Complement Factor P in Choroidal Neovascular Membranes of Patients With Age-Related Macular Degeneration

Wolf, Sebastian; Stuck, Anna K.; Hess, Roberto; Wolf, Sebastián; Enzmann, Volker

doi:10.1097/iae.0b013e3181a2f40f

Cited by 10 publications

(7 citation statements)

References 33 publications

(35 reference statements)

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“…Indeed, cfp expression has been shown to be quite stable in vivo and in vitro in response to several stimuli such as preeclampsia or renal tubular damage (Reis et al, 2006; Buurma et al, 2012; Nagamachi et al, 2014), while it has been described to be upregulated following shear stress in endothelium (Bongrazio et al, 2003). However, our results do not automatically imply, that CFP is not involved in degeneration, as we know from other studies that CFP deposition was positive in patient eyes with AMD (Wolf-Schnurrbusch et al, 2009) and was associated with drusen-like deposition in Alzheimer’s disease (Fonseca et al, 2011). Further studies have to be performed to decipher the expression pattern of CFP in more detail.…”

Section: Discussioncontrasting

confidence: 71%

Complement Components Showed a Time-Dependent Local Expression Pattern in Constant and Acute White Light-Induced Photoreceptor Damage

Schäfer

Grosche

Schmitt

et al. 2017

Front. Mol. Neurosci.

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Background: Photoreceptor cell death due to extensive light exposure and induced oxidative-stress are associated with retinal degeneration. A correlated dysregulation of the complement system amplifies the damaging effects, but the local and time-dependent progression of this mechanism is not thoroughly understood.Methods: Light-induced photoreceptor damage (LD) was induced in Balb/c mice with white light illumination either for 24 h with 1000 lux (constant model) or 0.5 h with 5000 lux (acute model). Complement protein and mRNA expression levels were compared at 1 and 3 days post-LD for C1s, complement factor B (CFB), mannose binding lectin A, mannose-binding protein-associated serine protease 1 (MASP-1), C3, C4, C9, and complement factor P in retina and RPE/choroid. Histological analyses visualized apoptosis, microglia/macrophage migration, gliosis and deposition of the complement activation marker C3d. Systemic anaphylatoxin serum concentrations were determined using an ELISA.Results: Apoptosis, gliosis and microglia/macrophage migration into the outer nuclear layer showed similar patterns in both models. Local complement factor expression revealed an early upregulation of complement factor mRNA in the acute and constant light regimen at 1 day post-treatment for c1s, cfb, masp-1, c3, c4 and c9 in the RPE/choroid. However, intraretinal complement mRNA expression for c1s, cfb, c3 and c4 was increased at 1 day in the constant and at 3 days in the acute model. A corresponding regulation on protein level in the retina following both LD models was observed for C3, which was upregulated at 1 day and correlated with increased C3d staining in the ganglion cell layer and at the RPE. In the RPE/choroid C1s-complex protein detection was increased at 3 days after LD irrespectively of the light intensities used.Conclusion: LD in mouse eyes is correlated with local complement activity. The time-dependent local progression of complement regulation on mRNA and protein levels were equivalent in the acute and constant LD model, except for the intraretinal, time-dependent mRNA expression. Knowing the relative time courses of local complement expression and cellular activity can help to elucidate novel therapeutic options in retinal degeneration indicating at which time point of disease complement has to be rebalanced.

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Section: Discussioncontrasting

confidence: 71%

Complement Components Showed a Time-Dependent Local Expression Pattern in Constant and Acute White Light-Induced Photoreceptor Damage

Schäfer

Grosche

Schmitt

et al. 2017

Front. Mol. Neurosci.

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“…Also unclarified is the role of complement in the manifestation of the more advanced forms of AMD, particularly geographic atrophy and choroidal neovascularization (CNV). Recent immunohistochemical evidence indicates that complement-related proteins are also present in the BLDs often associated with CNV (Lommatzsch et al, 2008; Lommatzsch et al, 2007; Wolf-Schnurrbusch et al, 2009). …”

Section: Future Directionsmentioning

confidence: 99%

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

Anderson

Radeke

Gallo

et al. 2010

Progress in Retinal and Eye Research

664

603

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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.

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“…However, three SNPs were intermittent and the fourth SNP of exon 10 is frequent, but not linked with AMD (Seitsonen et al, 2010). Properdin has also been found to be expressed in choroidal neovascular membranes of patients with AMD (Wolf-Schnurrbusch et al, 2009). …”

Section: Human Factor H-associated Diseasesmentioning

confidence: 99%

Properdin and Factor H: Opposing Players on the Alternative Complement Pathway “See-Saw”

Kouser¹,

Abdul-Aziz²,

Nayak³

et al. 2013

Front. Immunol.

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Properdin and factor H are two key regulatory proteins having opposite functions in the alternative complement pathway. Properdin up-regulates the alternative pathway by stabilizing the C3bBb complex, whereas factor H downregulates the pathway by promoting proteolytic degradation of C3b. While factor H is mainly produced in the liver, there are several extrahepatic sources. In addition to the liver, factor H is also synthesized in fetal tubuli, keratinocytes, skin fibroblasts, ocular tissue, adipose tissue, brain, lungs, heart, spleen, pancreas, kidney, muscle, and placenta. Neutrophils are the major source of properdin, and it is also produced by monocytes, T cells and bone marrow progenitor cell line. Properdin is released by neutrophils from intracellular stores following stimulation by N-formyl-methionine-leucine-phenylalanine (fMLP) and tumor necrosis factor alpha (TNF-α). The HEP G2 cells derived from human liver has been found to produce functional properdin. Endothelial cells also produce properdin when induced by shear stress, thus is a physiological source for plasma properdin. The diverse range of extrahepatic sites for synthesis of these two complement regulators suggests the importance and need for local availability of the proteins. Here, we discuss the significance of the local synthesis of properdin and factor H. This assumes greater importance in view of recently identified unexpected and novel roles of properdin and factor H that are potentially independent of their involvement in complement regulation.

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Complement Factor P in Choroidal Neovascular Membranes of Patients With Age-Related Macular Degeneration

Cited by 10 publications

References 33 publications

Complement Components Showed a Time-Dependent Local Expression Pattern in Constant and Acute White Light-Induced Photoreceptor Damage

Complement Components Showed a Time-Dependent Local Expression Pattern in Constant and Acute White Light-Induced Photoreceptor Damage

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

Properdin and Factor H: Opposing Players on the Alternative Complement Pathway “See-Saw”

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