March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
Ifn- Is Critical For Disease Pathogenesis In A Spontaneous Mouse Model Of Autoimmune Uveitis
Author Affiliations & Notes
  • Jun Chen
    Lab of Immunology, National Eye Inst/NIH, Bethesda, Maryland
  • Reiko Horai
    Lab of Immunology, National Eye Inst/NIH, Bethesda, Maryland
  • Phyllis Silver
    Lab of Immunology, National Eye Inst/NIH, Bethesda, Maryland
  • Chi-Chao Chan
    Lab of Immunology, National Eye Inst/NIH, Bethesda, Maryland
  • Rachel Caspi
    Lab of Immunology, National Eye Inst/NIH, Bethesda, Maryland
  • Footnotes
    Commercial Relationships  Jun Chen, None; Reiko Horai, None; Phyllis Silver, None; Chi-Chao Chan, None; Rachel Caspi, None
  • Footnotes
    Support  NEI intramural program
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 6901. doi:
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      Jun Chen, Reiko Horai, Phyllis Silver, Chi-Chao Chan, Rachel Caspi; Ifn- Is Critical For Disease Pathogenesis In A Spontaneous Mouse Model Of Autoimmune Uveitis. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6901.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : A pathogenic role for IFN-γ producing Th1 cells in autoimmunity was recently put in question by the discovery of IL-17 producing Th17 cells. Like other tissue-specific autoimmunity models induced by autoantigen in complete Freund’s adjuvant (CFA), experimental autoimmune uveitis (EAU) induced by IRBP/CFA is predominantly Th17-dependent and deficiency of IFN-γ exacerbates the disease. However, we also reported that EAU can be driven by either Th1 or Th17 effector cells. To elucidate the role of IFN-γ in IRBP-specific effector T cell responses and pathogenesis of uveitis in a more "physiologic" context without strong exogenous stimuli (CFA), we generated an IRBP-specific T cell receptor transgenic mouse (R161H) on an IFN-γ knockout (GKO) B10.RIII background.

Methods: : CFA emulsion was injected subcutaneously into R161H-GKO mice at 4-5 wks of age. Disease was evaluated by fundoscopy and histology. IRBP-specific T cells were detected using IRBP161-180/I-Ar/IgG1 dimers. Lymphocyte proliferation was measured by [3H]-Thymidine uptake. Cytokine levels were determined by cytometric bead array, ELISA, or by flow cytometry with intracellular staining.

Results: : Essentially all R161H mice developed severe spontaneous uveitis by 2-3 months of age. The ocular infiltrates contained both IFN-γ and IL-17 producing effector T cells, as well as other inflammatory leukocytes. Deficiency of IFN-γ delayed the onset and markedly decreased the severity of disease. Although the frequency of IRBP-specific T cells and their proliferative responses were not affected, IRBP-activated T cells from R161H-GKO mice transferred attenuated disease to recipient mice, indicating that the defect is T cell-intrinsic. Notably, deficiency of IFN-γ did not precipitate a compensatory Th17 response locally or systemically. However, injection of a "blank" CFA emulsion into R161H-GKO mice enhanced the IRBP-specific Th17 effector response, increased CCR6+IL-17+ cell infiltration into the eye and restored EAU incidence and scores.

Conclusions: : Our results point to a pathogenic role of IFN-γ and Th1 cells in spontaneous autoimmune disease. The findings suggest that while forcing a Th17 response can compensate for lack of IFN-γ, the central role of the Th17 effector in tissue-specific autoimmunity, as defined in CFA-driven models, may be less general than is currently believed.

Keywords: autoimmune disease • immunomodulation/immunoregulation • uveitis-clinical/animal model 
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