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Y. Lu, L. Jia, G. Grahek, N. Khan, J. R. Heckenlively; Two Mouse Models of Autoimmune Retinopoathy (AIR). Invest. Ophthalmol. Vis. Sci. 2009;50(13):2647.
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Currently, murine models of autoimmune retinopathy are not available, and attempts to produce them often give uveitis, which is not a feature of AIR. Recoverin has been demonstrated as one of causative antigenic retinal proteins common to many of the autoimmune retinopathies and was first identified as playing a central role in Cancer Associated Retinopathy (CAR). Strategies for producing two different mouse models were tested.
(1) Initially, screening of mouse sera for anti-retinal antibodies (ARAs) was performed on a number of mouse strains. After finding naturally occurring ARAs in lpr mice, 6-week old female lpr mice were immunized with recombinant recoverin for three times at 2-4 week intervals. Electroretinograms (ERG) and retinal histology were assessed after final immunization. (2) The second strategy was to make hybridoma mice using recoverin: 5 month old balb/cJ mice were injected with recoverin monoclonal antibody producing hybridoma cells; 7-10 days after injection, the ascites were drawn and ERGs and retinal histology assessed. Anti-recoverin antibody in sera or ascites was analyzed by immunoblot and ELISA.
Both recoverin immunized lpr mice and recoverin monoclonal antibody producing hybridoma cells-injected in balb/cJ mice had high anti-recoverin antibody levels. Both scotopic and photopic responses were reduced by 40% in these models. Retinal histology showed swollen cell bodies in the inner nuclear layer in recoverin immunized lpr mice, while shorter inner nuclear layer and ganglion cell layer were observed in recoverin monoclonal antibody producing hybridoma cells injected balb/cJ mice. GFAP staining detected a marked increase of Muller cell reactive gliosis in both mouse models, which indicated retinal degeneration.
Successful mouse models for AIR were produced by both experimental approaches. Having methodology for producing mouse models for AIR will allow specific retinal proteins that are found on Western blots in patients to be tested for pathogenecity. We found pathologic changes from anti-recoverin antibodies, but not as severe as might have been expected. These experimental models will help in developing new insights into immunological mechanisms of AIR.
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