Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration

Cipriani, Valentina; Lorés‐Motta, Laura; He, Fan; Fathalla, Dina; Tilakaratna, Viranga; McHarg, Selina; Bayatti, Nadhim; Acar, İlhan E.; Hoyng, Carel B.; Fauser, Sascha; Moore, Anthony T.; Yates, John R.; Jong, Eiko K. de; Morgan, B. Paul; Hollander, Anneke I. den; Bishop, Paul; Clark, Simon J.

doi:10.1038/s41467-020-14499-3

Cited by 85 publications

(138 citation statements)

References 66 publications

Supporting

Mentioning

124

Contrasting

Order By: Relevance

“…Complement proteins have been detected in the aqueous humor of AMD patients (Schick et al, 2017;Altay et al, 2019) and in drusen (Hageman et al, 2001;Crabb et al, 2002;Curcio, 2018). Moreover, most of the genetic variation underlying the risk of AMD resides in genes of the complement cascade (Fritsche et al, 2016;Cipriani et al, 2020). The rs1061170 single nucleotide polymorphism (SNP) in the complement factor H (CFH) gene (that leads to the Y402H amino acid substitution in the protein) has a strong association with the disease Edwards et al (2005), Hageman et al (2005), Haines et al (2005).…”

Section: Introductionmentioning

confidence: 99%

Control of Complement Activation by the Long Pentraxin PTX3: Implications in Age-Related Macular Degeneration

et al. 2020

Self Cite

View full text Add to dashboard Cite

Dysregulation of the complement system is central to age-related macular degeneration (AMD), the leading cause of blindness in the developed world. Most of the genetic variation associated with AMD resides in complement genes, with the greatest risk associated with polymorphisms in the complement factor H (CFH) gene; factor H (FH) is the major inhibitor of the alternative pathway (AP) of complement that specifically targets C3b and the AP C3 convertase. Long pentraxin 3 (PTX3) is a soluble pattern recognition molecule that has been proposed to inhibit AP activation via recruitment of FH. Although present in the human retina, if and how PTX3 plays a role in AMD is still unclear. In this work we demonstrated the presence of PTX3 in the human vitreous and studied the PTX3-FH-C3b crosstalk and its effects on complement activation in a model of retinal pigment epithelium (RPE). RPE cells cultured in inflammatory AMD-like conditions overexpressed the PTX3 protein, and up-regulated AP activating genes. PTX3 bound RPE cells in a physiological setting, however this interaction was reduced in inflammatory conditions, whereby PTX3 had no complement-inhibiting activity on inflamed RPE. However, on non-cellular surfaces, PTX3 formed a stable ternary complex with FH and C3b that acted as a “hot spot” for complement inhibition. Our findings suggest a protective role for PTX3 in response to complement dysregulation in AMD and point to a novel mechanism of complement regulation by this pentraxin with potential implications in pathology and pharmacology of AMD.

show abstract

Section: Introductionmentioning

confidence: 99%

Control of Complement Activation by the Long Pentraxin PTX3: Implications in Age-Related Macular Degeneration

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…Because it lacks the C-terminal CCP domains of FH, FHL-1 was thought to be less prone to deregulation by FH-related proteins than FH. Additionally, although some competition between FHR molecules and FHL-1 for selected functions have been observed (75), in AP serum assays on host cells, the deregulation by FHR-1 was considerably less for the splice variant FHL-1 than for FH (14). However, future studies are needed to further clarify the impact of deregulation of FH and its splice version by different FHRs.…”

Section: Discussionmentioning

confidence: 99%

Tuning the Functionality by Splicing: Factor H and Its Alternative Splice Variant FHL-1 Share a Gene but Not All Functions

et al. 2020

View full text Add to dashboard Cite

The alternative pathway regulator Factor H-like protein 1 (FHL-1) is composed of the first 7 N-terminal complement control protein domains of Factor H (FH) and protects host surfaces from uncontrolled complement attack. Although FHL-1 shares the N-terminal regulatory domains with FH, it was thought to be a weaker regulator. Recently, the regulatory activity of FHL-1 was shown to be comparable to FH. Nonetheless, the question remained whether FHL-1 is an indispensable, unique regulator. The discovery that FHL-1 is the predominant regulator on Bruch's membrane, a critical site for the onset and progression of age-related-macular degeneration (AMD), showed that FHL-1 is essential for complement regulation. A common single nucleotide polymorphism in FH/ FHL-1 that predisposes for AMD underlines the important role of FHL-1 in this context. Reports that some cancer tissues specifically upregulate FHL-1 expression, thereby evading immune surveillance, suggests a pronounced regulatory activity of the splice variant. Several microorganisms specifically recruit FHL-1 to evade complement attack. From a phylogenetic point of view, FHL-1 appears much later than other complement regulators, which could imply a specific role that is possibly not systemic but rather tissue specific. This review focuses on the current knowledge of FHL-1 and its physiological and pathophysiological roles.

show abstract

“…The BrM, located between retinal pigment epithelium and choroid, separates the retina strategically from the general circulation [57]. Beside lipids, it also accumulates local complement regulators such as complement factor H-like protein 1 and complement factor H-like protein 4 [58][59][60]. Disruptions in BrM are most likely to facilitate local complement imbalance, leading to lipid accumulation between RPE and BrM and ultimately to drusen formation [59].…”

Section: Discussionmentioning

confidence: 99%

Association of imaging biomarkers and local activation of complement in aqueous humor of patients with early forms of age-related macular degeneration

Sitnilska

Enders

Cursiefen

et al. 2020

Graefes Arch Clin Exp Ophthalmol

Self Cite

View full text Add to dashboard Cite

Purpose To investigate a possible correlation between established imaging biomarkers for age-related macular degeneration and local complement system activation, measured in aqueous humor (AH) of patients with early stages of age-related macular degeneration (AMD) and controls. Methods This analysis included prospectively acquired AH samples of 106 eyes (35 with early/intermediate AMD, 71 controls). The levels of complement protein 3 (C3), 4 (C4), 5 (C5); activation products of complement factor 3a (C3a) and Ba, C3b/iC3b; complement factors B, D, H, I (CFB, CFD, CFH, CFI); and total protein concentration were analyzed. Quantitative levels of complement factors were correlated to the presence of reticular pseudodrusen (RPD), the presence of hyperreflective foci (HRF), and total drusen volume (DV) graded on imaging by spectral-domain optical coherence tomography and using Spearman’s rank correlation test. Results DV correlated with C3b/iC3b (r = 0.285; P = 0.034), C3a (r = 0.200; P = 0.047), Ba (r = 0.262; P = 0.009), and C5 (r = 430; P = 0.005), and showed a tendency towards correlation with C3a (r = 0.198; P = 0.057). HRF correlated significantly with C5 (r = 0.388; P = 0.011) and RPD showed a tendency towards correlation with CFB (r = 0.196; P = 0.050). Conclusion In patients with early AMD, HRF and drusen parameters but not RPD show low to fair levels of correlation with local complement activation in patients’ AH. Better understanding of complement activation could provide some insights into the pathogenesis of AMD. Imaging biomarkers could be useful to identify suitable patients for future clinical trials with complement-modulating therapies.

show abstract

Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration

Cited by 85 publications

References 66 publications

Control of Complement Activation by the Long Pentraxin PTX3: Implications in Age-Related Macular Degeneration

Control of Complement Activation by the Long Pentraxin PTX3: Implications in Age-Related Macular Degeneration

Tuning the Functionality by Splicing: Factor H and Its Alternative Splice Variant FHL-1 Share a Gene but Not All Functions

Association of imaging biomarkers and local activation of complement in aqueous humor of patients with early forms of age-related macular degeneration

Contact Info

Product

Resources

About