnson syndrome with high-dose corticosteroid pulse therapy at disease onset. 2008 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, Florida, USA, 2008.4.28.
  53. Ueta M, Sotozono C, Inatomi T, Hamuro J, Kinoshita S: Association of combined IL-13/IL-4R signaling pathway gene polymorphismwith Stevens-Johnson syndrome. 2008 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, Florida, USA, 2008.4.28.
  54. Kojima K, Ueta M, Hozono Y, Hamuro J, Kinoshita S: Human ocular surface epithelial cells express TLR5 and respond to bacterial flagellin. 13 th International Congress of Mucosal Immunology, Tokyo, JAPAN, 2007. 7.10.
  55. Ueta M, Sotozono C, Inatomi T, Kojima K, Tashiro K, Hamuro J, Kinoshita S: Toll like receptor 3 gene polymorphisms in Japanese patients with Stevens-Johnson syndrome. 13 th International Congress of Mucosal Immunology, Tokyo, JAPAN, 2007. 7.10.
  56. Sotozono C, Ueta M, Koizumi N, Hibino S, Inatomi T, Kinoshita S: Acute conjunctivitis as the initial symptom of Stevens-Johnson syndrome with ocular complications and the consequence of topical steroids. 2007 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, Florida, USA, 2007.5.6.
  57. Kojima K, Ueta M, Hamuro J, Yokoi N, Kinoshita S: Expression and function of TLR2 in human conjunctival epithelial cells. 2007 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, Florida, USA, 2007.5.10.
  58. Ueta M, Sotozono C, Inatomi T, Hamuro J, Kinoshita S: Gene expression analysis of monocytes derived from the patients of Stevens-Johnson syndrome with ocular complications. 2007 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, Florida, USA, 2007.5.6.
  59. Hozono Y, Ueta M, Hamuro J, Kinoshita S: Human corneal epithelial cells respond to ocular pathogenic, but not to non-pathogenic bacterial flagellin. 2006 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, Florida, USA, 2006.5.1.
  60. Kojima K, Ueta M, Hozono Y, Hamuro J, Kinoshita S: Response to human corneal epithelial cells to various toll-like receptor 2 ligands. 2006 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, Florida, USA, 2006.5.1.
  61. Ueta M, Hamuro J, Ueda E, Yamamoto M, Akira S, Kinoshita S: Spontaneous ocular surface inflammation in IkappaBzeta gene-disrupted mice. 2006 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, Florida, USA, 2006.5.3.
  62. Ueta M, Iida T, Sakamoto M, Sotozono C, Takahashi J, Okada K, Kinoshita S, Honda T: Polyclonality of staphylococcus epidermidis on healthy ocular surface  4th international conference on ocular infections JAPAN, Hokkaido, Japan, 2005. 10.2.
  63. Ueta M, Hamuro J, Kiyono H, Kinoshita S: Triggering of TLR3 by polyI:C in human corneal epithelial cells to induce inflammatory cytokines. 12th International Congress of Mucosal Immunology, Boston, Massachusetts, USA, 2005. 6. 29.
  64. Ueta M, Sotozono C, Sakamoto M, Takahashi J, Okada K, Honda T, Kinoshita S: Meaning of staphylococcus epidermidis residing on ocular surface. World Cornea Congress V, Washington DC, USA, 2005.4.14.
  65. Ueta M, Hamuro J, Yamamoto M, Akira S, Kinoshita S: Spontaneous ocular surface inflammation and goblet cell disapperance in IkBz gene-disrupted mice. 2005 Keystone Symposia, Innate Immunity to Pathogens, Steamboat Springs, Colorado, USA, 2005.1.11.
  66. Ueta M, Hamuro J, Kinoshita S: Expression of NF-kB negative regulators on ocular surface. 2004 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, Florida, USA, 2004.4.29.
  67. Ueta M, Jang MH, Kawasaki S, Shikina T, Hiroi T, Kinoshita S: Expression and function of TLRs in human ocular surface epithelium. 2003 American Association of Immunologists 90th Anniversary Annual Meeting (AAI) Denver,  Colorado, USA, 2003.5.7.
  68. Ueta M, Jang MH, Kawasaki S, Shikina T, Hiroi T, Kinoshita S: Expression and function of TLRs in human ocular surface epithelium. 2003 Keystone Symposia, The Regulation of Mucosal Inflammation, Keystone Colorado, USA, 2003.4.4.
  69. Ueta M, Sano Y, Sotozono C, Yamada J, Koizumi N, Kinoshita S: Immunosuppressive properties of human amniotic membrane. 2001 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, Florida,USA, 2001.5.1.

Research

Genetic predisposition of Stevens-Johnson Syndrome with Severe ocular surface complications

Stevens-Johnson syndrome (SJS) is an acute inflammatory vesiculobullous reaction of the skin and mucosa, such as the ocular surface, oral cavity, and genitals. In patients with extensive skin detachment and a poor prognosis, the condition is called toxic epidermal necrolysis (TEN). In the acute stage, patients manifest vesiculobullous lesions of the skin and mucosa, severe conjunctivitis, and ocular surface epithelial defects. In the chronic stage, despite the healing of the skin lesions, severe ocular surface complications persist such as severe dry eye, symblepharon, trichiasis, conjunctival invasion into the cornea and sometimes result in visual disturbance.

This proceeding consists of three subject, first subject is“Position of ophthalmic SJS”, second subject is “HLA analysis”, third subject is “Genome wide association study”, and forth subject is “other findings”.

1. Position of ophthalmic SJS

Diagnostic criteria for SJS in Japan 1.
Major Criteria consist of three findings; 1. Severe, hyperemic and/or hemorrhagic mucocutaneous lesions, 2. Epidermal detachment involves less than 10% of the total body surface area, 3. High fever (>38.0℃). The definite diagnosis of SJS need these all 3 major findings, which include mucosal lesions

Diagnostic criteria for TEN in Japan 1.
Major Criteria consist of three fondings; 1. Epidermal detachment involves more than 10% of the total body surface area, 2. Exclusion of staphylococcal scalded skin syndrome, 3. High fever (>38.0℃). The definite diagnosis of TEN need these all 3 major findings but they do not include mucosal lesions. So, some, not all, of TEN might have mucosal lesions.

Thus, SJS/TEN with mucosal lesion consist of SJS and a part of TEN. Moreover, not all, but some of SJS/TEN with mucosal lesions complicate severe ocular lesion such as severe conjunctivitis with psedomembrane and ocular surface epithelial defects. Furthermore, dermatologists see patients only in their acute stage. On the other hand, ophthalmologists encounter SJS/TEN patients not only in the acute stage but also in the chronic stage. So, it is difficult for ophthalmologists to render a differential diagnosis of SJS or TEN when patients present in the chronic stage because the vesiculobullous skin lesion expressed in the acute stage have healed by the chronic stage. Thus, ophthalmologists tend to report both SJS and TEN with severe ocular complications as “SJS” in a broad sense (Fig.1) 2. Our diagnosis of SJS/TEN (SJS in the broad sense) was based on a confirmed history of acute-onset high fever, serious mucocutaneous illness with skin eruptions, and involvement of at least 2 mucosal sites including the ocular surface.

Short summary is “Ophthalmic lesions appear in not all, but some of SJS/TEN patients who were diagnosed by dermatologists.”

2. HLA analysis
SJS/TEN are rare, but often associated with inciting drugs. Some causative drugs were reported, and some associations between HLA type and the drugs have also been reported. SJS/TEN induced by Allopurinol, a uric acid-lowering drug, was strongly associated with HLA-B* 58:01 in Han Chinese 3, Caucasian 4, and Japanese patients 5(Fig. 2). SJS/TEN induced by Carbamazepine, an anticonvulsant, was strongly associated with HLA-B*15:02 in Han Chinese 6, and HLA-A*31:01 in European 7 and Japanese 8(Fig. 2).
We have reported that cold medicines including NSAIDs and multi-ingredient cold medications were the main causative drugs for SJS/TEN with severe ocular complications 9, 10. About 80% of our patients have developed SJS/TEN after treatment for the common cold 10. Interestingly, allopurinol induces SJS/TEN without severe ocular complications (in submission). Moreover, not all cases of Carbamazepine-induced SJS/TEN have severe ocular complications 11. We performed HLA analysis of cold medicine related SJS/TEN with severe ocular complications (CM-SJS/TEN with SOC).
In Japanese, HLA-A*02:06 was strongly associated with CM-SJS/TEN with SOC, and HLA-B*44:03 also significantly associated with them (Table 1) 9.
Furthermore, compared to the Japanese CM-SJS/TEN without SOC, the significants remain 9. This result showed that HLA-A*02:06 is strongly associated with the Japanese CM-SJS/TEN with SOC, but not CM-SJS/TEN without SOC.
On the other hands, HLA-A*02:06 and HLA-B*44:03 are not associated with cold medicine unrelated (other medicine related) SJS/TEN with severe ocular surface complications9.
We also examined the association with HLA-A*02:06 and HLA-B*44:03 using other ethnic samples such as Korean, Indian and Brazilian samples. HLA-A*02:06 is also associated with Korean CM-SJS/TEN with SOC, but not Indian and Brazilian (Table2) 12. HLA-B*44:03 is associated with CM-SJS/TEN with SOC in Indian and Brazilian, but not Korean (Table2) 12. Especially in Indian, HLA-B*44:03 is strongly associated, 60% of the patients have HLA-B*44:03, while only 11% of controls have it, and odd’s ratio is 12. In Brazilian, when we focused only brazilian caucasian, 40% of the patients have HLA-B*44:03, while 11% of controls have it, odd’s ration is 6 12.

Short summary is “CM-SJS/TEN with SOC was associated with HLA-A*02:06 in Japanese and Korean and HLA-B*44:03 in Japanese, Indian and Brazilian Caucasian.” (Fig. 2).


3. Genome wide association study
We performed a genome-wide association study (GWAS) of CM-SJS/TEN with SOC. We first enrolled Japanese 117 cases and 691 controls. We found that the HLA-A region showed the strongest association with susceptibility to CM-SJS/TEN with SOC. Outside of the HLA region, there were 57 SNPs with p < 10-3 (44 genes) in the allele frequency, and 9 SNPs of them (8 genes) were p < 10-5 13.
We selected 8 SNPs of 6 genes, for which functional TaqMan probe available, for the first replication study. There are 9 SNPs p< 10-5 in GWAS using Japanese samples (KPUM samples), for which functional TaqMan probe available 13. So, we focused the IKZF1 SNPs, we genotyped additional two SNPs of the gene (total 4 SNPs), which were included in the 57 SNPs with p < 10-3 outside of the HLA region in the GWAS 13. In the Korean samples, the 3 SNPs of IKZF1 were significantly associated, in the Indian samples, the 1 SNPs of IKZF1 were significantly associated 13. In the Brazillian samples, there were no significant associations with these IKZF1 SNPs; however, the ORs for these four SNPs with the Brazilian sample set showed the same direction of association as with Japanese samples13. Furthermore, the meta-analysis with Japanese, Korean, Indian and Brazillian samples showed a genome-wide significant association between CM-SJS/TEN with SOC and the IKZF1 SNP (rs4917014 (G vs T), OR = 0.5, p = 8.5×10-11, rs4917129 (C vs T), OR = 0.5, p = 8.1×10-9, rs10276619 (G vs A), OR = 1.8, p = 4.3×10-9) 13. These findings show that IKZF1 may be a universal marker for susceptibility to CM-SJS/TEN with SMI.
Finally, we examined the quantitative ratios of IKZF1 alternative splicing isoforms as functional analysis, and found that the ratio of Ik2/Ik1 was significantly associated with the SNPs of IKZF1 13.These results indicate that the ratio of Ik2/Ik1 may be influenced by IKZF1 SNP.”

Short summary is “We conducted a GWAS for CM-SJS/TEN with SMI in Japanese individuals and performed a replication study with Korean and Indian individuals, and found that IKZF1 SNPs were significantly associated with CM-SJS/TEN with SMI, and that the ratio of Ik2/Ik1 isoform may be influenced by these IKZF1 SNPs.”

4. Other finding
For the past decade, SNPs have been widely used as genetic markers for identifying human disease-susceptibility genes. However, it has become apparent that gene-gene interactions should be considered in addition to major single-locus effects 14. We previously reported that in addition HLA-A*02:06, TLR3 14-16, PTGER3 10, 14, IL-4R 17, 18, FasL 19 and IL-13 18 SNPs showed significant associations with SJS/TEN with severe ocular surface complications (Fig.3) and that HLA-A*02:06 with TLR3 polymorphisms exerted more than additive effects in SJS/TEN with SOC 16 (Fig.4).

Furthermore, we also compared EP3 (protein of PTGER3 gene)expression in SJS and chemical burn. The chemical-burn conjunctival epithelium expressed the EP3 protein, the same as in conjunctivochalasis. However, we could not detect EP3 immunoreactivity in the conjunctival epithelium obtained from SJS, in either the chronic and sub-acute stages (Fig. 5) 20. These findings suggest that EP3 is strongly down-regulated in the conjunctival epithelium of SJS.
Cold medicines including NSAIDs (e.g., ibuprofen and loxoprofen) and cold medicine ingredients (e.g., acetaminophen), which were the main causative drugs for SJS/TEN with severe ocular complications, have the shared effect of down-regulating the production of prostanoid, including PGE2. Because the PGE2-EP3 pathway suppresses inflammation of the ocular surface 21, skin 22 and respiratory tract 23, we suggest that down-regulation of PGE2 by NSAIDs or acetaminophen might deeply contribute to the onset of CM-SJS/TEN with SOC.
Thus, some complicated mechanisms involving HLA-A*02:06, TLR3, EP3 and IKZF1 might contribute the pathogenesis of SJS with SOC (Fig.6).

Moreover, CM-SJS/TEN patients have developed SJS/TEN by taking cold medicines after having a common cold as a result of some viral or mycoplasma infections. We postulate that not only cold medicine, but also an infectious agent, virus or other microbe, could together be important and necessary to trigger the onset of SJS/TEN with SOC. Ueta’s hypothesis about onset of SJS/TEN with SOC is that If a person has no genetic background of SJS/TEN with SOC when some microbial infection happens, he/she has normal immune responses, then takes cold medicine, resulting in cure of the common cold, but If a person has genetic background of SJS/TEN with SOC when some microbial infection happens, he/she has abnormal immune responses, then takes cold medicine, which triggers the onset of SJS/TEN with SOC (Fig.7).

HLA
genotype
Carrier frequency (%) Dominant model analysis
CM-SJS/TEN with SOC Control P value Odds ratio
(95% CI)
A*02:06 71/151 (47.0%) 87/639 (13.6%) 2.72 × 10-20 5.63 (3.81-8.33)
B*44:03 39/151 (25.8%) 95/639 (14.9%) 0.00125 1.99 (1.30-3.05)
CM-SJS/TEN: Cold medicine related SJS/TEN
SOC: severe ocular complications

References

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