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Salome Murinello, Andrew Lotery, V. Hugh Perry, Robert Mullins, Jessica L. Teeling; The role of Fcγ receptors in immune-complex-mediated inflammation in the retina: implications for early age related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2013;54(15):156. doi: https://doi.org/.
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The association of immunoglobulin G (IgG), complement and activated macrophages/microglia with drusen implicates immune complex (IC) inflammation in age-related macular degeneration (AMD), but IC responses in the eye have been poorly characterised. This study assessed the role of complement and IgG Fcγ Receptors (FcγRs) using a localized IC reaction (Arthus) in the retina of wild-type, C1q and Fcγ chain deficient mice and evaluated the inflammatory response. We then investigated the IC mediated inflammation in AMD by looking for the presence of IgG, complement activation and Fcγ receptor expression in donor eye tissue from AMD patients.
Wild-type, C1q-/- and Fcγ chain-/- BALB/c mice were immunized against ovalbumin (OVA), followed by intravitreal challenge of OVA or saline. Eye tissue was collected three days following OVA challenge and analysed for the presence of IC and microglial activation by immunohistochemical staining of the retina. Human donor eyes were used for immunohistochemical detection of IgG, membrane attack complex (MAC, C5b-9), FcγRIIb and FcγRIIa, and the leukocyte marker CD45.
IC formed throughout the retina of all mice, following intravitrous injection of OVA, including large deposits in the subretinal space. In wild-type and C1q-/- these deposits were associated with inflammation and increased expression of MHC II and all four murine FcγRs. These changes were not observed in Fcγ chain-/- or OVA immunized wild type mice challenged with saline. IgG and MAC deposition was increased in the choroid of AMD donor eyes, when compared to aged matched controls. This was accompanied by increased numbers of CD45+ leukocytes and upregulation of FcγRIIb and FcRIIa on these cells.
Our results suggest that IC formed in the retina can induce a potent inflammatory response with up-regulation of FcγRs and MHCII on microglia and recruitment of macrophages. We show FcγRs, but not C1q, are crucial for the generation of this inflammatory response. We confirmed the presence of IgG and MAC in the eyes of AMD patients, as well as increased numbers of leukocytes and upregulation of the FcγRIIb and FcRIIa. Our results suggest that immune-complexes in the eye could mediate local inflammation and contribute to AMD through the interaction of IgG with FcγRs. These findings may have implications for antibody therapies for AMD.
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