Genetic Control of Complement Activation in Humans and Age Related Macular Degeneration

Hecker, Laura A.; Edwards, Albert O.

doi:10.1007/978-1-4419-5635-4_4

Cited by 13 publications

(9 citation statements)

References 54 publications

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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: 78%

“…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.…”

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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: 78%

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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“…An extension of the excellent studies by Newman and colleagues would be comparing the transcriptome of anatomically healthy eyes at genetically low- or high-risk for developing AMD. Identifying altered patterns of complement proteins has been explored in human tissues with known AMD-associated genotypes [25,26]. Systems based analysis of tissues with different genotypes may uncover the initial molecular events in eyes predisposed to disease, even before the genesis of any overt pathology.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome changes in age-related macular degeneration

Whitmore

Mullins

2012

BMC Medicine

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Age-related macular degeneration (AMD) is a debilitating, common cause of visual impairment. While the last decade has seen great progress in understanding the pathophysiology of AMD, the molecular changes that occur in eyes with AMD are still poorly understood. In the current issue of Genome Medicine, Newman and colleagues present the first systematic transcriptional profile analysis of AMD-affected tissues, providing a comprehensive set of expression data for different regions (macula versus periphery), tissues (retina versus retinal pigment epithelium (RPE)/choroid), and disease state (control versus early or advanced AMD). Their findings will serve as a foundation for additional systems-level research into the pathogenesis of this blinding disease.

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“…[16][17][18][19] Presuming an analogous role in AMD pathogenesis, multiple groups are exploring the possibility that complement inhibition may be effective for preventing or slowing AMD progression. 12,[20][21][22] Several findings, however, argue against this strategy. For example, mice lacking C3a and/or C5a signaling have abnormal susceptibility to neuroexcitotoxicity, 23 abnormal neurogenesis, 24 abnormal differentiation and migration of neural progenitor cells, 25 abnormal liver cell survival/regeneration, 26 and abnormal remyelination.…”

mentioning

confidence: 99%