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

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Abstract

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.

Section snippets

The complement cascade

As a component of the innate immune system, the complement system provides for opsonization and lysis of microorganisms, removal of foreign particles and dead cells, recruitment and activation of inflammatory cells, regulation of antibody production, and elimination of immune complexes (Markiewski and Lambris, 2007). The complement cascade's four activation pathways converge upon a common terminal pathway that culminates in the formation of the cytolytic membrane attack complex (MAC) (see Fig. 1

Complement-related gene expression in the RPE, choroid, and neural retina

Most complement components and many circulating complement regulatory proteins are synthesized primarily by liver hepatocytes and then released into the bloodstream. As such, most tissues and organs depend upon the circulation as a primary source for many complement-related proteins. However, in some tissues with limited access to circulating plasma proteins such as the brain, an extrahepatic system of complement biosynthesis also exists (Gasque et al., 1995, Johnson et al., 1992, Walker and

Localization of complement-related proteins in neural retina, RPE, and choroid

For those complement-related genes that showed relatively high transcription levels in the neural retina, RPE, and/or choroid, we localized some of the corresponding proteins to specific cells and extracellular compartments within these tissues. Some of the most salient results are illustrated in Fig. 6, Fig. 7.

Abundant plasma proteins such as albumin (Rs = 3.5 nm; 66 kDa) are localized throughout the choroid (Fig. 6A). In contrast, immunolabeling for factor H (142 kDa), a larger elongated

Functional implications of the local complement system in the RPE–choroid

The results from the qPCR analyses indicate that cells in the human RPE–choroid complex express a virtually complete set of transcripts for complement components and regulatory molecules associated with both the classical (Fig. 2, Fig. 3) and alternative branches of the complement cascade (Fig. 2, Fig. 4). In contrast, we found little evidence for gene expression of lectin pathway components or terminal pathway components (Fig. 2, Fig. 5), with the exception of C5 and C7, thereby indicating the

Similarities between the local complement systems in the RPE–choroid and kidney

The overall complement expression profile in the RPE–choroid is quite similar to the one identified previously in the kidney [reviewed by Zhou et al., 2001]. In both tissues, expression appears to be limited primarily to activation pathway components and a subset of complement inhibitors, with limited or no expression of terminal pathway components. The functional implications of this shared tissue-specific expression pattern strengthens the general concept that extrahepatic complement

Potential role(s) of the local complement system in aging and AMD

The identification of a local complement system in the RPE–choroid adds a new dimension, and imparts an extra level of biological complexity, to the role of the alternative pathway in the context of aging and AMD. The expression of complement pathway components by resident cells in the choroid constitutes a supplemental system for complement activation/regulation that may be mediated through either the alternative or classical pathways. In contrast, complement component expression in the RPE is

A transcriptional signature of AMD

It is highly likely that AMD, as well as many other diseases, possesses a characteristic transcriptional disease signature that is indicative of its pathogenic mechanisms (Kittleson and Hare, 2005, Klee, 2008). In the case of AMD, however, its transcriptional signature may be masked to varying degrees by different phenotypic manifestations, disease stage and duration, concurrent age-related changes, and multiple genetic linkages that have not as yet been characterized completely. In order to

Conflict of interest statement

GSH has a financial interest in Optherion, Inc., New Haven, CT.

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    This study was supported by NIH R24 EY017404 (GSH, LVJ, DHA), EY00331 (DB), EY014799 (LVJ), the Dolly Green Endowed Chair in Ophthalmology at UCLA (DB), the Foundation Fighting Blindness (CBR), the Ruth and Milton Steinbach Fund (CBR), and an unrestricted grants to the Duke Eye Center and the University of Utah Department of Ophthalmology and Visual Sciences from Research to prevent Blindness.

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