Association of Blood Group Antigen CD59 with Disease

Age Related ◽

Life Threatening ◽

Membrane Bound

In 2014, the membrane-bound protein CD59 became a blood group antigen. CD59 has been known for decades as an inhibitor of the complement system, located on erythrocytes and on many other cell types. In paroxysmal nocturnal haemoglobinuria (PNH), a stem cell clone with acquired deficiency to express GPI-anchored molecules, including the complement inhibitor CD59, causes severe and life-threatening disease. The lack of CD59, which is the only membrane-bound inhibitor of the membrane attack complex, contributes a major part of the intravascular haemolysis observed in PNH patients. This crucial effect of CD59 in PNH disease prompted studies to investigate its role in other diseases. In this review, the role of CD59 in inflammation, rheumatic disease, and age-related macular degeneration is investigated. Further, the pivotal role of CD59 in PNH and congenital CD59 deficiency is reviewed.

Infectious Keratitis: An Update on Role of Epigenetics

Frontiers in Immunology ◽

10.3389/fimmu.2021.765890 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sudhir Verma ◽

Aastha Singh ◽

Akhil Varshney ◽

R. Arun Chandru ◽

Manisha Acharya ◽

...

Keyword(s):

Therapeutic Potential ◽

Corneal Dystrophy ◽

Cell Types ◽

Future Perspective ◽

Epigenetic Mechanisms ◽

Infectious Keratitis ◽

Novel Treatments ◽

Epigenetic mechanisms modulate gene expression and function without altering the base sequence of DNA. These reversible, heritable, and environment-influenced mechanisms generate various cell types during development and orchestrate the cellular responses to external stimuli by regulating the expression of genome. Also, the epigenetic modifications influence common pathological and physiological responses including inflammation, ischemia, neoplasia, aging and neurodegeneration etc. In recent past, the field of epigenetics has gained momentum and become an increasingly important area of biomedical research As far as eye is concerned, epigenetic mechanisms may play an important role in many complex diseases such as corneal dystrophy, cataract, glaucoma, diabetic retinopathy, ocular neoplasia, uveitis, and age-related macular degeneration. Focusing on the epigenetic mechanisms in ocular diseases may provide new understanding and insights into the pathogenesis of complex eye diseases and thus can aid in the development of novel treatments for these diseases. In the present review, we summarize the clinical perspective of infectious keratitis, role of epigenetics in infectious keratitis, therapeutic potential of epigenetic modifiers and the future perspective.

Inhibition of Ocular Neovascularization by Co-Inhibition of VEGF-A and PLGF

Cellular Physiology and Biochemistry ◽

10.1159/000373990 ◽

2015 ◽

Vol 35 (5) ◽

pp. 1787-1796 ◽

Cited By ~ 21

Author(s):

Xiaochuan Huo ◽

Youxiang Li ◽

Yuhua Jiang ◽

Xiaoyun Sun ◽

Lixue Gu ◽

...

Keyword(s):

Endothelial Cells ◽

Growth Factor ◽

Molecular Mechanisms ◽

Cell Types ◽

Angiogenic Factors ◽

Vessel Density ◽

Ocular Injury ◽

Background/Aims: Age-related macular degeneration (AMD) appears to be a disease with increasing incidence in Western countries and may develop into acquired blindness. Choroidal neovascularization (CNV) is the most frequent cause for AMD, and is commonly induced by regional inflammation. Past studies have highlighted vascular endothelial growth factor A (VEGF-A) as a major trigger for CNV. However, studies on the associated angiogenic factors other than VEGF-A are lacking. Methods: Here, we used a well-established laser burn (LB)-induced experimental CNV mouse model to study the molecular mechanisms underlying the development of CNV after ocular injury. We analyzed vessel density by lectin labeling. We isolated macrophages, endothelial cells and other cell types by flow cytometry, and analyzed levels of different angiogenic factors in these populations. We used antisera against VEGF-A (aVEGF) and/or antisera against placental growth factor (PLGF; aPLGF) to antagonize CNV. We used an antibody-driven toxin to selectively eliminate macrophages to evaluate the role of macrophages in CNV. We also examined expression of PLGF in macrophage subtypes. Results: The choroidal vessel density increased significantly 7 days after LB. LB increased significantly the levels of VEGF-A and PLGF in mouse eyes. Treatment with aVEGF significantly blunted increases in vessel density by LB. Treatment with aPLGF alone did not significantly reduce increases in vessel density. However, aPLGF significantly increased the inhibitory effects of aVEGF on vessel density increases. While VEGF-A was produced by endothelial cells, macrophages and other types at similar levels, PLGF seemed to be predominantly produced by macrophages. Selective macrophage depletion significantly reduced CNV. M2, but M1 macrophages produced high levels of PLGF. Conclusions: Together, our data suggest a previously unappreciated role of PLGF in coordination with VEGF-A to regulate CNV during ocular injury. Our study highlights macrophages and their production of PLGF as novel targets for CNV therapy.

Complement C5 is not critical for the formation of sub-RPE deposits in Efemp1 mutant mice

Scientific Reports ◽

10.1038/s41598-021-89978-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Donita L. Garland ◽

Eric A. Pierce ◽

Rosario Fernandez-Godino

Keyword(s):

Macular Degeneration ◽

Retinal Pigment ◽

Deposit Formation ◽

Genetic Ablation ◽

Age Related ◽

Complement Dysregulation

AbstractThe complement system plays a role in the formation of sub-retinal pigment epithelial (RPE) deposits in early stages of age-related macular degeneration (AMD). But the specific mechanisms that connect complement activation and deposit formation in AMD patients are unknown, which limits the development of efficient therapies to reduce or stop disease progression. We have previously demonstrated that C3 blockage prevents the formation of sub-RPE deposits in a mouse model of EFEMP1-associated macular degeneration. In this study, we have used double mutant Efemp1R345W/R345W:C5-/- mice to investigate the role of C5 in the formation of sub-RPE deposits in vivo and in vitro. The data revealed that the genetic ablation of C5 does not eliminate the formation of sub-RPE deposits. Contrarily, the absence of C5 in RPE cultures promotes complement dysregulation that results in increased activation of C3, which likely contributes to deposit formation even in the absence of EFEMP1-R345W mutant protein. The results also suggest that genetic ablation of C5 alters the extracellular matrix turnover through an effect on matrix metalloproteinases in RPE cell cultures. These results confirm that C3 rather than C5 could be an effective therapeutic target to treat early AMD.

Exacerbation of AMD Phenotype in Lasered CNV Murine Model by Dysbiotic Oral Pathogens

Antioxidants ◽

10.3390/antiox10020309 ◽

2021 ◽

Vol 10 (2) ◽

pp. 309

Author(s):

Pachiappan Arjunan ◽

Radhika Swaminathan ◽

Jessie Yuan ◽

Mohamed Elashiry ◽

Amany Tawfik ◽

...

Keyword(s):

Murine Model ◽

Retinal Thickness ◽

Periodontal Pathogen ◽

Fundus Photography ◽

Mouse Retina ◽

Rrna Gene ◽

Age Related ◽

Periodontal Infection

Emerging evidence underscores an association between age-related macular degeneration (AMD) and periodontal disease (PD), yet the biological basis of this linkage and the specific role of oral dysbiosis caused by PD in AMD pathophysiology remains unclear. Furthermore, a simple reproducible model that emulates characteristics of both AMD and PD has been lacking. Hence, we established a novel AMD+PD murine model to decipher the potential role of oral infection (ligature-enhanced) with the keystone periodontal pathogen Porphyromonas gingivalis, in the progression of neovasculogenesis in a laser-induced choroidal-neovascularization (Li-CNV) mouse retina. By a combination of fundus photography, optical coherence tomography, and fluorescein angiography, we documented inflammatory drusen-like lesions, reduced retinal thickness, and increased vascular leakage in AMD+PD mice retinae. H&E further confirmed a significant reduction of retinal thickness and subretinal drusen-like deposits. Immunofluorescence microscopy revealed significant induction of choroidal/retinal vasculogenesis in AMD+PD mice. qPCR identified increased expression of oxidative-stress, angiogenesis, pro-inflammatory mediators, whereas antioxidants and anti-inflammatory genes in AMD+PD mice retinae were notably decreased. Through qPCR, we detected Pg and its fimbrial 16s-RrNA gene expression in the AMD+PD mice retinae. To sum-up, this is the first in vivo study signifying a role of periodontal infection in augmentation of AMD phenotype, with the aid of a pioneering AMD+PD murine model established in our laboratory.

FHL-1 interacts with human RPE cells through the α5β1 integrin and confers protection against oxidative stress

Scientific Reports ◽

10.1038/s41598-021-93708-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Rawshan Choudhury ◽

Nadhim Bayatti ◽

Richard Scharff ◽

Ewa Szula ◽

Viranga Tilakaratna ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Fate ◽

Retinal Pigment ◽

Factor H ◽

Bruch's Membrane ◽

Bruch’S Membrane ◽

Rpe Cells ◽

AbstractRetinal pigment epithelial (RPE) cells that underlie the neurosensory retina are essential for the maintenance of photoreceptor cells and hence vision. Interactions between the RPE and their basement membrane, i.e. the inner layer of Bruch’s membrane, are essential for RPE cell health and function, but the signals induced by Bruch’s membrane engagement, and their contributions to RPE cell fate determination remain poorly defined. Here, we studied the functional role of the soluble complement regulator and component of Bruch’s membrane, Factor H-like protein 1 (FHL-1). Human primary RPE cells adhered to FHL-1 in a manner that was eliminated by either mutagenesis of the integrin-binding RGD motif in FHL-1 or by using competing antibodies directed against the α5 and β1 integrin subunits. These short-term experiments reveal an immediate protein-integrin interaction that were obtained from primary RPE cells and replicated using the hTERT-RPE1 cell line. Separate, longer term experiments utilising RNAseq analysis of hTERT-RPE1 cells bound to FHL-1, showed an increased expression of the heat-shock protein genes HSPA6, CRYAB, HSPA1A and HSPA1B when compared to cells bound to fibronectin (FN) or laminin (LA). Pathway analysis implicated changes in EIF2 signalling, the unfolded protein response, and mineralocorticoid receptor signalling as putative pathways. Subsequent cell survival assays using H2O2 to induce oxidative stress-induced cell death suggest hTERT-RPE1 cells had significantly greater protection when bound to FHL-1 or LA compared to plastic or FN. These data show a non-canonical role of FHL-1 in protecting RPE cells against oxidative stress and identifies a novel interaction that has implications for ocular diseases such as age-related macular degeneration.

Age-Related Macular Degeneration: Role of Oxidative Stress and Blood Vessels

International Journal of Molecular Sciences ◽

10.3390/ijms22031296 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1296

Author(s):

Yue Ruan ◽

Subao Jiang ◽

Adrian Gericke

Keyword(s):

Oxidative Stress ◽

Macular Degeneration ◽

Vascular Function ◽

Vascular Dysfunction ◽

Therapeutic Strategies ◽

Vision Impairment ◽

Oxygen Species ◽

Age-related macular degeneration (AMD) is a common irreversible ocular disease characterized by vision impairment among older people. Many risk factors are related to AMD and interact with each other in its pathogenesis. Notably, oxidative stress and choroidal vascular dysfunction were suggested to be critically involved in AMD pathogenesis. In this review, we give an overview on the factors contributing to the pathophysiology of this multifactorial disease and discuss the role of reactive oxygen species and vascular function in more detail. Moreover, we give an overview on therapeutic strategies for patients suffering from AMD.

The role of Aflibercept in the management of age-related macular degeneration

Expert Opinion on Biological Therapy ◽

10.1517/14712598.2016.1167182 ◽

2016 ◽

Vol 16 (5) ◽

pp. 699-709 ◽

Cited By ~ 6

Author(s):

Muhammad Hassan ◽

Rubbia Afridi ◽

Mohammad Ali Sadiq ◽

Mohamed Kamel Soliman ◽

Aniruddha Agarwal ◽

...

Keyword(s):

Macular Degeneration ◽

Role of Factor H and Related Proteins in Regulating Complement Activation in the Macula, and Relevance to Age-Related Macular Degeneration

Journal of Clinical Medicine ◽

10.3390/jcm4010018 ◽

2014 ◽

Vol 4 (1) ◽

pp. 18-31 ◽

Cited By ~ 24

Author(s):

Simon Clark ◽

Paul Bishop

Keyword(s):

Macular Degeneration ◽

Complement Activation ◽

Factor H ◽

Age Related ◽

Related Proteins

A Review of the Role of the Intestinal Microbiota in Age-Related Macular Degeneration

Journal of Clinical Medicine ◽

10.3390/jcm10102072 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2072

Author(s):

Phoebe Lin ◽

Scott M. McClintic ◽

Urooba Nadeem ◽

Dimitra Skondra

Keyword(s):

Macular Degeneration ◽

Intestinal Microbiota ◽

Retinal Disease ◽

Intestinal Microbiome ◽

Age Related ◽

Intestinal Dysbiosis ◽

Apo E ◽

Dry Amd

Blindness from age-related macular degeneration (AMD) is an escalating problem, yet AMD pathogenesis is incompletely understood and treatments are limited. The intestinal microbiota is highly influential in ocular and extraocular diseases with inflammatory components, such as AMD. This article reviews data supporting the role of the intestinal microbiota in AMD pathogenesis. Multiple groups have found an intestinal dysbiosis in advanced AMD. There is growing evidence that environmental factors associated with AMD progression potentially work through the intestinal microbiota. A high-fat diet in apo-E-/- mice exacerbated wet and dry AMD features, presumably through changes in the intestinal microbiome, though other independent mechanisms related to lipid metabolism are also likely at play. AREDS supplementation reversed some adverse intestinal microbial changes in AMD patients. Part of the mechanism of intestinal microbial effects on retinal disease progression is via microbiota-induced microglial activation. The microbiota are at the intersection of genetics and AMD. Higher genetic risk was associated with lower intestinal bacterial diversity in AMD. Microbiota-induced metabolite production and gene expression occur in pathways important in AMD pathogenesis. These studies suggest a crucial link between the intestinal microbiota and AMD pathogenesis, thus providing a novel potential therapeutic target. Thus, the need for large longitudinal studies in patients and germ-free or gnotobiotic animal models has never been more pressing.