Complement System In Age-related Macular Degeneration Research Articles

Altered Elastin Turnover, Immune Response, and Age-Related Retinal Thinning in a Transgenic Mouse Model With RPE-Specific HTRA1 Overexpression.

A single-nucleotide polymorphism in HTRA1 has been linked to age-related macular degeneration (AMD). Here we investigated the potential links between age-related retinal changes, elastin turnover, elastin autoantibody production, and complement C3 deposition in a mouse model with RPE-specific human HTRA1 overexpression. HTRA1 transgenic mice and age-matched CD1 wild-type mice were analyzed at 6 weeks and 4, 6, and 12 to 14months of age using in vivo retinal imaging by optical coherence tomography (OCT) and fundus photography, as well as molecular readouts, focusing on elastin and elastin-derived peptide quantification, antielastin autoantibody, and total Ig antibody measurements and immunohistochemistry to examine elastin, IgG, and C3 protein levels in retinal sections. OCT imaging indicated thinning of inner nuclear layer as an early phenotype in HTRA1 mice, followed by age and age/genotype-related thinning of the photoreceptor layer, RPE, and total retina. HTRA1 mice exhibited reduced elastin protein levels in the RPE/choroid and increased elastin breakdown products in the retina and serum. A corresponding age-dependent increase of serum antielastin IgG and IgM autoantibodies and total Ig antibody levels was observed. In the RPE/choroid, these changes were associated with an age-related increase of IgG and C3 deposition. Our results confirm that RPE-specific overexpression of human HTRA1 induces certain AMD-like phenotypes in mice. This includes altered elastin turnover, immune response, and complement deposition in the RPE/choroid in addition to age-related outer retinal and photoreceptor layer thinning. The identification of elastin-derived peptides and corresponding antielastin autoantibodies, together with increased C3 deposition in the RPE/choroid, provides a rationale for an overactive complement system in AMD irrespective of the underlying genetic risk.

Complement System and Potential Therapeutics in Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a complex multifactorial disease characterized in its late form by neovascularization (wet type) or geographic atrophy of the retinal pigment epithelium cell layer (dry type). The complement system is an intrinsic component of innate immunity. There has been growing evidence that the complement system plays an integral role in maintaining immune surveillance and homeostasis in AMD. Based on the association between the genotypes of complement variants and AMD occurrence and the presence of complement in drusen from AMD patients, the complement system has become a therapeutic target for AMD. However, the mechanism of complement disease propagation in AMD has not been fully understood. This concise review focuses on an overall understanding of the role of the complement system in AMD and its ongoing clinical trials. It provides further insights into a strategy for the treatment of AMD targeting the complement system.

The Challenges and Promise of Complement Therapeutics for Ocular Diseases.

Ocular inflammation is a defining feature of sight threating diseases and its dysregulation can catalyze and or propagate ocular neurodegenerative maladies such as age-related macular degeneration (AMD). The complement system, an intrinsic component of the innate immunity, has an integral role in maintaining immune-surveillance and homeostasis in the ocular microenvironment; however, overstimulation can drive ocular inflammatory diseases. The mechanism for complement disease propagation in AMD is not fully understood, although there is accumulating evidence showing that targeted modulation of complement-specific proteins has the potential to become a viable therapeutic approach. To date, a major focus of complement therapeutics has been on targeting the alternative complement system in AMD. Recent studies have outlined potential complement cascade inhibitors that might mitigate AMD disease progression. First-in-class complement inhibitors target the modulation of complement proteins C3, C5, factor B, factor D, and properdin. Herein, we will summarize ocular inflammation in the context of AMD disease progression, current clinical outcomes and complications of complement-mediated therapeutics. Given the need for additional therapeutic approaches for ocular inflammatory diseases, targeted complement modulation has emerged as a leading candidate for eliminating inflammation-driven ocular maladies.

Detection of Chlamydia and Complement Factors in Neovascular Membranes of Patients with Age-related Macular Degeneration

Purpose: To investigate whether Chlamydia pneumoniae and complement factors were present in surgically removed choroidal neovascular membranes (CNV) of patients with age-related macular degeneration (AMD).Methods: Paraffin sections of 26 CNV were stained for C. pneumoniae or the complement factors H (CFH) and C5, whereas macrophages were identified by positive CD68 staining. Clinical characteristics have been correlated to the immunohistochemical findings.Results: C. pneumoniae was found in 68% of the investigated membranes, and 88% of these membranes were also positive for CD68. Staining for CFH and C5 gave a positive reaction in 68 and 41% of the membranes, respectively. Patients with C5-positive membranes had significantly larger CNV mean area and were younger than patients with CFH-positive membranes at the operation time point.Conclusions: Correlations between clinical symptoms and complement factor C5 could be shown. The results strengthen the hypothesis of an involvement of the complement system in AMD.

Therapeutic targeting of the complement system in age‐related macular degeneration: a review

The last decade has produced pivotal change in our understanding of the molecular mechanisms underlying age-related macular degeneration (AMD), a leading cause of global blindness. In this time, the complement system has featured as a unifying theme for several elements of new evidence: initially, the discovery of complement proteins within drusen and subsequently, the association between AMD and mutations in various complement pathway genes, most notably complement factor H. Increasingly, a wealth of data are pointing towards a role for chronic local inflammation and complement activation in the patho-aetiology of AMD. These findings have paved the way for the exploration of a new paradigm of therapy in AMD management; targeting of specific molecular constituents in the complement pathway thus producing dampening or inhibition of the inflammatory response. Such an approach has the potential to intervene earlier in the disease process and ideally before vision is compromised. In this review we discuss the role of the complement system in AMD, novel therapies in preclinical evaluation and clinical trial, and whether these have a part to play in reducing the burden of disease.

Implication of CD21, CD35, and CD55 in the Pathogenesis of Age-Related Macular Degeneration

To determine a possible implication of CD21, CD35, and CD55 in the pathogenesis of age-related macular degeneration (AMD) by assessing the difference in expression rates of these factors on AMD patients and a control group. Case-control study. Fifty unrelated AMD patients and 48 unrelated sex- and age-matched control subjects participated in this case-control study. Samples of fresh EDTA-blood were stained and flow cytometry was chosen to measure fluorescence emissions. The association between exudative AMD and CD21, CD35, and CD55 was evaluated from all patients who completed the study. Our study shows CD35 to be expressed in a significantly higher frequency in AMD patients on monocytes (P = .00586), lymphocytes (P = .000605), and granulocytes (P < .000033). In contrast, the expression rate of CD21 (P > .05) and CD55 (P > .05) are similar in both groups. More regulative factors of the complement system are involved in pathogenesis of AMD. Our study underlines the key role of the complement system in AMD and shows the involvement of the whole immune system through more regulative factors.

The pivotal role of the complement system in aging and age-related macular degeneration: Hypothesis re-visited

During the past ten years, dramatic advances have been made in unraveling the biological bases of age-related macular degeneration (AMD), the most common cause of irreversible blindness in western populations. In that timeframe, two distinct lines of evidence emerged which implicated chronic local inflammation and activation of the complement cascade in AMD pathogenesis. First, a number of complement system proteins, complement activators, and complement regulatory proteins were identified as molecular constituents of drusen, the hallmark extracellular deposits associated with early AMD. Subsequently, genetic studies revealed highly significant statistical associations between AMD and variants of several complement pathway-associated genes including: Complement factor H (CFH), complement factor H-related 1 and 3 (CFHR1 and CFHR3), complement factor B (CFB), complement component 2 (C2), and complement component 3 (C3). In this article, we revisit our original hypothesis that chronic local inflammatory and immune-mediated events at the level of Bruch's membrane play critical roles in drusen biogenesis and, by extension, in the pathobiology of AMD. Secondly, we report the results of a new screening for additional AMD-associated polymorphisms in a battery of 63 complement-related genes. Third, we identify and characterize the local complement system in the RPE-choroid complex - thus adding a new dimension of biological complexity to the role of the complement system in ocular aging and AMD. Finally, we evaluate the most salient, recent evidence that bears directly on the role of complement in AMD pathogenesis and progression. Collectively, these recent findings strongly re-affirm the importance of the complement system in AMD. They lay the groundwork for further studies that may lead to the identification of a transcriptional disease signature of AMD, and hasten the development of new therapeutic approaches that will restore the complement-modulating activity that appears to be compromised in genetically susceptible individuals.