The pivotal role of the complement system in aging and age-related macular degeneration: Hypothesis re-visited☆
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.
References (116)
- et al.
Mesangial immune complex glomerulonephritis due to complement factor D deficiency
Kidney Int.
(2007) - et al.
The SERPING1 gene and age-related macular degeneration
Lancet
(2009) - et al.
A role for local inflammation in the formation of drusen in the aging eye
Am. J. Ophthalmol.
(2002) - et al.
Characterization of beta amyloid assemblies in drusen: the deposits associated with aging and age-related macular degeneration
Exp. Eye Res.
(2004) - et al.
C-reactive protein
J. Biol. Chem.
(2004) - et al.
Role of complement in neurodegeneration and neuroinflammation
Mol. Immunol.
(2007) - et al.
The spectrum of phenotypes caused by variants in the CFH gene
Mol. Immunol.
(2009) - et al.
C7 is expressed on endothelial cells as a trap for the assembling terminal complement complex and may exert anti-inflammatory function
Blood
(2009) - et al.
Adipsin and an endogenous pathway of complement from adipose cells
J. Biol. Chem.
(1992) - et al.
His-384 allotypic variant of factor H associated with age-related macular degeneration has different heparin binding properties from the non-disease-associated form
J. Biol. Chem.
(2006)
The blood–retinal barriers system. Basic concepts and clinical evaluation
Exp. Eye Res.
Basal deposits and drusen in eyes with age-related maculopathy: evidence for solid lipid particles
Exp. Eye Res.
C1 inhibitor: biologic activities that are independent of protease inhibition
Immunobiology
Two genetic pathways for age-related macular degeneration
Curr. Opin. Genet. Dev.
The role of inflammation in the pathogenesis of age-related macular degeneration
Surv. Ophthalmol.
Association between the SERPING1 gene and age-related macular degeneration: a two-stage case-control study
Lancet
An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the rpe-bruch's membrane interface in aging and age-related macular degeneration
Prog. Retin. Eye Res.
Complement factor H binds to denatured rather than to native pentameric C-reactive protein
J. Biol. Chem.
Functional SNPs in the human ficolin (FCN) genes reveal distinct geographical patterns
Mol. Immunol.
The role of complement system in ocular diseases including uveitis and macular degeneration
Mol. Immunol.
Complement mRNA in the mammalian brain: responses to Alzheimer's disease and experimental brain lesioning
Neurobiol. Aging
A potential role for immune complex pathogenesis in drusen formation
Exp. Eye Res.
Complement activation and inflammatory processes in drusen formation and age related macular degeneration
Exp. Eye Res.
Factor H family proteins and human diseases
Trends Immunol.
Molecular signature analysis: using the myocardial transcriptome as a biomarker in cardiovascular disease
Trends Cardiovasc. Med.
Data mining for biomarker development: a review of tissue specificity analysis
Clin. Lab. Med.
Retinal synthesis and deposition of complement components induced by ocular hypertension
Exp. Eye Res.
Extrahepatic synthesis of complement proteins in inflammation
Mol. Immunol.
Distribution and composition of esterified and unesterified cholesterol in extra-macular drusen
Exp. Eye Res.
The role of complement in inflammatory diseases from behind the scenes into the spotlight
Am. J. Pathol.
Genetic deficiency of complement factor H in a patient with age-related macular degeneration and membranoproliferative glomerulonephritis
Mol. Immunol.
Disease susceptibility of the human macula: differential gene transcription in the retinal pigmented epithelium/choroid
Exp. Eye Res.
Clusterin is present in drusen in age-related macular degeneration
Exp. Eye Res.
The factor H variant associated with age-related macular degeneration (His-384) and the non-disease-associated form bind differentially to C-reactive protein, fibromodulin, DNA, and necrotic cells
J. Biol. Chem.
Defective complement control of factor H (Y402H) and FHL-1 in age-related macular degeneration
Mol. Immunol.
Multilocus analysis of age-related macular degeneration
Eur. J. Hum. Genet.
Differential expression of the complement regulatory proteins in the human eye
Invest. Ophthalmol. Vis. Sci.
Translational mini-review series on complement factor H: genetics and disease associations of human complement factor H
Clin. Exp. Immunol.
Drusen proteome analysis: an approach to the etiology of age-related macular degeneration
Proc. Natl. Acad. Sci. U.S.A.
Accumulation of cholesterol with age in human Bruch's membrane
Invest. Ophthalmol. Vis. Sci.
Amyloid-beta is found in drusen from some age-related macular degeneration retinas, but not in drusen from normal retinas
Mol. Vis.
Complement component C3 and risk of age-related macular degeneration
Ophthalmology
Genetics of age-related macular degeneration
Adv. Exp. Med. Biol.
Complement factor H polymorphism and age-related macular degeneration
Science
Support for the involvement of complement factor I in age-related macular degeneration
Eur. J. Hum. Genet.
Variation near complement factor I is associated with risk of advanced AMD
Eur. J. Hum. Genet.
SNP discovery in pooled samples with mismatch repair detection
Genome Res.
Analysis of major alleles associated with age-related macular degeneration in patients with multifocal choroiditis: strong association with complement factor h
Arch. Ophthalmol.
Complement expression in human brain. Biosynthesis of terminal pathway components and regulators in human glial cells and cell lines
J. Immunol.
C-Reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustains an antiinflammatory innate immune response: implications for systemic autoimmunity
J. Exp. Med.
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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.