Implication of CD21, CD35, and CD55 in the Pathogenesis of Age-Related Macular Degeneration

Haas, Paulina; Aggermann, Tina; Nagl, Manfred; Steindl-Kuscher, Kerstin; Krugluger, Walter; Binder, Susanne

doi:10.1016/j.ajo.2011.02.017

Cited by 16 publications

(8 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, homozygous mutations in CD55, known to results in loss-of-function, have been found in patients suffering from complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy (MIM 226300) 23 . While two studies measured CD55 expression in blood cells of AMD patients, they consistently failed to observe significant differences compared to healthy individuals 24,25 . This is well in line with our current study which predicts CD55 expression to be AMD-associated exclusively in "Esophagus Muscularis", "Heart Atrial Appendage", and "Nerve Tibial", but not in "Whole Blood".…”

Section: Discussionmentioning

confidence: 99%

A transcriptome-wide association study based on 27 tissues identifies 106 genes potentially relevant for disease pathology in age-related macular degeneration

Strunz

Kiel

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Genome-wide association studies (GWAS) for late stage age-related macular degeneration (AMD) have identified 52 independent genetic variants with genome-wide significance at 34 genomic loci. Typically, such an approach rarely results in the identification of functional variants implicating a defined gene in the disease process. We now performed a transcriptome-wide association study (TWAS) allowing the prediction of effects of AMD-associated genetic variants on gene expression. The TWAS was based on the genotypes of 16,144 late-stage AMD cases and 17,832 healthy controls, and gene expression was imputed for 27 different human tissues which were obtained from 134 to 421 individuals. A linear regression model including each individuals imputed gene expression data and the respective AMD status identified 106 genes significantly associated to AMD variants in at least one tissue (Q-value < 0.001). Gene enrichment analysis highlighted rather systemic than tissue-or cellspecific processes. Remarkably, 31 of the 106 genes overlapped with significant GWAS signals of other complex traits and diseases, such as neurological or autoimmune conditions. Taken together, our study highlights the fact that expression of genes associated with AMD is not restricted to retinal tissue as could be expected for an eye disease of the posterior pole, but instead is rather ubiquitous suggesting processes underlying AMD pathology to be of systemic nature. Age-related macular degeneration (AMD) is a frequent disease of the choroid, Bruch's membrane, retinal pigment epithelium and photoreceptor complex characterized by a progressive loss of vision in older individuals of industrialized countries. For the year 2016, it was estimated that worldwide approximately 162 million were affected by early AMD (prevalence 8.0%) and 10 million people by late AMD (prevalence 0.4%). These numbers were predicted to increase to 260 million patients with early and 19 million with late AMD by the year 2040 1. It is well established that AMD is a complex disease, involving environmental and genetic risk factors. The International AMD Genomics Consortium (IAMDGC) performed a genome-wide association study (GWAS) and reported 7,218 genetic variants to be associated with late-stage AMD at a genome-wide significance level (P-value ≤ 5 × 10 −8). Sequential forward selection finally identified 52 independent association signals, which are distributed over 34 genomic loci 2. An additional 11,768 variants (P-value ≤ 5 × 10 −4) failed to reach genome-wide significance in this study but may well play a role in AMD pathogenesis. These variants may become relevant only with an increase in sample-size in future GWAS, or by gathering additional information on the functional impact of these variants in relation to AMD pathology.

show abstract

Section: Discussionmentioning

confidence: 99%

A transcriptome-wide association study based on 27 tissues identifies 106 genes potentially relevant for disease pathology in age-related macular degeneration

Strunz

Kiel

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…For example, increased levels of complement components have been assayed in the blood of AMD patients [ 252 – 255 ]. Elevated levels of regulatory proteins, such as CD21 (complement receptor 2), CD35 (complement receptor 1), CD46 (membrane cofactor protein, MCP), CD55 (decay-accelerating factor, DAF), or CD59 (protectin), may resemble increased complement activity but a significantly lower expression can be evidence of dysregulated control [ 256 , 257 ]. Instead, the lack of association between AMD and SNPs in CFP (properdin), CD46, CD55, and CD59 suggests that the gene variants of those regulatory proteins do not increase an individual’s susceptibility to AMD [ 258 ].…”

Section: Inflammation Is Clearly Present In the Amd Pathologymentioning

confidence: 99%

Inflammation and its role in age-related macular degeneration

Kauppinen

Paterno

Błasiak

et al. 2016

Cell. Mol. Life Sci.

534

503

View full text Add to dashboard Cite

Inflammation is a cellular response to factors that challenge the homeostasis of cells and tissues. Cell-associated and soluble pattern-recognition receptors, e.g. Toll-like receptors, inflammasome receptors, and complement components initiate complex cellular cascades by recognizing or sensing different pathogen and damage-associated molecular patterns, respectively. Cytokines and chemokines represent alarm messages for leukocytes and once activated, these cells travel long distances to targeted inflamed tissues. Although it is a crucial survival mechanism, prolonged inflammation is detrimental and participates in numerous chronic age-related diseases. This article will review the onset of inflammation and link its functions to the pathogenesis of age-related macular degeneration (AMD), which is the leading cause of severe vision loss in aged individuals in the developed countries. In this progressive disease, degeneration of the retinal pigment epithelium (RPE) results in the death of photoreceptors, leading to a loss of central vision. The RPE is prone to oxidative stress, a factor that together with deteriorating functionality, e.g. decreased intracellular recycling and degradation due to attenuated heterophagy/autophagy, induces inflammation. In the early phases, accumulation of intracellular lipofuscin in the RPE and extracellular drusen between RPE cells and Bruch’s membrane can be clinically detected. Subsequently, in dry (atrophic) AMD there is geographic atrophy with discrete areas of RPE loss whereas in the wet (exudative) form there is neovascularization penetrating from the choroid to retinal layers. Elevations in levels of local and systemic biomarkers indicate that chronic inflammation is involved in the pathogenesis of both disease forms.

show abstract

“…20 Another study found increased CD35 levels on monocytes, lymphocytes, and granulocytes. 6 CFH is an AP regulator, and genetic variants in the CFH gene are associated with an increased risk of developing AMD. In mice, the absence of the gene for CFH leads to reduced CD59 expression with age in the RPE, resulting in increased MAC formation.…”

Section: Chronic Inflammationmentioning

confidence: 99%

“…17−19 Our group and others have shown systemic Cregs dysregulation on monocytes in AMD patients compared to healthy controls. 6,20 Several studies have shown elevated levels of complement components, and associations between AMD and single nucleotide polymorphisms (SNPs) in genes encoding complement proteins and regulators have been documented. Further, by-products of chronic inflammatory events, including the complement system, are thought to play a role in drusen formation since various inflammatory mediators, including complement products, have been identified in drusen.…”

Section: Introductionmentioning

confidence: 99%

Patients with MPNs and retinal drusen show signs of complement system dysregulation and a high degree of chronic low-grade inflammation

et al. 2022

View full text Add to dashboard Cite

Background The hematopoietic stem cell disorders, myeloproliferative neoplasms (MPNs), are characterised by chronic low-grade inflammation (CLI). Recently, we showed that patients with MPNs have an increased prevalence of drusen and age-related macular degeneration (AMD), and drusen prevalence seemed associated with higher CLI. Studying MPNs may reveal more about drusen pathophysiology. This study investigated CLI further by measuring cytokine levels and complement system markers, comparing these between patients with MPNs and AMD.Methods This cross-sectional study, between July 2018 and November 2020 conducted at Zealand University Hospital (ZUH) − Roskilde, Denmark, included 29 patients with neovascular AMD (nAMD), 28 with intermediate-stage AMD (iAMD), 62 with MPNs (35 with drusen -MPNd and 27 with healthy retinas -MPNn). With flow cytometry, we measured complement-regulatory-proteins (Cregs). With immunoassays, we investigated cytokine levels combined into a summary-inflammation-score (SIS).Findings The MPNd and nAMD groups had similar SIS, significantly higher than the MPNn and iAMD groups. Additionally, we found SIS to increase over the MPN biological continuum from early cancer stage, essential thrombocytaemia (ET), over polycythaemia vera (PV) to the late-stage primary myelofibrosis (PMF). MPNs showed signs of complement dysregulation, with Cregs expression lower in PV than ET and PMF and even lower in PV patients with drusen.Interpretation This study suggests that MPNd have a higher CLI than MPNn and may indicate systemic CLI to play a greater part in, and even initiate drusen formation. We suggest using MPNs as a "Human Inflammation Model" of drusen development. The CLI in MPNs elicits drusen formation, triggering more CLI creating a vicious cycle, increasing the risk of developing AMD.

show abstract

Implication of CD21, CD35, and CD55 in the Pathogenesis of Age-Related Macular Degeneration

Cited by 16 publications

References 16 publications

A transcriptome-wide association study based on 27 tissues identifies 106 genes potentially relevant for disease pathology in age-related macular degeneration

A transcriptome-wide association study based on 27 tissues identifies 106 genes potentially relevant for disease pathology in age-related macular degeneration

Inflammation and its role in age-related macular degeneration

Patients with MPNs and retinal drusen show signs of complement system dysregulation and a high degree of chronic low-grade inflammation

Contact Info

Product

Resources

About