Targeting the complement system for the management of retinal inflammatory and degenerative diseases

Abstract

The retina, an immune privileged tissue, has specialized immune defense mechanisms against noxious insults that may exist in diseases such as age-related macular degeneration (AMD), diabetic retinopathy (DR), uveoretinitis and glaucoma. The defense system consists of retinal innate immune cells (including microglia, perivascular macrophages, and a small population of dendritic cells) and the complement system. Under normal aging conditions, retinal innate immune cells and the complement system undergo a low-grade activation (parainflammation) which is important for retinal homeostasis. In disease states such as AMD and DR, the parainflammatory response is dysregulated and develops into detrimental chronic inflammation. Complement activation in the retina is an important part of chronic inflammation and may contribute to retinal pathology in these disease states. Here, we review the evidence that supports the role of uncontrolled or dysregulated complement activation in various retinal degenerative and angiogenic conditions. We also discuss current strategies that are used to develop complement-based therapies for retinal diseases such as AMD. The potential benefits of complement inhibition in DR, uveoretinitis and glaucoma are also discussed, as well as the need for further research to better understand the mechanisms of complement-mediated retinal damage in these disease states.

Keywords: Age-related macular degeneration; Complement; Diabetic retinopathy; Glaucoma; Inflammation; Treatment; Uveoretinitis.

Fig. 1

Retinal neuronal and vascular structure and retinal disease. A, diagram of a human eye. Light passes through the pupil and is focused by the lens onto the macula of the retinal layer at the back of the eye. B, the retina consists of three layers of neurons, photoreceptor, bipolar, and ganglion cells. The RPE monolayer together with Bruch's membrane (BM) form the outer blood retinal barrier that separates the neuroretina from the choroid. Choroidal circulation provides oxygen and nutrients to the outer retina. C, the retina has an interconnected network of three vascular layers located in the ganglion cell/nerve fibre layer, inner plexiform layer (IPL), and outer plexiform layer (OPL). D, retinal tissue and cells that are affected under different disease conditions.

Fig. 2

Complement activation and immune regulation. The complement system can be activated by the classical pathway (CP), mannose-binding lectin (MBL) pathway and the alternative pathway (AP); all leads to the cleavage of C3 and C5 and the formation of C5b-C9. C3 is cleavaged by C3 convertases, which include C4bC2b of the CP and MBL pathways and C3bBb of the AP. C5 is cleavaged by C5 convertases, which include C4bC2bC3b of the CP and MBL pathways and C3bBbC3b of the AP. Activation of the complement system generates C4a, C3a, C3b and C5a fragments that are actively involved in immune responses. C3b opsonizes foreign antigens and apoptotic cells, promoting phagocytosis. C3a and C5a are anaphylatoxins that have multiple immune regulatory roles. The C5b-C9 may directly kill pathogens or cells. The sub-lytic C5b-9 can also promote inflammation.