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Carlos R. Zarate-Blades, Reikp Horai, Jun Chen, Phyllis B. Silver, Chi-Chao Chan, Rachel R. Caspi; Influence Of The Intestinal Microbiota In The Development Of Spontaneous Autoimmune Uveitis. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2234.
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Involvement of microorganisms in triggering human autoimmune uveitis has been repeatedly suggested based on anecdotal evidence, but has never been proven. Recently, we developed an IRBP-specific T cell receptor (TCR) transgenic mouse (R161H) that develops autoimmune uveitis spontaneously by 2 months of age. We previously reported that R161H mice treated with broad-spectrum antibiotic to reduce intestinal flora experienced a concomitant reduction of retinal inflammation. The aim of this project is to understand how the microbiota regulate the immune response and thereby modulate the development of spontaneous uveitis
R161H mice were kept untreated or received the antibiotic cocktail AMNV (ampicillin, metronidazole, neomycin and vancomycin) in the drinking water continuously throughout life. Uveitis was evaluated by fundus examination. Bacterial composition in fecal pellets was determined by 16S rRNA gene detection. Immune cell profiles in lymphoid tissues and intestinal lamina propria were examined by flow cytometry
Analysis of the gut microflora revealed that mice receiving the AMNV cocktail had a substantially decreased number of culturable species and a reduced bacterial mass as defined by the relative amount of 16S rRNA. This was accompanied by an increase in the size of the cecum, without an apparent alteration in the histological morphology along the gut. R161H mice treated with the AMNV cocktail had a lower incidence of uveitis, and reduced intensity of inflammation at the age of 6-8 weeks. Attenuation of spontaneous uveitis was not due to general immunosuppression by AMNV treatment, because proliferative responses to polyclonal stimuli were comparable between AMNV-treated and untreated mice. Importantly, the percentage of IL-17-producing lymphocytes was lower in the lamina propria of AMNV-treated compared to control untreated mice and some of these cells appeared to express the IRBP-specific TCR
Retina-specific lymphocytes may be activated by commensal microbiota in the gut of R161H mice to trigger spontaneous uveitis. Production of IL-17 by these cells, which is reduced in AMNV-protected animals, may contribute to the development of ocular disease in this model. These findings may have important implications for pathogenesis of autoimmune uveitis in humans
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