title: EBI3 is pivotal for the initiation of experimental autoimmune uveitis.
abstract: Murine experimental autoimmune uveitis (EAU) is a model for human autoimmune uveitis, whose pathogenesis is caused by both Th1 and Th17 cell responses. Epstein-Barr virus-induced gene 3 (EBI3) is a component of the heterodimeric cytokines: interleukin (IL)-27 and IL-35. Although IL-27 was shown to initiate Th1 cell development, it is also recognized as a negative regulator of fully activated CD4+ T cells, including Th17 cells. Recently, IL-35 also has also been reported to play immunosuppressive roles in autoimmunity. To investigate the roles of EBI3 in EAU, EBI3(-/-) mice were immunized with human interphotoreceptor retinoid binding protein peptide 1-20 (IRBP) to induce EAU. We observed that the clinical score in EBI3(-/-) mice was diminished compared with that in EBI3(+/+) mice up to day 22 after immunization, whereas the score in EBI3(-/-) mice reached the same levels as that of EBI3(+/+) mice after day 28. Histological analysis revealed a significant reduction of cellular infiltration into the retina in EBI3(-/-) mice on day 16. Although Th1 cell responses and IRBP-specific IL-10 production were reduced in EBI3(-/-) mice, the development of Th17 cell responses was unaffected on day 9. On day 21, Th1 cell responses and IRBP-specific IL-10 production was restored to the same levels as that in EBI3(+/+) mice, and Th17 cell responses significantly increased in EBI3(-/-) mice. Furthermore, Foxp3 expression in CD4+ T cells was comparable between EBI3(+/+) and EBI3(-/-) mice on days 9 and 21. Therefore, these results indicate that EBI3 may be important in EAU initiation by Th1 cell responses and may suppress EAU by inhibition of both Th1 and Th17 cell responses in the late/maintenance phase.
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: atakeda@med.kyushu-u.ac.jp.
authors.forename: Atsunobu
authors.initials: A
authors.lastname: Takeda
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Hasegawa
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Fukuhara
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Hirakawa
authors.affiliation: Division of Host Defense, Research Center for Prevention of Infectious Diseases, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Hisakata
authors.initials: H
authors.lastname: Yamada
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Takeru
authors.initials: T
authors.lastname: Yoshimura
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Hisatomi
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Oshima
authors.affiliation: Division of Molecular and Cellular Immunosciences, Department of Biomolecular Sciences, Saga Medical School, 5-1-1 Nabeshima Saga, Saga 849-8501, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Koh-Hei
authors.initials: KH
authors.lastname: Sonoda
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Ishibashi
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D007378:Interleukins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens; D018121:Receptors, Cytokine / Q000172:deficiency / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D014605:Uveitis / Q000276:immunology / Q000378:metabolism
chemical_list: C499601:Ebi3 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007378:Interleukins; D015778:Minor Histocompatibility Antigens; D018121:Receptors, Cytokine
keywords: CD4(+) T cells; EBI3; IL-27; Th1 cells; Th17 cells; uveitis