Fc? receptors and immune complex-mediated inflammation in age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the developed world, but the mechanisms leading to AMD are poorly understood. Circulating retinal autoantibodies and antibody deposits in the retina are associated with AMD but despite this relationship, immune complex (IC)-mediated responses and underlying mechanisms of inflammation in the retina have not been characterised. IgG antibodies can activate immune effector function through formation of IC and their interaction with Fc? receptors (Fc?R) expressed by immune cells. This study aims to test the hypothesis that IC formed in the retina induce an inflammatory response following interaction with activating Fc?Rs expressed on microglia and/or macrophages, which may contribute to the pathogenesis of AMD.
To study the biological effect of IC formation in the retina a model of IC injury was developed and fully characterised. The involvement of mouse Fc?Rs (mFc?Rs) was first studied using Fc gamma chain deficient (?-/-) mice, lacking cellular expression of activating mFc?Rs, and further characterised using Fc?RI-/-, Fc?RIII-/- and Fc?RIV-/- mice. The presence of IC and human Fc?R (hFc?R) expression was investigated in human donor eyes from early and wet AMD patients and healthy controls. Finally the effect of inflammatory mediators on human retinal pigmented epithelium (RPE) function was investigated by direct stimulation with cytokines or indirect stimulation using conditioned medium of polarised human macrophages.
IC deposition in the mouse retina led to an inflammatory response that depended on the presence of activating mFc?Rs, particularly mFc?RI and mFc?RIII, but not on mFc?RIV. Immune complex deposition and increased numbers of immune cells expressing hFc?RIIa and hFc?RIIb were found in the choroid of early AMD donors and microglia in the retina of wet AMD donor eyes. Finally, macrophage activation differentially impacted on RPE cell function, with regards to barrier function and VEGF secretion.
The results in this thesis support the hypothesis that immune complex-mediated inflammation could play a role in the pathogenesis of AMD.

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ORCID for Jessica Teeling: orcid.org/0000-0003-4004-7391

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