title: IFN-gamma-deficient mice develop experimental autoimmune uveitis in the context of a deviant effector response.
abstract: Experimental autoimmune uveitis (EAU) is a T cell-mediated disease that targets the neural retina and serves as a model of human uveitis. Uveitogenic effector T cells have a Th1-like phenotype (high IFN-gamma, low IL-4), and genetic susceptibility to EAU is associated with an elevated Th1 response. Here we investigate whether the ability to produce IFN-gamma is necessary for the development of EAU by immunizing IFN-gamma-deficient (GKO) mice with the uveitogenic protein interphotoreceptor retinoid binding protein (IRBP) and characterize the associated immunologic responses. GKO mice developed EAU comparable in severity and incidence to that of their wild-type littermates. However, the cytokine profile in their uveitic eyes as well as the cytokines produced by primed lymph node cells in response to IRBP showed a distinct profile: undiminished TNF-alpha and elevated IL-5, IL-6, IL-10, and lymphotoxin (but not IL-4) responses. The inflammatory infiltrate in GKO eyes contained an excess of granulocytes and IL-5- and IL-6-producing cells, but uveitic GKO mice did not up-regulate inducible nitric oxide synthase. GKOs had enhanced lymphocyte proliferation and delayed-type hypersensitivity responses to IRBP. Histology of the delayed-type hypersensitivity lesion in GKO had superimposed elements of an allergic-like response. Anti-IRBP Ab isotypes of GKO mice showed a reduction of IgG2a, but no enhancement of IgG1. Comparison of responses in +/+ and +/- wild-type mice revealed some limited evidence of a gene-dose effect. We conclude that IFN-gamma is not required for priming of pathogenic T cells or for effecting the retinal damage and photoreceptor loss typical of EAU. However, what appears to be a grossly similar disease is caused in the GKO by a deviant type of effector response.
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: L S
authors.initials: LS
authors.lastname: Jones
authors.forename: L V
authors.initials: LV
authors.lastname: Rizzo
authors.forename: R K
authors.initials: RK
authors.lastname: Agarwal
authors.forename: T K
authors.initials: TK
authors.lastname: Tarrant
authors.forename: C C
authors.initials: CC
authors.lastname: Chan
authors.forename: B
authors.initials: B
authors.lastname: Wiggert
authors.forename: R R
authors.initials: RR
authors.lastname: Caspi
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D005136:Eye Proteins / Q000276:immunology; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000172:deficiency*; D016753:Interleukin-10 / Q000032:analysis; D015848:Interleukin-5 / Q000032:analysis; D015850:Interleukin-6 / Q000032:analysis; D008198:Lymph Nodes / Q000276:immunology; D008233:Lymphotoxin-alpha / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D019001:Nitric Oxide Synthase / Q000378:metabolism; D012177:Retinol-Binding Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D015854:Up-Regulation; D014605:Uveitis / Q000276:immunology*; D000099214:Retinol-Binding Proteins, Interstitial
chemical_list: D005136:Eye Proteins; D007371:Interferon-gamma; D016753:Interleukin-10; D015848:Interleukin-5; D015850:Interleukin-6; D008233:Lymphotoxin-alpha; D019001:Nitric Oxide Synthase; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial