The Role of Complement Dysregulation in Glaucoma

Abstract

Glaucoma is a progressive neurodegenerative disease characterized by damage to the optic nerve that results in irreversible vision loss. While the exact pathology of glaucoma is not well understood, emerging evidence suggests that dysregulation of the complement system, a key component of innate immunity, plays a crucial role. In glaucoma, dysregulation of the complement cascade and impaired regulation of complement factors contribute to chronic inflammation and neurodegeneration. Complement components such as C1Q, C3, and the membrane attack complex have been implicated in glaucomatous neuroinflammation and retinal ganglion cell death. This review will provide a summary of human and experimental studies that document the dysregulation of the complement system observed in glaucoma patients and animal models of glaucoma driving chronic inflammation and neurodegeneration. Understanding how complement-mediated damage contributes to glaucoma will provide opportunities for new therapies.

Keywords: complement system; glaucoma; inflammation.

Figure 1

Overview of the complement system and its inhibitors. The complement system is made of the classical, lectin, and alternative pathways. The classical pathway is initiated by the binding of the C1Q complex to IgG, IgM, or CRP present on the target surface, cleaving C4 and C2, and generating the C3 convertase C4bC2a. The lectin pathway becomes activated when MBL or ficolins bind to a carbohydrate on the target surface. The associated MASP1 and MASP2 will then activate the cleavage of C4 and C2 to form the C3 convertase C4bC2a. The alternative pathway can be activated by spontaneous hydrolysis of C3 (tick-over) to form C3(H₂O), which in the presence of CFB and CFD will lead to the formation of C3 convertase C3(H₂O)Bb that cleaves C3 into C3a and C3b—similar to the other C3 convertase. C3b is produced by all three pathways and can interact with CFB, CFD, and CFP to form the membrane-bound C3 convertase C3bBb, which serves as an amplification loop for the entire complement system. C3b will be further bound to the C4bC2a or C3bBb complex to form the C5 convertase C4bC2aC3b and C3bBbC3b, respectively. These C5 convertases convert C5 into C5a and C5b, which initiate the terminal pathway. C5b binds with C6, C7, C8, and C9 to form the membrane attack complex (MAC, C5b-9). The MAC forms a pore in the target cell membrane, leading to cell lysis. Cleavage products C4a, C3a, and C5a are anaphylatoxins, which mediate inflammation by recruiting neutrophils and monocytes. In addition, C3b and iC3b act as opsonins, bind to the target cell surface, and mark them for phagocytosis. Figure was created with BioRender.com.