The Role of the Complement Pathway in AMD
AT A GLANCE
- Activation of the complement system occurs via three distinct channels: the classical, alternative, and lectin pathways.
- Although complement can be activated by the three pathways, they all converge at a common point that results in the formation of C3 convertase.
- Unregulated complement activation in humans is responsible for both nonexudative, or dry, AMD and exudative, or wet, AMD.
Age-related macular degeneration (AMD) is a retinal/choroidal pathology that can lead to vision loss and is thought of as a progressive degenerative disease process in patients 55 years of age and older. It has been predicted that, within the next 20 years, the number of individuals with AMD will near 300 million globally, with the Asian population being most at risk.1
AMD is classified into stages ranging from early to severe (Figure 1). Extensive research has shown that vitamin supplementation with zinc and antioxidants can slow the progression of the disease.2 Treatment for the severe form of AMD (choroidal neovascularization [CNV]) involves intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF).2 The prevalence in total cases of non-neovascular, or dry AMD, (Figure 2) is approximately 80%, whereas the neovascular, or wet form, (Figure 3) is approximately 20% of cases. Additionally, there is a 10% to 15% risk that a patient with dry AMD will progress to the wet form.3
Observable risk factors such as the type of drusen present and pigmentary changes in the macula are often good predictors of disease progression once a diagnosis has been established. Certain genetic, demographic, and environmental factors can also contribute to the onset of the disease.4 As research continues, the etiology of AMD and its treatment modalities are becoming more widely understood. This article examines the role of the complement cascade and immune system in the etiology of dry and wet AMD.
UNDERSTANDING THE COMPLEMENT CASCADE
The complement cascade is an important part of the innate and adaptive immune system. Complement consists of a large group of plasma and membrane-bound proteins that are critical for the defense against infection and in the modulation of immune and inflammatory responses (recognition and opsonization of a microorganism or foreign pathogen). These proteins are responsible for initiating, activating, and regulating the complement pathways. Activation of the complement system occurs via three distinct channels: the classical, alternative, and lectin pathways.
The Classical Pathway
This pathway can be activated when the complement component C1 (a complex of C1q, C1r, and C1s) binds to the antigen-bound IgM, IgG, or other substances such as C-reactive protein (CRP). This binding changes the conformation of C1q, resulting in the activation of the C1 complex. Once activated, the C1 complex then cleaves C4 to C2 to form the C4bC2a complex, also known as C3 convertase because it cleaves C3.
The Alternative Pathway
This pathway provides an antibody-independent route of complement activation. In this pathway, C3 is cleaved and activated either directly by enzymes or spontaneously when in contact with certain activating surfaces, such as a lipopolysaccharide. The membrane-bound C3b will bind to complement factor B and is eventually cleaved by complement factor D into Ba and Bb. This C3bBb complex will cleave additional C3, activating the entire complement cascade.
The Lectin Pathway
This pathway is activated by the interaction of certain serum lectins, such as mannose-binding lectin (MBL), with mannose and N-acetyl glucosamine residues that are present on the surfaces of pathogens. When lectins bind to mannose, they activate the MBL-serine proteases (MASP-1 and MASP-2), which are functionally similar to the classical pathway’s C1r and C1s. MASP-1 and MASP-2 then cleave C4 and C2, creating the C4bC2a complex (C3 convertase).
THE COMPLEMENT CASCADE: BASICS
Although complement can be activated by three pathways, they all converge at a common step that results in the formation of the C3 convertase. Once the C3 convertase is formed, the known terminal pathway (membrane attack complex [MAC]) is activated. Cleavage of C3 results in the release of fragments C3a and C3b. C3 convertase will bind to C3b to form C5 convertase. C5 forms C6, which subsequently binds to C7 and then to C8. Once C8 is bound to the complex, the C5b678 complex inserts into lipid membranes and several C9 molecules bind to form a pore-forming polymer on the membrane. This MAC (C5b6789) on a specific cell surface, such as bacteria, eventually causes pore formation and cell lysis.
Tight regulation of the complement cascade is warranted to prevent immune-mediated complications and disease. Once activated, the complement system is not equipped to distinguish between self- and non-self cells. If unregulated, the complement system can destroy self-components. The body protects itself from the complement system by expressing various complement regulatory proteins (CRegs), which act at different stages of the complement cascade. These regulatory proteins are either membrane-bound or soluble. Decay accelerating factor (DAF, CD55), membrane cofactor protein (MCP, CD46), complement receptor 1 (CR1, CD35), and membrane inhibitor of reactive lysis (MIRL, CD59) are some of the membrane-bound CRegs. C1 inhibitory protein (C1INH), C4-binding protein (C4bp), complement factor H (CFH), and complement factor I (CFI) are some of the known soluble CRegs. As stated earlier, these CRegs regulate the complement system at various stages of the cascade.5
THE CONNECTION BETWEEN AMD AND THE COMPLEMENT CASCADE
Current evidence tends to suggest that AMD is a cumulative effect of insults to the retina that include oxidative stress, endoplasmic reticulum stress, and an accumulation of retinal pigment epithelium (RPE) byproducts such as glycoproteins, lipids, and cellular debris beneath the RPE and inside Bruch membrane.6 Current research in both human and animal models shows that AMD is also an immunologic disease and that the complement cascade system plays an important role in its etiology and progression.5,6 In AMD, the RPE becomes injured (eg, mitochondrial injury), eliciting a chronic dysfunctional inflammatory response in the RPE itself, Bruch membrane, and the underlying choroidal layers.7 Unregulated complement activation in humans is responsible for both nonexudative, or dry, AMD and exudative, or wet, AMD.5 Components of the complement system (C1q C3a, C5a, MAC) and complement regulatory proteins (CR1, CFH, CD 46, and vitronectin) are present within drusen (the earliest clinical finding of AMD) and in patients with both AMD and geographic atrophy (GA).5,8
As noted above, the complement system is tightly regulated.6 Polymorphisms of the complement factor H gene (CFH) increase the risk of AMD in humans. This single nucleotide polymorphism occurs at position 402 of the codon-encoding factor H. The variant of factor H with tyrosine to histidine at position 402 is called the risk variant for AMD (Y402H). The CFH gene (found on chromosome 1) encodes the major complement control protein found in plasma that binds to heparin expressed on host cells. CFH inactivates C3b within the cascade to inhibit the “alternative” pathway, thus protecting host cells from the innate immune system. By binding to C3b, CFH eventually prevents the formation of C3 convertase that will ultimately form the MAC.8
Other polymorphisms with the complement components C2, C3, and factor B are also associated with AMD. The effect of risk to AMD on each variation is different. A reduction of complement factor H and an increase in the activity of factor B and C2 result in an increase in complement activation that initiates inflammation and drusen formation.5
Another inflammatory protein, C-reactive protein (CRP), is produced in the liver and activates the classical pathway to remove foreign cells and cellular debris. A current hypothesis is that an elevated CRP (high-sensitivity CRP) may serve as an important biomarker of AMD because it suggests amplified inflammation. CRP may also participate in the AMD disease process over time. Individuals with the Y402H polymorphism and a high CRP are more susceptible to acquiring the advanced stage of AMD.8,9 It is interesting to note that the CFH variant Y402H also increases a patient’s risk for acquiring GA and choroidal neovascularization (CNV) independent of their smoking status.10
Ultimately, complement activation and time lead to VEGF upregulation and eventual choroidal neovascularization membrane (CNVM).6 For wet AMD, the formation of the MAC via the C3 pathway is a critical step in the etiology of a CNVM. MAC is crucial for the upregulation of VEGF, transforming growth factor Beta (TGF-Beta 2), and Beta fibroblast growth factor (FGF).5
To summarize, any genetic polymorphism (Y402H CFH) or environmental stressor (increased C-reactive protein or A2E photooxidation—a major component of lipofuscin accumulating in the RPE) leads to overactivity of the complement system and further outer retina/choroidal chronic tissue damage.6 Once the complement cascade has been activated, C3 acts as the linchpin of complement overaction, leading to the advanced stage of the disease process, especially in the expression of the phenotype of GA.11,12
KNOWLEDGE AND TREATMENTS IMPROVING OVER TIME
Intravitreal anti-VEGF injections remain the mainstay of wet AMD therapy; however, treatments targeting the complement system while a patient is in the dry phase of AMD are also being investigated.13 Other approaches being considered to reduce the rate of disease progression include drugs with antioxidative properties, neuroprotective agents, visual cycle inhibitors, and gene therapy.14
AMD is a leading cause of vision loss that affects the elderly population. As research into the disease process continues, and we now have a clearer understanding that AMD is an inflammatory condition and, more specifically, that the proteins of the complement cascade system are central to its etiology and progression.15
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