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J. M. Kezic, M. P. Davey, T. T. Glant, K. Dahlhausen, S. R. Planck, T. M. Martin, J. T. Rosenbaum, H. L. Rosenzweig; Absence of Gamma Interferon Markedly Exacerbates Uveitis Without Comparable Joint Effects in a Mouse Transgenic Model Resembling Ankylosing Spondylitis. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5162.
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Ankylosing spondylitis is the most common systemic disease associated with uveitis in North America and Europe, with approximately 40% of patients developing anterior uveitis. Prior data implicated eye inflammation in the context of a murine model of proteoglycan-induced arthritis (PGIA). Here we sought to further analyze the onset and severity of eye disease through the course of PGIA and dissect the role of IFN-gamma in the eye, since this cytokine is inflammatory in the joint disease.
Female BALB/c mice transgenic for the T cell receptor specific for an epitope of aggrecan (TCR-Tg mice) or IFN-gamma knockout (KO)/TCR-Tg mice were immunized with proteoglycan (PG) in the adjuvant dimethy-dioctadecyl ammonium bromide and pertussis toxin. Ocular inflammation was assessed by intravital microscopy and histological analysis, with corresponding joint inflammation examined using an established clinical scoring system. Immunofluorescence staining of eye tissue wholemounts was performed to localize ocular expression of the neo-epitope of aggrecan.
Intravital microscopy and histological analysis of eyes from PG-treated TCR-Tg mice showed mild ocular inflammation from week 2 post-immunization, whilst clinical signs of arthritis were typically present from week 3. By comparison, PG-treated IFN-gamma KO/TCR-Tg mice demonstrated a higher number of rolling, adherent and infiltrating cells in the iris by intravital microscopy than TCR-Tg mice. Histological analysis of IFN-gamma KO/TCR-Tg mice at weeks 3 and 4 post-immunization revealed a heavy infiltrate in the anterior chamber and vitreous, as well as inflammation of the iris, ciliary body and choroid. Surprisingly, retinal vasculitis, retinal folding and photoreceptor damage were also evident. This is in contrast to the joint inflammation, where IFN-gamma KO/TCR-Tg mice had lower arthritis scores than TCR-Tg mice. Immunofluorescence staining of wholemounts revealed the expression of aggrecan on nerve fibres in the cornea, retina, iris and optic nerve.
This study describes a new model of ocular inflammation accompanying joint disease in murine arthritis/spondylitis. Whilst IFN-gamma plays a pathogenic role in the joint, the exacerbation of ocular inflammation in the absence of this cytokine reveals an essential protective role in the eye during PGIA.
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