Complement regulation in the eye: implications for age-related macular degeneration
Georgia A. Wilke, Rajendra S. Apte
Georgia A. Wilke, Rajendra S. Apte
Published May 1, 2024
Citation Information: J Clin Invest. 2024;134(9):e178296. https://doi.org/10.1172/JCI178296.
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Review

Complement regulation in the eye: implications for age-related macular degeneration

Abstract

Careful regulation of the complement system is critical for enabling complement proteins to titrate immune defense while also preventing collateral tissue damage from poorly controlled inflammation. In the eye, this balance between complement activity and inhibition is crucial, as a low level of basal complement activity is necessary to support ocular immune privilege, a prerequisite for maintaining vision. Dysregulated complement activation contributes to parainflammation, a low level of inflammation triggered by cellular damage that functions to reestablish homeostasis, or outright inflammation that disrupts the visual axis. Complement dysregulation has been implicated in many ocular diseases, including glaucoma, diabetic retinopathy, and age-related macular degeneration (AMD). In the last two decades, complement activity has been the focus of intense investigation in AMD pathogenesis, leading to the development of novel therapeutics for the treatment of atrophic AMD. This Review outlines recent advances and challenges, highlighting therapeutic approaches that have advanced to clinical trials, as well as providing a general overview of the complement system in the posterior segment of the eye and selected ocular diseases.

Authors

Georgia A. Wilke, Rajendra S. Apte

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Figure 3

The retina in AMD.

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The retina in AMD. (A) In neovascular AMD, it is hypothesized that chori...
(A) In neovascular AMD, it is hypothesized that choriocapillaris atrophy leads to ischemia of the RPE, which triggers VEGF secretion and the growth of abnormal choroidal blood vessels. These vessels breach BM and grow in the sub-RPE or subretinal space, causing accumulation of subretinal and intraretinal fluid. (B) In atrophic AMD, it is thought that some primary insult leads to RPE degeneration, which causes choriocapillaris atrophy due to the role of the RPE in supporting choriocapillaris function. As the RPE degenerates, the overlying photoreceptors die. In both types of AMD, there is choriocapillaris atrophy and RPE degeneration, though the sequence of events in each disease may be different. In terms of complement activity in AMD, increased concentrations of C3, C3a, Bb, FB, and FD have been detected within BM and choriocapillaris of human donor eyes with AMD (denoted by asterisks) (100). Cadaver studies have found MAC deposition in the RPE and choriocapillaris of patients with the Y402H polymorphism in CFH regardless of whether AMD changes are present (88, 89). The Y402H polymorphism is believed to contribute to AMD pathogenesis primarily through its effect on FHL-1, as FHL-1 is the major complement regulator of BM (83, 84).