A Potential Role for Immune Complex Pathogenesis in Drusen Formation

Johnson, Lincoln V.; Ozaki, Shiro; Staples, Michelle K; Erickson, Page A.; Anderson, Don H.

doi:10.1006/exer.1999.0798

Cited by 324 publications

(264 citation statements)

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“…CFH is the major complement regulatory protein, without which the regulation of complement activation is lost completely, leading to continuous activation of C3 and uncontrolled inflammation (Anderson et al, 2002). The presence of complement factor proteins in drusen represents yet further evidence that inflammation plays an important role in the pathogenesis of AMD (Crabb et al, 2002;Hollyfield et al, 2008;Johnson et al, 2000). However, in this study we did not detect any significant association between CFH risk alleles and MP optical density at any degree of retinal eccentricity, MP optical density Area or serum concentrations of L or Z.…”

Section: Discussionmentioning

confidence: 99%

The association between macular pigment optical density and CFH, ARMS2, C2/BF, and C3 genotype

Loane

Nolan

McKay

et al. 2011

Experimental Eye Research

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Keywords: age-related macular degeneration age-related maculopathy susceptibility 2 gene carotenoids Complement factor H lutein macular pigment zeaxanthin a b s t r a c t Age-related macular degeneration (AMD) is the most common cause of blindness in older people in developed countries, and risk for this condition may be classified as genetic or environmental, with an interaction between such factors predisposing to this disease. This study investigated the relationship between AMD risk genes, macular pigment optical density (MPOD), which may protect against AMD, and serum concentrations of the macular carotenoids, lutein (L) and zeaxanthin (Z). This was a cross-sectional study of 302 healthy adult subjects. Dietary intake of L and Z was assessed by food frequency questionnaire, and MPOD was measured by customized heterochromatic flicker photometry. We also calculated MPOD Area as the area of MP under the spatial profile curve, to reflect MP across the macula. Serum L and Z were measured by HPLC. Genotyping of tag SNPs in the genes CFH, ARMS2, C3, C2 and BF was undertaken with multiplex polymerase chain reaction (PCR) and primer extension methodology (ABI Snapshot, ABI Warrington UK) on DNA extracted from peripheral blood. The mean AE SD (range) age of the subjects in this study was 48 AE 11 (21e66) years. There was a statistically significant association between CFH genotype and family history of AMD, with subjects having two non-risk CFH haplotypes (n ¼ 35), or one non-risk and one protective CFH haplotype (n ¼ 33), being significantly more likely to have a negative family history of AMD (Pearson Chi square: p ¼ 0.001). There was no significant association between the AMD risk genes investigated and either MPOD (One way ANOVA: p > 0.05) or serum concentrations of L or Z (One way ANOVA: p > 0.05, for both). Subjects who were homozygous for risk alleles of both CFH and ARMS2 (n ¼ 4) had significantly lower MPOD at 0.5 and 1 retinal eccentricity (Independent samples t test: p < 0.05) and lower MPOD Area which approached statistical significance (Independent samples t test: p ¼ 0.058), compared to other subjects (n ¼ 291). In conclusion, this study did not detect an association between individual AMD risk genotypes and the putatively protective MP, or serum concentrations of its constituent carotenoids. However, the combination of homozygous risk alleles at both CFH and ARMS2 loci was associated with significantly lower MPOD centrally, despite comparable serum concentrations of the macular carotenoids. These findings suggest that the maculae of subjects at very high genetic risk of AMD represent a hostile environment for accumulation and/or stabilization of MP.

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Section: Discussionmentioning

confidence: 99%

The association between macular pigment optical density and CFH, ARMS2, C2/BF, and C3 genotype

Loane

Nolan

McKay

et al. 2011

Experimental Eye Research

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“…Membrane-bound cofactor proteins (MCP, CD46), decay acceleration factor (DAF, CD55), membrane inhibitor of reactive lysis (MIRL, CD59), and complement receptors (CR1, CD35) help in clearance of soluble immune complexes. 16 Both vitronectin and clusterin have been identified in healthy donor RPE-choroid complex 13,14 indicating their role in containing proinflammatory local stimuli. The co-precipitation of CD46 with b1 integrin in the basolateral membrane of healthy RPE cells suggest that this complement regulatory protein may be useful both in adhesion of RPE cells and in integrin-signalling pathways.…”

Section: Complement Regulatory Proteinsmentioning

confidence: 99%

“…[13][14][15] A recent study demonstrated that the deposition of C5b-9 in drusen is associated with degeneration of the macular choriocapillaris. 27 In addition, fluid phase regulatory proteins such as vitronectin and clusterin have been localised in drusen.…”

Section: Immunolocalisation Of Complement Components In Drusenmentioning

confidence: 99%

“…Vitronectin binds to C5b-9 complexes at the site of their generation. 13 Membrane-bound regulatory proteins such as MCP and CR1 have also been identified in drusen. MCP tends to colocalize with C3 fragments in drusen.…”

Section: Immunolocalisation Of Complement Components In Drusenmentioning

confidence: 99%

“…6,[13][14][15] Although they may serve as a protective function in innate immunity, it also suggests the presence of chronic low-grade local complement activation that is controlled by complement regulatory proteins.…”

Section: Introductionmentioning

confidence: 99%

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The complement system and age-related macular degeneration

Sivaprasad

Chong

2006

Eye

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Purpose Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world. There are increasing evidences to suggest the complement system may play a significant role on the pathogenesis of AMD. In this review, we summarise the current research in this area. Methods Review of literature. Results The complement system is a complex system with several activation pathways. Complement factor H (CFH) polymorphisms has been associated with increase risk of AMD. CFH is an inhibitor protein; the polymorphisms might cause uncontrolled activation by initiation events. Conclusion Further studies on the molecular basis of the complement-mediated pathogenesis of AMD may offer novel therapy to AMD Eye (2006) 20, 867-872.

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Current Concepts in the Pathogenesis of Age-Related Macular Degeneration

Zarbin¹

2004

Arch Ophthalmol

916

697

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To review and synthesize information concerning the pathogenesis of age-related macular degeneration (AMD).Methods: Review of the English-language literature.Results: Five concepts relevant to the cell biology of AMD are as follows: (1) AMD involves aging changes plus additional pathological changes (ie, AMD is not just an aging change); (2) in aging and AMD, oxidative stress causes retinal pigment epithelial (RPE) and, possibly, choriocapillaris injury; (3) in AMD (and perhaps in aging), RPE and, possibly, choriocapillaris injury results in a chronic inflammatory response within the Bruch membrane and the choroid; (4) in AMD, RPE and, possibly, choriocapillaris injury and inflammation lead to formation of an abnormal extracellular matrix (ECM), which causes altered diffusion of nutrients to the retina and RPE, possibly precipitating further RPE and retinal damage; and(5) the abnormal ECM results in altered RPE-choriocapillaris behavior leading ultimately to atrophy of the retina, RPE, and choriocapillaris and/or choroidal new vessel growth. In this sequence of events, both the environment and multiple genes can alter a patient's susceptibility to AMD. Implicit in this characterization of AMD pathogenesis is the concept that there is linear progression from one stage of the disease to the next. This assumption may be incorrect, and different biochemical pathways leading to geographic atrophy and/or choroidal new vessels may operate simultaneously.Conclusions: Better knowledge of AMD cell biology will lead to better treatments for AMD at all stages of the disease. Many unanswered questions regarding AMD pathogenesis remain. Multiple animal models and in vitro models of specific aspects of AMD are needed to make rapid progress in developing effective therapies for different stages of the disease.

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A Potential Role for Immune Complex Pathogenesis in Drusen Formation

Cited by 324 publications

References 39 publications

The association between macular pigment optical density and CFH, ARMS2, C2/BF, and C3 genotype

The association between macular pigment optical density and CFH, ARMS2, C2/BF, and C3 genotype

The complement system and age-related macular degeneration

Current Concepts in the Pathogenesis of Age-Related Macular Degeneration

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