Complement Activation and Inflammatory Processes in Drusen Formation and Age Related Macular Degeneration

Johnson, Lincoln V.; Leitner, William P.; Staples, Michelle K; Anderson, Don H.

doi:10.1006/exer.2001.1094

Cited by 567 publications

(419 citation statements)

References 44 publications

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“…[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%

“…Metabolic end products such as lipofuscin, phospholipids, advanced glycation end products, cholesterol, and microfibrillar proteins may also serve as powerful chemotactic stimuli for leucocytes via the complement cascade. 15 Other than the abnormal tissue deposits, other acute phase proteins such as CRP and serum amyloid-P can also augment the inflammatory cascade. CRP activates the classic pathway but inhibits binding of C5b-9 through the direct binding of CFH.…”

Section: Activators Of the Complement Systemmentioning

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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Section: Immunolocalisation Of Complement Components In Drusenmentioning

confidence: 99%

Section: Activators Of the Complement Systemmentioning

confidence: 99%

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The complement system and age-related macular degeneration

Sivaprasad

Chong

2006

Eye

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“…Proposed mechanisms of AMD pathogenesis include chronic oxidative stress, ER stress, light damage, increased polyunsaturated fatty acids, abnormal phagocytosis, complement activation and inflammation [142][143][144][145][146][147][148][149][150][151][152]. In human RPE, induction of oxidative stress by H2O2 or photo-oxidation led to proteasome inhibition and accumulation of polyubiquitinated proteins and aggregates [152].…”

Section: Pdmentioning

confidence: 99%

“…Complement pathway dysregulation is thought to play a critical role in the formation of drusen [142,144,148]. An analysis of drusen components showed an abundance of regulatory proteins of the common complement pathway.…”

Section: Pdmentioning

confidence: 99%

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

et al. 2015

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Cells have a number of mechanisms to maintain protein homeostasis, including proteasomemediated degradation of ubiquitinated proteins and autophagy, a regulated process of 'self-eating' where the contents of entire organelles can be recycled for other uses. The unfolded protein response prevents protein overload in the secretory pathway. In the past decade, it has become clear that these fundamental cellular processes also help contain inflammation though degrading pro-inflammatory protein complexes such as the NLRP3 inflammasome. Signaling pathways such as the UPR can also be co-opted by tolllike receptor and mitochondrial reactive oxygen species signaling to induce inflammatory responses.Mutations that alter key inflammatory proteins, such as NLRP3 or TNFR1, can overcome normal protein homeostasis mechanisms, resulting in autoinflammatory diseases. Conversely, Mendelian defects in the proteasome cause protein accumulation, which can trigger interferon-dependent autoinflammatory disease. In non-Mendelian inflammatory diseases, polymorphisms in genes affecting the UPR or autophagy pathways can contribute to disease, and in diseases not formerly considered inflammatory such as neurodegenerative conditions and type 2 diabetes, there is increasing evidence that cell intrinsic or environmental alterations in protein homeostasis may contribute to pathogenesis.3 Cells must maintain a delicate balance between the demands for protein synthesis and the need to avoid accumulation of incompletely processed or unfolded proteins that can accumulate under normal conditions and even more so when cells face a variety of stresses. The unfolded protein response (UPR) is an evolutionarily conserved mechanism to maintain cellular homeostasis by preventing the accumulation of misfolded proteins in the endoplasmic reticulum (ER). Disturbed protein folding in the ER is primarily detected by three transmembrane (TM) proteins: activating transcription factor 6 (ATF6), inositol-requiring transmembrane kinase/endonuclease 1 (IRE1) and pancreatic ER kinase (PERK). The combined action of these sensors reduces global protein synthesis while upregulating the production of chaperone proteins that can stabilize misfolded proteins. Apart from ER homeostasis, the UPR can modulate other biological functions, including apoptosis, protein secretion, and as we will discuss further, inflammatory responses [1,2].A series of molecular changes are initiated in response to cellular stressors in order to minimize damage caused by unfavorable environmental conditions, such as temperature changes, toxins (e.g. bacterial, chemical), radiation, mechanical damage, nutritional status as well as incompletely folded proteins intracellularly (Figure 1). The UPR serves the adaptive purpose of protecting the cell by activating a series of mechanisms including the induction of molecular chaperones to assist with correct folding -e.g. heat shock proteins and foldases. Interestingly there are a number of connections between the UPR and inflammatory signaling pat...

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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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Complement Activation and Inflammatory Processes in Drusen Formation and Age Related Macular Degeneration

Cited by 567 publications

References 44 publications

The complement system and age-related macular degeneration

The complement system and age-related macular degeneration

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

Current Concepts in the Pathogenesis of Age-Related Macular Degeneration

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