Complement, Age-Related Macular Degeneration and a Vision of the Future

Gehrs, Karen M.

doi:10.1001/archophthalmol.2010.18

Cited by 147 publications

(118 citation statements)

References 105 publications

(100 reference statements)

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“…A number of the proteins detected in drusen are either complement components or related molecules. Importantly, variations in several complement-related genes have been shown to be highly significant risk factors for the development of AMD (20,21). Taken together, these findings are consistent with the general conclusion that chronic local inflammation at the RPE/ Bruch's membrane interface contributes to drusen formation and to AMD pathogenesis (12,14,22,23).…”

supporting

confidence: 80%

“…Although the primary biosynthetic source for most of these circulating molecules is the liver, a number of them are also known to be synthesized locally by RPE cells (15)(16)(17)(18)(19). The respective contributions of RPE-derived and plasma-derived molecules to the process of drusen biogenesis, as well as the relevant molecular interactions leading to drusen deposition, have not yet been fully elucidated.During the past decade, compelling evidence has emerged implicating the immune system-and the complement system in particular-in drusen biogenesis and AMD (15,20,21). A number of the proteins detected in drusen are either complement components or related molecules.…”

mentioning

confidence: 99%

“…During the past decade, compelling evidence has emerged implicating the immune system-and the complement system in particular-in drusen biogenesis and AMD (15,20,21). A number of the proteins detected in drusen are either complement components or related molecules.…”

mentioning

confidence: 99%

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Cell culture model that mimics drusen formation and triggers complement activation associated with age-related macular degeneration

Johnson

Forest

Banna

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

180

186

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We introduce a human retinal pigmented epithelial (RPE) cell-culture model that mimics several key aspects of early stage age-related macular degeneration (AMD). These include accumulation of sub-RPE deposits that contain molecular constituents of human drusen, and activation of complement leading to formation of deposit-associated terminal complement complexes. Abundant sub-RPE deposits that are rich in apolipoprotein E (APOE), a prominent drusen constituent, are formed by RPE cells grown on porous supports. Exposure to human serum results in selective, deposit-associated accumulation of additional known drusen components, including vitronectin, clusterin, and serum amyloid P, thus suggesting that specific proteinprotein interactions contribute to the accretion of plasma proteins during drusen formation. Serum exposure also leads to complement activation, as evidenced by the generation of C5b-9 immunoreactive terminal complement complexes in association with APOE-containing deposits. Ultrastructural analyses reveal two morphologically distinct forms of deposits: One consisting of membrane-bounded multivescicular material, and the other of nonmembrane-bounded particle conglomerates. Collectively, these results suggest that drusen formation involves the accumulation of sub-RPE material rich in APOE, a prominent biosynthetic product of the RPE, which interacts with a select group of drusen-associated plasma proteins. Activation of the complement cascade appears to be mediated via the classical pathway by the binding of C1q to ligands in APOE-rich deposits, triggering direct activation of complement by C1q, deposition of terminal complement complexes and inflammatory sequelae. This model system will facilitate the analysis of molecular and cellular aspects of AMD pathogenesis, and the testing of new therapeutic agents for its treatment.A ge-related macular degeneration (AMD) is characterized in its early stages by the presence of extracellular deposits, known as drusen, that accumulate between the basal surface of the retinal pigmented epithelium (RPE) and Bruch's membrane, an extracellular matrix complex that separates the neural retina from the capillary network in the choroid. Early electron microscopic studies suggested that drusen formation may be a consequence of degeneration of the RPE (1-3), initiated by membranous debris shed from its basal surface (4, 5). These early morphological observations have since been confirmed by a number of more recent studies (6-13).Contemporary investigations of the molecular composition of drusen have provided additional insights into their biogenesis. Immunohistochemical and proteomic studies show that drusen contain a variety of protein and lipid components (14, 15). Among these are several plasma proteins, the presence of which implies a systemic contribution to their genesis. Although the primary biosynthetic source for most of these circulating molecules is the liver, a number of them are also known to be synthesized locally by RPE cells (15)(16)(17)(18)(19). The respect...

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supporting

confidence: 80%

mentioning

confidence: 99%

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Cell culture model that mimics drusen formation and triggers complement activation associated with age-related macular degeneration

Johnson

Forest

Banna

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

180

186

View full text Add to dashboard Cite

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“…As with other human diseases, AMD is a complex disease with environmental and genetic factors impacting its development. The strongest identifiable risk factors for AMD are age, family history, smoking, and genetics (Gehrs et al, 2010). Although the precise etiology of AMD remains elusive, genetic studies have provided insights into the molecular basis of AMD.…”

Section: Introductionmentioning

confidence: 99%

Association between a functional genetic polymorphism (rs2230199) and age-related macular degeneration risk: a meta-analysis

et al. 2015

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ABSTRACT. The association between the rs2230199 C>G single nucleotide polymorphism (SNP) in complement component 3 and agerelated macular degeneration (AMD) risk has been examined extensively but the results are not consistent among studies. The aim of this study was to perform a meta-analysis of all available studies on this SNP in relation to AMD. The comprehensive databases of PubMed, Medline, Web of Knowledge, CNKI, and Google Scholar were searched for case-control studies investigating the association between the rs2230199 polymorphism and AMD susceptibility. ORs with 95%CIs were estimated to assess the 12568 M.X. Zhang et al.©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (4): 12567-12576 (2015) association. Sensitivity analysis, test of heterogeneity, cumulative metaanalysis, and assessment of bias were also performed. A total of 15 published studies including 5593 cases and 5181 controls were used in this meta-analysis. Overall, the rs2230299 SNP was significantly associated with the risk of AMD in the overall population under the additive model (OR = 1.571, 95%CI = 1.414-1.745, P = 0.000), dominant model (OR = 1.681, 95%CI = 1.521-1.858, P = 0.000), and allelic model (OR = 1.597, 95%CI = 1.470-1.734, P = 0.000). In the subgroup analysis by ethnicity, the same results were found in Caucasian populations, while no significant correlations were found in Asian populations for all comparison models. In conclusion, our meta-analysis provides evidence that the rs2230199 polymorphism contributes to the development of AMD. Further large-scale multicenter epidemiological studies are warranted to confirm this finding.

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“…A number of clinical trials have been proposed to control activation of the complement system in AMD. These include trials using intravitreal monoclonal anti-C5 and anti-FD therapies (Gehrs et al 2010;Zarbin & Rosenfeld 2010;Ambati et al 2013). The anti-C5 trials have not yet appeared to be successful, whereas unpublished data of a phase 2 study using intravitreal lampalizumab (anti-factor D, Roche) slowed the progression of geographic atrophy in patients with advanced dry AMD.…”

Section: Discussionmentioning

confidence: 99%

Lutein supplementation leads to decreased soluble complement membrane attack complex sC5b‐9 plasma levels

Tian

Kijlstra

Veen

et al. 2014

Acta Ophthalmologica

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ABSTRACT.Purpose: The purpose of this study was to investigate the effect of lutein on systemic complement activation in elderly individuals. Methods: Seventy patients with signs of early age-related macular degeneration (AMD) were included in this study. All subjects were randomly assigned to receive a 10 mg daily dose of lutein or a placebo for a time period of 1 year. EDTA blood was collected before and at various time-points during the study (0, 4, 8 and 12 months). The plasma level of the soluble complement membrane attack complex sC5b-9 was measured by ELISA. Results: We found a significant 1.1 ng/ml monthly decrease in the plasma sC5b-9 concentration in the lutein group (p < 0.001), resulting in a decrease from 60.3 ng/ml at baseline to 46.3 ng/ml at 12 months. For the placebo group, we found a significant 0.6 ng/ml monthly increase in plasma sC5b-9 concentration (p = 0.001), resulting in an increase from 51.6 ng/ml at baseline to 58.4 ng/ml at 12 months. Conclusions: Lutein supplementation inhibits the systemic activation of the complement system, which provides further functional evidence for the reported beneficial effects of this carotenoid in the management of AMD.

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Complement, Age-Related Macular Degeneration and a Vision of the Future

Cited by 147 publications

References 105 publications

Cell culture model that mimics drusen formation and triggers complement activation associated with age-related macular degeneration

Cell culture model that mimics drusen formation and triggers complement activation associated with age-related macular degeneration

Association between a functional genetic polymorphism (rs2230199) and age-related macular degeneration risk: a meta-analysis

Lutein supplementation leads to decreased soluble complement membrane attack complex sC5b‐9 plasma levels

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