Two mouse models for recoverin-associated autoimmune retinopathy.

PURPOSE:Recoverin has been demonstrated to be one of the main causative antigenic retinal proteins common in many cases of autoimmune retinopathy (AIR). Strategies for producing two different AIR mouse models associated with anti-recoverin antibodies were tested. METHODS:(1) Six-week-old female B6.MRL-Fal(lpr)/J mice (LPR) mice were immunized with recombinant recoverin three times at 2-4 week intervals. (2) Five-month-old Balb/cJ mice were injected with hybridoma cells designed to produce recoverin monoclonal antibodies. Anti-recoverin antibodies were analyzed by immunoblot and enzyme-linked immunosorbent assay (ELISA). Electroretinograms (ERG), histopathologic examination, and flow cytometric analysis were assessed. RESULTS:High anti-recoverin antibody levels were achieved in both models, accompanied by significantly reduced scotopic and photopic responses on the ERGs. Retinal histology showed swollen cell bodies in the inner nuclear layer in recoverin-immunized LPR mice, while photoreceptor and outer nuclear layer swelling was observed in recoverin hybridoma cells injected into balb/cJ mice. Glial fibrillary acidic protein (GFAP) staining detected a marked increase of Müller cells and astrocyte reactive gliosis in both mouse models. Rhodopsin and S-opsin staining was similar to controls, while decreased numbers of bipolar cells were observed in both models. Complement component C1q and C3 deposits increased upon immunohistopathologic retinal staining in both models, while increased numbers of CD4+ and CD68+ cells from retinas were found upon flow cytometric analysis. CONCLUSIONS:These two models had similar pathology in the retina, indicating the retinal antigens to recoverin antibody set off pathologic events that include leukocyte invasion, complement deposition, reactive gliosis in the retina, and selective retinal degeneration of inner nuclear layer neurons. These two AIR mouse models will allow for detailed pathologic investigation and testing of protein antigens associated with human AIR and can be used to test treatments. It is important to note that, since most AIR patients have multiple anti-retinal antibodies, it will be possible to study which antibodies are pathologic and which have no retinal pathologic effects. These models can also serve as an important research resource for studying the pathophysiology of specific retinal proteins by creating autoantibodies, which potentially will give a better understanding of retinal protein interactions.

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