title: Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category.
abstract: Experimental autoimmune uveitis (EAU) represents autoimmune uveitis in humans. We examined the role of the interleukin (IL)-23-IL-17 and IL-12-T helper cell (Th)1 pathways in the pathogenesis of EAU. IL-23 but not IL-12 was necessary to elicit disease by immunization with the retinal antigen (Ag) interphotoreceptor retinoid-binding protein (IRBP) in complete Freund's adjuvant. IL-17 played a dominant role in this model; its neutralization prevented or reversed disease, and Th17 effector cells induced EAU in the absence of interferon (IFN)-gamma. In a transfer model, however, a polarized Th1 line could induce severe EAU independently of host IL-17. Furthermore, induction of EAU with IRBP-pulsed mature dendritic cells required generation of an IFN-gamma-producing effector response, and an IL-17 response by itself was insufficient to elicit pathology. Finally, genetic deficiency of IL-17 did not abrogate EAU susceptibility. Thus, autoimmune pathology can develop in the context of either a Th17 or a Th1 effector response depending on the model. The data suggest that the dominant effector phenotype may be determined at least in part by conditions present during initial exposure to Ag, including the quality/quantity of Toll-like receptor stimulation and/or type of Ag-presenting cells. These data also raise the possibility that the nonredundant requirement for IL-23 in EAU may extend beyond its role in promoting the Th17 effector response and help provide a balance in the current Th1 versus Th17 paradigm.
authors.affiliation: Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Dror
authors.initials: D
authors.lastname: Luger
authors.forename: Phyllis B
authors.initials: PB
authors.lastname: Silver
authors.forename: Jun
authors.initials: J
authors.lastname: Tang
authors.forename: Daniel
authors.initials: D
authors.lastname: Cua
authors.forename: Zoe
authors.initials: Z
authors.lastname: Chen
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Edward P
authors.initials: EP
authors.lastname: Bowman
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Sgambellone
authors.forename: Chi-Chao
authors.initials: CC
authors.lastname: Chan
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Caspi
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000201:enzymology* / Q000473:pathology* / Q000517:prevention & control; D015551:Autoimmunity / Q000276:immunology*; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology; D004198:Disease Susceptibility; D005123:Eye / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000172:deficiency / Q000276:immunology; D053765:Interleukin-12 Subunit p35 / Q000172:deficiency / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D053759:Interleukin-23 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018448:Models, Immunological; D009500:Neutralization Tests; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D015854:Up-Regulation; D014605:Uveitis / Q000276:immunology / Q000517:prevention & control
chemical_list: D000941:Antigens; D018836:Inflammation Mediators; D053765:Interleukin-12 Subunit p35; D020381:Interleukin-17; D053759:Interleukin-23; D007371:Interferon-gamma