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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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 1

Pathways of the complement system.

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Pathways of the complement system. The complement system is composed of ...
The complement system is composed of three pathways (classical, lectin, and alternative) that converge on the formation of a C3 convertase complex that is unique to each pathway. The classical pathway begins with binding of the C1 complex (composed of C1q, C1r, and C1s) to an antigen-antibody complex of pathogen surface directly; this leads to cleavage of C4 and then C2 to form the C3 convertase of the classical pathway. The lectin pathway is similar in that it begins with MBL recognizing mannose residues on a pathogen surface; this activates the MBL-associated serine proteases MASP-1 and MASP-2, which cleave C4 and C2. The alternative pathway is initiated by spontaneous hydrolysis of C3, which binds FB, leading to cleavage of FB by FD; this complex is stabilized by properdin. C3 convertase activity leads to the formation of the C5 convertase and eventually the MAC, triggering membrane destabilization of foreign material. Host complement inhibitors (light blue: FH, FI, MCP, DAF, CD59) target C3 convertase and MAC formation. FDA-approved complement inhibitors for GA (orange) are pegcetacoplan, which targets C3, and avacincaptad, which targets C5. Investigational therapies for GA (dark red) target components of the classical and alternative pathways.