Complement factor B is critical for sub-RPE deposit accumulation in a model of Doyne honeycomb retinal dystrophy with features of age-related macular degeneration
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE210492 | GEO | 2022/08/10
REPOSITORIES: GEO
Similar Datasets
Project description:This dataset represent supplemental data for publication submitted to Human Molecular Genetics in 2022. Briefly, Efemp1 R345W is a protein misfolding-prone mutation in humans causing Doyne honeycomb retinal dystrophy/Mallatia Leventinese (DHRD/ML), a disease sharing similar clinical pathology with age-related macular degeneration (AMD). Efemp1R345W/R345W knock-in mice (Efemp1ki/ki mice) develop deposits on the basal side of retinal pigment epithelial (RPE) cells, which is complement C3- dependent. We assessed alternative complement pathway component factor B (Cfb) in sub-RPE deposit formation in Efemp1ki/ki mice.
2023-03-11 | PXD035772 | Pride
Project description:Purpose: This study aims to reveal retinal abnormities in a spontaneous diabetic nonhuman primate (NHP) model and explore the mechanism of featured injuries. Methods: Twenty-eight cynomolgus monkeys were identified to suffer from spontaneous Type 2 diabetes from a colony of more than eight hundred aged monkeys and twenty-six age-matched ones were used as controls. Their blood biochemistry profiles were determined and the retinal changes were examined by multimodal imaging, hematoxylin-eosin (H&E) staining and immunofluorescence. Retinal pigment epithelium (RPE) cells were isolated and determined by RNA-sequencing and computational analyses. Results: Diabetic monkeys were characterized by early vascular and neural damage in the retina and dyslipidemia. The typical acellular capillaries and pericyte ghost were found in the diabetic retina, which also exhibited reduced retinal nerve fiber layer (RNFL) thickness compared to the controls. Of note, distinct sub-RPE drusenoid lesions were extensively observed in these diabetic monkeys and complements deposition including C3 and C5b-9 were accumulated in these lesions. The RNA-seq data of RPE cells showed complement activation, AGE/RAGE activation and 18 inflammatory response at the setting of diabetes. Consistently, the plasma levels of C3 and C4 were also increased in the diabetic monkeys. Conclusions: The spontaneous Type 2 diabetic cynomolgus monkeys featured with early-stage retinopathy including not only typical vascular and neural damage, but also a distinct sub-RPE deposition. The complement activation and metabolic stress of RPE cells in response to hyperglycemia might contribute to the deposition, revealing an unrecognized role of RPE cells in the early-stage pathological process of diabetic retinopathy (DR).
2021-03-31 | GSE160617 | GEO
Project description:Inherited and age-related macular degenerations (AMDs) are important causes of vision loss. An early hallmark of these disorders is the formation of sub-retinal pigment epithelium (RPE) basal deposits. A role for the complement system in MDs was suggested by genetic association studies, but direct functional connections between alterations in the complement system and the pathogenesis of MD remain to be defined. We used primary RPE cells from a mouse model of inherited MD due to a p.R345W mutation in EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1) to investigate the role of the RPE in early MD pathogenesis. Efemp1(R345W) RPE cells recapitulate the basal deposit formation observed in vivo by producing sub-RPE deposits in vitro. The deposits share features with basal deposits, and their formation was mediated by EFEMP1(R345W) or complement component 3a (C3a), but not by complement component 5a (C5a). Increased activation of complement appears to occur in response to an abnormal extracellular matrix (ECM), generated by the mutant EFEMP1(R345W) protein and reduced ECM turnover due to inhibition of matrix metalloproteinase 2 by EFEMP1(R345W) and C3a. Increased production of C3a also stimulated the release of cytokines such as interleukin (IL)-6 and IL-1B, which appear to have a role in deposit formation, albeit downstream of C3a. These studies provide the first direct indication that complement components produced locally by the RPE are involved in the formation of basal deposits. Furthermore, these results suggest that C3a generated by RPE is a potential therapeutic target for the treatment of EFEMP1-associated MD as well as AMD.
| S-EPMC4572070 | biostudies-literature
Project description:PurposeThis study aims to reveal retinal abnormities in a spontaneous diabetic nonhuman primate model and explore the mechanism of featured injuries.MethodsTwenty-eight cynomolgus monkeys were identified to suffer from spontaneous type 2 diabetes from a colony of more than eight-hundred aged monkeys, and twenty-six age-matched ones were chosen as controls. Their blood biochemistry profiles were determined and retinal changes were examined by multimodal imaging, hematoxylin and eosin staining, and immunofluorescence. Retinal pigment epithelium (RPE) cells were further investigated by RNA sequencing and computational analyses.ResultsThese diabetic monkeys were characterized by early retinal vascular and neural damage and dyslipidemia. The typical acellular capillaries and pericyte ghost were found in the diabetic retina, which also exhibited reduced retinal nerve fiber layer thickness compared to controls (all P < 0.05). Of note, distinct sub-RPE drusenoid lesions were extensively observed in these diabetic monkeys (46.43% vs. 7.69%), and complements including C3 and C5b-9 were deposited in these lesions. RNA-seq analysis revealed complement activation, AGE/RAGE activation and inflammatory response in diabetic RPE cells. Consistently, the plasma C3 and C4 were particularly increased in the diabetic monkeys with drusenoid lesions (P = 0.028 and 0.029).ConclusionsThe spontaneous type 2 diabetic monkeys featured with early-stage retinopathy including not only typical vascular and neural damage but also a distinct sub-RPE deposition. The complement activation of RPE cells in response to hyperglycemia might contribute to the deposition, revealing an unrecognized role of RPE cells in the early-stage pathological process of diabetic retinopathy.
| S-EPMC7991921 | biostudies-literature
Project description:The renal disorder C3 glomerulopathy with dense deposit disease (C3G-DDD) pattern results from complement dysfunction and primarily affects children and young adults. There is no effective treatment, and patients often progress to end-stage renal failure. A small fraction of C3G-DDD cases linked to factor H or C3 gene mutations as well as autoantibodies have been reported. Here, we examined an index family with 2 patients with C3G-DDD and identified a chromosomal deletion in the complement factor H-related (CFHR) gene cluster. This deletion resulted in expression of a hybrid CFHR2-CFHR5 plasma protein. The recombinant hybrid protein stabilized the C3 convertase and reduced factor H-mediated convertase decay. One patient was refractory to plasma replacement and exchange therapy, as evidenced by the hybrid protein quickly returning to pretreatment plasma levels. Subsequently, complement inhibitors were tested on serum from the patient for their ability to block activity of CFHR2-CFHR5. Soluble CR1 restored defective C3 convertase regulation; however, neither eculizumab nor tagged compstatin had any effect. Our findings provide insight into the importance of CFHR proteins for C3 convertase regulation and identify a genetic variation in the CFHR gene cluster that promotes C3G-DDD. Monitoring copy number and sequence variations in the CFHR gene cluster in C3G-DDD and kidney patients with C3G-DDD variations will help guide treatment strategies.
| S-EPMC3871254 | biostudies-literature
Project description:The 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.
| S-EPMC8128922 | biostudies-literature
Project description:Microarray analysis was performed on retina/RPE/choroid samples taken from the right eyes of male chicks across control and recovery from form deprivation conditions.
2018-06-05 | GSE89325 | GEO
Project description:PurposeBasal linear deposit (BLinD) is a thin layer of soft drusen material. To elucidate the biology of extracellular deposits conferring age-related macular degeneration (AMD) progression risk and inform multimodal clinical imaging based on optical coherence tomography (OCT), we examined lipid content and regional prevalence of BLinD, soft drusen, pre-BLinD, and subretinal drusenoid deposit (SDD) in AMD and non-AMD aged eyes. We estimated BLinD volume and illustrated its relation to type 1 macular neovascularization (MNV).MethodsDonor eyes were classified as early to intermediate AMD (n = 25) and age-matched controls (n = 54). In high-resolution histology, we assessed BLinD/soft drusen thickness at 836 and 1716 locations in AMD and control eyes, respectively. BLinD volume was estimated using solid geometry in donor eyes, one clinically characterized.ResultsBLinD, drusen, type 1 MNV, and fluid occupy the sub-RPE-basal laminar space. BLinD volume in a 3-mm diameter circle may be as much as 0.0315 mm3. Osmophilic lipid was more concentrated in BLinD/drusen than SDD. In the fovea, BLinD/drusen was prevalent in AMD eyes; pre-BLinD was prevalent in control eyes. SDD was low in the fovea and high in perifovea, especially in AMD eyes.ConclusionsAlthough invisible, BLinD may presage type 1 MNV. BLinD volume approaches the criterion OCT drusen volume of 0.03 mm3 for AMD progression risk. BLinD culminates years of subfoveal lipid accumulation. SDD is detected relatively late in life, with currently unknown precursors. Deposit topography suggests one outer retinal lipid recycling system serving specialized cone and rod physiology, and its dysregulation in AMD is due to impaired transfer to the circulation.
| S-EPMC7846955 | biostudies-literature
Project description:The alternative pathway of the complement cascade plays a role in the pathogenesis of dense deposit disease (DDD). Deficiency of complement factor H and mutations in CFH associate with the development of DDD, but it is unknown whether allelic variants in other complement genes also associate with this disease. We studied patients with DDD and identified previously unreported sequence alterations in several genes in addition to allelic variants and haplotypes common to patients with DDD. We found that the likelihood of developing DDD increases with the presence of two or more risk alleles in CFH and C3. To determine the functional consequence of this finding, we measured the activity of the alternative pathway in serum samples from phenotypically normal controls genotyped for variants in CFH and C3. Alternative pathway activity was higher in the presence of variants associated with DDD. Taken together, these data confirm that DDD is a complex genetic disease and may provide targets for the development of disease-specific therapies.
| S-EPMC3148710 | biostudies-literature
Project description:Complement Factor H-Related 3 (FHR-3) is a major regulator of the complement system, which is associated with different diseases, such as age-related macular degeneration (AMD). However, the non-canonical local, cellular functions of FHR-3 remained poorly understood. Here, we report that FHR-3 bound to oxidative stress epitopes and competed with FH for interaction. Furthermore, FHR-3 was internalized by viable RPE cells and modulated time-dependently complement component (C3, FB) and receptor (C3aR, CR3) expression of human RPE cells. Independently of any external blood-derived proteins, complement activation products were detected. Anaphylatoxin C3a was visualized in treated cells and showed a translocation from the cytoplasm to the cell membrane after FHR-3 exposure. Subsequently, FHR-3 induced a RPE cell dependent pro-inflammatory microenvironment. Inflammasome NLRP3 activation and pro-inflammatory cytokine secretion of IL-1ß, IL-18, IL-6 and TNF-α were induced after FHR-3-RPE interaction. Our previously published monoclonal anti-FHR-3 antibody, which was chimerized to reduce immunogenicity, RETC-2-ximab, ameliorated the effect of FHR-3 on ARPE-19 cells. Our studies suggest FHR-3 as an exogenous trigger molecule for the RPE cell "complosome" and as a putative target for a therapeutic approach for associated degenerative diseases.
| S-EPMC8606654 | biostudies-literature