RESUMEN
VEGF-A antagonists have revolutionized wet AMD treatment. Several challenges remain including high treatment burden requiring repeated intraocular injections for persistent disease. Brolucizumab directly inhibits VEGF-A function, providing visual outcomes comparable to aflibercept (an FDA-approved VEGF-A antagonist). Anatomic retinal outcomes including retinal fluid, a marker of disease activity, favored brolucizumab. To view this Bench to Bedisde, open or download the PDF.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Degeneración Macular/inmunología , Degeneración Macular/terapia , Inhibidores de la Angiogénesis , Humanos , Retina , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Agudeza VisualRESUMEN
Variants of the CFH gene, encoding complement factor H (CFH), show strong association with age-related macular degeneration (AMD), a major cause of blindness. Here, we used murine models of AMD to examine the contribution of CFH to disease etiology. Cfh deletion protected the mice from the pathogenic subretinal accumulation of mononuclear phagocytes (MP) that characterize AMD and showed accelerated resolution of inflammation. MP persistence arose secondary to binding of CFH to CD11b, which obstructed the homeostatic elimination of MPs from the subretinal space mediated by thrombospsondin-1 (TSP-1) activation of CD47. The AMD-associated CFH(H402) variant markedly increased this inhibitory effect on microglial cells, supporting a causal link to disease etiology. This mechanism is not restricted to the eye, as similar results were observed in a model of acute sterile peritonitis. Pharmacological activation of CD47 accelerated resolution of both subretinal and peritoneal inflammation, with implications for the treatment of chronic inflammatory disease.
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Antígeno CD47/inmunología , Factor H de Complemento/inmunología , Inflamación/inmunología , Degeneración Macular/inmunología , Animales , Factor H de Complemento/genética , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Inmunohistoquímica , Inflamación/genética , Degeneración Macular/genética , Ratones , Ratones Noqueados , Peritonitis/genética , Peritonitis/inmunología , Polimorfismo de Nucleótido SimpleRESUMEN
Neutrophils, traditionally viewed as first responders to infection or tissue damage, exhibit dynamic and diverse roles in ocular health and disease. This review elaborates on previous findings that showed how neutrophils contribute to ocular diseases. In ocular infections, neutrophils play a pivotal role in host defense by orchestrating inflammatory responses to combat pathogens. Furthermore, in optic nerve neuropathies and retinal degenerative diseases like age-related macular degeneration (AMD) and diabetic retinopathy (DR), neutrophils are implicated in neuroinflammation and tissue damage owing to their ability to undergo neutrophil extracellular trap formation (NETosis) and secretion of inflammatory molecules. Targeting neutrophil-dependent processes holds promise as a therapeutic strategy, offering potential avenues for intervention in ocular infections, cancers, and retinal degenerative diseases. Understanding the multifaceted roles of neutrophils in ocular diseases is crucial for developing targeted therapies to improve patient outcomes.
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Oftalmopatías , Neutrófilos , Humanos , Neutrófilos/inmunología , Neutrófilos/metabolismo , Oftalmopatías/inmunología , Oftalmopatías/terapia , Animales , Trampas Extracelulares/metabolismo , Trampas Extracelulares/inmunología , Degeneración Macular/inmunología , Degeneración Macular/patología , Degeneración Macular/metabolismoRESUMEN
Genetic polymorphisms in the region of the trimeric serine hydrolase high-temperature requirement 1 (HTRA1) are associated with increased risk of age-related macular degeneration (AMD) and disease progression, but the precise biological function of HtrA1 in the eye and its contribution to disease etiologies remain undefined. In this study, we have developed an HtrA1-blocking Fab fragment to test the therapeutic hypothesis that HtrA1 protease activity is involved in the progression of AMD. Next, we generated an activity-based small-molecule probe (ABP) to track target engagement in vivo. In addition, we used N-terminomic proteomic profiling in preclinical models to elucidate the in vivo repertoire of HtrA1-specific substrates, and identified substrates that can serve as robust pharmacodynamic biomarkers of HtrA1 activity. One of these HtrA1 substrates, Dickkopf-related protein 3 (DKK3), was successfully used as a biomarker to demonstrate the inhibition of HtrA1 activity in patients with AMD who were treated with the HtrA1-blocking Fab fragment. This pharmacodynamic biomarker provides important information on HtrA1 activity and pharmacological inhibition within the ocular compartment.
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Proteínas Adaptadoras Transductoras de Señales/genética , Anticuerpos Antiidiotipos/farmacología , Atrofia Geográfica/tratamiento farmacológico , Serina Peptidasa A1 que Requiere Temperaturas Altas/genética , Degeneración Macular/tratamiento farmacológico , Proteínas Adaptadoras Transductoras de Señales/aislamiento & purificación , Anciano , Animales , Anticuerpos Antiidiotipos/genética , Anticuerpos Antiidiotipos/inmunología , Biomarcadores/sangre , Progresión de la Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Atrofia Geográfica/sangre , Atrofia Geográfica/genética , Atrofia Geográfica/inmunología , Serina Peptidasa A1 que Requiere Temperaturas Altas/antagonistas & inhibidores , Humanos , Fragmentos Fab de Inmunoglobulinas/inmunología , Fragmentos Fab de Inmunoglobulinas/farmacología , Degeneración Macular/sangre , Degeneración Macular/genética , Degeneración Macular/inmunología , Masculino , Polimorfismo de Nucleótido Simple/genética , Proteoma/genética , Proteoma/inmunología , Ratas , Retina/efectos de los fármacos , Retina/inmunología , Retina/patología , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
Age-related macular degeneration (AMD) is a chronic and progressive degenerative disease of the retina, which culminates in blindness and affects mainly the elderly population. AMD pathogenesis and pathophysiology are incredibly complex due to the structural and cellular complexity of the retina, and the variety of risk factors and molecular mechanisms that contribute to disease onset and progression. AMD is driven by a combination of genetic predisposition, natural ageing changes and lifestyle factors, such as smoking or nutritional intake. The mechanism by which these risk factors interact and converge towards AMD are not fully understood and therefore drug discovery is challenging, where no therapeutic attempt has been fully effective thus far. Genetic and molecular studies have identified the complement system as an important player in AMD. Indeed, many of the genetic risk variants cluster in genes of the alternative pathway of the complement system and complement activation products are elevated in AMD patients. Nevertheless, attempts in treating AMD via complement regulators have not yet been successful, suggesting a level of complexity that could not be predicted only from a genetic point of view. In this review, we will explore the role of complement system in AMD development and in the main molecular and cellular features of AMD, including complement activation itself, inflammation, ECM stability, energy metabolism and oxidative stress.
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Envejecimiento , Activación de Complemento , Proteínas del Sistema Complemento/metabolismo , Inflamación/fisiopatología , Degeneración Macular/patología , Estrés Oxidativo , Animales , Predisposición Genética a la Enfermedad , Humanos , Degeneración Macular/inmunología , Degeneración Macular/metabolismo , Factores de RiesgoRESUMEN
Age-related macular degeneration (AMD) is a leading cause of visual impairment of the elderly population. Since AMD is a multifactorial age-related disease with various genetic risk factors, the understanding of its complex pathophysiology is still limited. However, animal experiments, genome-wide association data and the molecular profiling of AMD patient samples have highlighted a key role of systemic and local immune processes that contribute to this chronic eye disease. In this overview article, we concentrate on the role of lymphocytes and mononuclear phagocytes and their interplay in triggering a persistent immune response in the AMD retina. We preferentially review findings from human immune cell analyses and complement these with related findings in experimental models. We conclude that both immune cell types as their signaling network may be a rich source to identify novel molecular targets for immunomodulation in AMD.
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Linfocitos B/inmunología , Linfocitos T CD8-positivos/inmunología , Degeneración Macular/inmunología , Fagocitos/inmunología , Células TH1/inmunología , Células Th17/inmunología , Anciano de 80 o más Años , Proteínas del Sistema Complemento/inmunología , Humanos , Inmunomodulación/fisiología , Degeneración Macular/patología , Retina/inmunología , Retina/patología , Trastornos de la Visión/inmunologíaRESUMEN
Considering the immunological impairment in age-related macular degeneration (AMD), we aimed to determine the associations of IL-9 rs1859430, rs2069870, rs11741137, rs2069885, and rs2069884 and IL-10 rs1800871, rs1800872, and rs1800896 polymorphisms and their haplotypes, as well as the serum levels of IL-9 and IL-10 with AMD. 1209 participants were enrolled in our study. SNPs were genotyped using TaqMan SNP genotyping assays by real-time PCR method. IL-9 and IL-10 serum levels were evaluated using ELISA kits. Our study results have shown that haplotypes A-G-C-G-G and G-A-T-A-T of IL-9 SNPs are associated with the decreased odds of early AMD occurrence (p = 0.035 and p = 0.015, respectively). A set of rare haplotypes was associated with the decreased odds of exudative AMD occurrence (p = 0.033). Also, IL-10 serum levels were lower in exudative AMD than in controls (p = 0.049), patients with early AMD (p = 0.017), and atrophic AMD (p = 0.008). Furthermore, exudative AMD patients with IL-10 rs1800896 CT and TT genotypes had lower IL-10 serum concentrations than those with wild-type (CC) genotype (p = 0.048). In conclusion, our study suggests that IL-10 serum levels can be associated with a minor allele at IL-10 rs1800896 and exudative AMD. The haplotypes of IL-9 SNPs were also associated with the decreased odds of early and exudative AMD.
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Interleucina-10/genética , Interleucina-9/genética , Degeneración Macular/genética , Polimorfismo de Nucleótido Simple , Anciano , Anciano de 80 o más Años , Femenino , Haplotipos , Humanos , Interleucina-10/sangre , Interleucina-9/sangre , Degeneración Macular/etiología , Degeneración Macular/inmunología , Masculino , Persona de Mediana Edad , Población BlancaRESUMEN
Age-related macular degeneration (AMD), the leading cause of vision loss in the elderly, is a degenerative disease of the macula, where retinal pigment epithelium (RPE) cells are damaged in the early stages of the disease, and chronic inflammatory processes may be involved. Besides aging and lifestyle factors as drivers of AMD, a strong genetic association to AMD is found in genes of the complement system, with a single polymorphism in the complement factor H gene (CFH), accounting for the majority of AMD risk. However, the exact mechanism of CFH dysregulation confers such a great risk for AMD and its role in RPE cell homeostasis is unclear. To explore the role of endogenous CFH locally in RPE cells, we silenced CFH in human hTERT-RPE1 cells. We demonstrate that endogenously expressed CFH in RPE cells modulates inflammatory cytokine production and complement regulation, independent of external complement sources, or stressors. We show that loss of the factor H protein (FH) results in increased levels of inflammatory mediators (e.g., IL-6, IL-8, GM-CSF) and altered levels of complement proteins (e.g., C3, CFB upregulation, and C5 downregulation) that are known to play a role in AMD. Moreover, our results identify the NF-κB pathway as the major pathway involved in regulating these inflammatory and complement factors. Our findings suggest that in RPE cells, FH and the NF-κB pathway work in synergy to maintain inflammatory and complement balance, and in case either one of them is dysregulated, the RPE microenvironment changes towards a proinflammatory AMD-like phenotype.
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Citocinas/metabolismo , Silenciador del Gen , Degeneración Macular/genética , Epitelio Pigmentado de la Retina/inmunología , Línea Celular , Factor H de Complemento/genética , Proteínas del Sistema Complemento/metabolismo , Citocinas/genética , Regulación de la Expresión Génica , Humanos , Degeneración Macular/inmunología , Modelos Biológicos , FN-kappa B/genética , FN-kappa B/metabolismo , Epitelio Pigmentado de la Retina/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND: Macular fibrosis causes irreparable vision loss in neovascular age-related macular degeneration (nAMD) even with anti-vascular endothelial growth factor (VEGF) therapy. Inflammation is known to play an important role in macular fibrosis although the underlying mechanism remains poorly defined. The aim of this study was to understand how infiltrating macrophages and complement proteins may contribute to macular fibrosis. METHODS: Subretinal fibrosis was induced in C57BL/6J mice using the two-stage laser protocol developed by our group. The eyes were collected at 10, 20, 30 and 40 days after the second laser and processed for immunohistochemistry for infiltrating macrophages (F4/80 and Iba-1), complement components (C3a and C3aR) and fibrovascular lesions (collagen-1, Isolectin B4 and α-SMA). Human retinal sections with macular fibrosis were also used in the study. Bone marrow-derived macrophages (BMDMs) from C57BL/6J mice were treated with recombinant C3a, C5a or TGF-ß for 48 and 96 h. qPCR, Western blot and immunohistochemistry were used to examine the expression of myofibroblast markers. The involvement of C3a-C3aR pathway in macrophage to myofibroblast transition (MMT) and subretinal fibrosis was further investigated using a C3aR antagonist (C3aRA) and a C3a blocking antibody in vitro and in vivo. RESULTS: Approximately 20~30% of F4/80+ (or Iba-1+) infiltrating macrophages co-expressed α-SMA in subretinal fibrotic lesions both in human nAMD eyes and in the mouse model. TGF-ß and C3a, but not C5a treatment, significantly upregulated expression of α-SMA, fibronectin and collagen-1 in BMDMs. C3a-induced upregulation of α-SMA, fibronectin and collagen-1 in BMDMs was prevented by C3aRA treatment. In the two-stage laser model of induced subretinal fibrosis, treatment with C3a blocking antibody but not C3aRA significantly reduced vascular leakage and Isolectin B4+ lesions. The treatment did not significantly alter collagen-1+ fibrotic lesions. CONCLUSIONS: MMT plays a role in macular fibrosis secondary to nAMD. MMT can be induced by TGF-ß and C3a but not C5a. Further research is required to fully understand the role of MMT in macular fibrosis. Macrophage to myofibroblast transition (MMT) contributes to subretinal fibrosis. Subretinal fibrosis lesions contain various cell types, including macrophages and myofibroblasts, and are fibrovascular. Myofibroblasts are key cells driving pathogenic fibrosis, and they do so by producing excessive amount of extracellular matrix proteins. We have found that infiltrating macrophages can transdifferentiate into myofibroblasts, a phenomenon termed macrophage to myofibroblast transition (MMT) in macular fibrosis. In addition to TGF-ß1, C3a generated during complement activation in CNV can also induce MMT contributing to macular fibrosis. RPE = retinal pigment epithelium. BM = Bruch's membrane. MMT = macrophage to myofibroblast transition. TGFB = transforming growth factor ß. a-SMA = alpha smooth muscle actin. C3a = complement C3a.
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Macrófagos/patología , Degeneración Macular/patología , Miofibroblastos/patología , Neovascularización Patológica/patología , Retina/patología , Animales , Células Cultivadas , Complemento C3a/toxicidad , Femenino , Fibrosis , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Degeneración Macular/inducido químicamente , Degeneración Macular/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Miofibroblastos/efectos de los fármacos , Miofibroblastos/inmunología , Neovascularización Patológica/inducido químicamente , Neovascularización Patológica/inmunología , Retina/efectos de los fármacos , Retina/inmunologíaRESUMEN
Diabetic retinopathy (DR) is an ocular complication of diabetes mellitus (DM). International Diabetic Federations (IDF) estimates up to 629 million people with DM by the year 2045 worldwide. Nearly 50% of DM patients will show evidence of diabetic-related eye problems. Therapeutic interventions for DR are limited and mostly involve surgical intervention at the late-stages of the disease. The lack of early-stage diagnostic tools and therapies, especially in DR, demands a better understanding of the biological processes involved in the etiology of disease progression. The recent surge in literature associated with NOD-like receptors (NLRs) has gained massive attraction due to their involvement in mediating the innate immune response and perpetuating inflammatory pathways, a central phenomenon found in the pathogenesis of ocular diseases including DR. The NLR family of receptors are expressed in different eye tissues during pathological conditions suggesting their potential roles in dry eye, ocular infection, retinal ischemia, cataract, glaucoma, age-related macular degeneration (AMD), diabetic macular edema (DME) and DR. Our group is interested in studying the critical early components involved in the immune cell infiltration and inflammatory pathways involved in the progression of DR. Recently, we reported that NLRP3 inflammasome might play a pivotal role in the pathogenesis of DR. This comprehensive review summarizes the findings of NLRs expression in the ocular tissues with special emphasis on its presence in the retinal microglia and DR pathogenesis.
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Retinopatía Diabética/inmunología , Glaucoma/inmunología , Inflamasomas/inmunología , Degeneración Macular/inmunología , Edema Macular/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Proteínas NLR/inmunología , Ojo/inmunología , Humanos , Inmunidad InnataRESUMEN
Purpose: Smoking and the incidence of age-related macular degeneration (AMD) have been linked to an overactive complement system. Here, we examined in a retrospective cohort study whether AMD-associated single nucleotide polymorphisms (SNPs), smoking, ethnicity, and disease status are correlated with blood complement levels. Methods: Population: The study involved 91 AMD patients and 133 controls, which included 73% Americans of European descent (EUR) and 27% Americans of African descent (AFR) in South Carolina. Readouts: Participants were genotyped for 10 SNPs and systemic levels of complement factor H (CFH) activity, and the complement activation products C3a, C5a, and Bb were assessed. Main Outcome Measures: Univariate and multivariable logistic regression models were used to examine associations between AMD status and distinct readouts. Results: AMD affects EUR individuals more than AFRs. EUR but not AFR AMD subjects revealed higher levels of Factors C3a and Bb. In all subjects, a 10-unit increase in C3a levels was associated with an approximately 10% increase in the odds of being AMD-positive, and C3a and Bb were associated with smoking. While CFH activity levels were not correlated with AMD, a significant interaction was evident between patient age and CFH activity. Finally, EURs had lower odds of AMD with enhanced copies of rs1536304 (VEGFA) and higher odds with more copy numbers of rs3766404 (CFH). Conclusions: Our results support previous studies of systemic complement components being potential biomarkers for AMD, but they suggest that smoking and disease do not synergistically affect complement levels. We also suggest a novel susceptibility and protective haplotypes in the South Carolinian AMD population. Our studies indicate that augmented complement activation associated with advanced AMD could be attributed to a decrease in CFH activity in younger patients.
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Activación de Complemento/genética , Factor H de Complemento/genética , Degeneración Macular/genética , Polimorfismo de Nucleótido Simple , Fumar/genética , Factores de Edad , Anciano , Anciano de 80 o más Años , Población Negra , Estudios de Casos y Controles , Complemento C3a/genética , Complemento C3a/inmunología , Complemento C5a/genética , Complemento C5a/inmunología , Factor B del Complemento/genética , Factor B del Complemento/inmunología , Factor H de Complemento/inmunología , Femenino , Expresión Génica , Humanos , Modelos Logísticos , Degeneración Macular/etnología , Degeneración Macular/inmunología , Degeneración Macular/patología , Masculino , Estudios Retrospectivos , Fumar/etnología , Fumar/inmunología , Fumar/fisiopatología , South Carolina , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/inmunología , Población BlancaRESUMEN
Factor H-related protein (FHR) 1 is one of the five human FHRs that share sequence and structural homology with the alternative pathway complement inhibitor FH. Genetic studies on disease associations and functional analyses indicate that FHR-1 enhances complement activation by competitive inhibition of FH binding to some surfaces and immune proteins. We have recently shown that FHR-1 binds to pentraxin 3. In this study, our aim was to investigate whether FHR-1 binds to another pentraxin, C-reactive protein (CRP), analyze the functional relevance of this interaction, and study the role of FHR-1 in complement activation and regulation. FHR-1 did not bind to native, pentameric CRP, but it bound strongly to monomeric CRP via its C-terminal domains. FHR-1 at high concentration competed with FH for CRP binding, indicating possible complement deregulation also on this ligand. FHR-1 did not inhibit regulation of solid-phase C3 convertase by FH and did not inhibit terminal complement complex formation induced by zymosan. On the contrary, by binding C3b, FHR-1 allowed C3 convertase formation and thereby enhanced complement activation. FHR-1/CRP interactions increased complement activation via the classical and alternative pathways on surfaces such as the extracellular matrix and necrotic cells. Altogether, these results identify CRP as a ligand for FHR-1 and suggest that FHR-1 enhances, rather than inhibits, complement activation, which may explain the protective effect of FHR-1 deficiency in age-related macular degeneration.
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Proteína C-Reactiva/inmunología , Proteína C-Reactiva/metabolismo , Activación de Complemento , Proteínas Inactivadoras del Complemento C3b/inmunología , Proteínas Inactivadoras del Complemento C3b/metabolismo , Sitios de Unión , Proteína C-Reactiva/química , Proteína C-Reactiva/farmacología , Convertasas de Complemento C3-C5 , Complemento C3b/inmunología , Complemento C3b/farmacología , Proteínas Inactivadoras del Complemento C3b/farmacología , Factor H de Complemento , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/inmunología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/inmunología , Humanos , Ligandos , Degeneración Macular/inmunología , Unión Proteica , Componente Amiloide P Sérico/inmunología , Componente Amiloide P Sérico/metabolismoRESUMEN
Purpose: A recent genome-wide association study by the International Age-related Macular Degeneration Genomics Consortium (IAMDGC) identified seven rare variants that are individually associated with age-related macular degeneration (AMD), the most common cause of vision loss in the elderly. In literature, several of these rare variants have been reported with different frequencies and odds ratios across populations of Europe and North America. Here, we aim to describe the representation of these seven AMD-associated rare variants in different geographic regions based on 24 AMD studies. Methods: We explored the occurrence of seven rare variants independently associated with AMD (CFH rs121913059 (p.Arg1210Cys), CFI rs141853578 (p.Gly119Arg), C3 rs147859257 (p.Lys155Gln), and C9 rs34882957 (p.Pro167Ser)) and three non-coding variants in or near the CFH gene (rs148553336, rs35292876, and rs191281603) in 24 AMD case-control studies. We studied the difference in distribution, interaction, and effect size for each of the rare variants based on the minor allele frequency within the different geographic regions. Results: We demonstrate that two rare AMD-associated variants in the CFH gene (rs121913059 [p.Arg1210Cys] and rs35292876) deviate in frequency among different geographic regions (p=0.004 and p=0.001, respectively). The risk estimates of each of the seven rare variants were comparable across the geographic regions. Conclusions: The results emphasize the importance of identifying population-specific rare variants, for example, by performing sequencing studies in case-control studies of various populations, because their identification may have implications for diagnostic screening and personalized treatment.
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Factor H de Complemento/genética , Predisposición Genética a la Enfermedad , Degeneración Macular/genética , Polimorfismo de Nucleótido Simple , Anciano , Alelos , Estudios de Casos y Controles , Complemento C3/genética , Complemento C3/inmunología , Complemento C9/genética , Complemento C9/inmunología , Factor H de Complemento/inmunología , Factor I de Complemento/genética , Factor I de Complemento/inmunología , Europa (Continente) , Femenino , Expresión Génica , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Geografía , Humanos , Degeneración Macular/diagnóstico , Degeneración Macular/inmunología , Degeneración Macular/patología , MasculinoRESUMEN
It has recently been recognized that pathology of age-associated degenerative eye diseases such as adult macular degeneration (AMD), glaucoma and diabetic retinopathy, have strong immunological underpinnings. Attempts have been made to extrapolate to age-related degenerative disease insights from inflammatory processes associated with non-infectious uveitis, but these have not yet been sufficiently informative. Here we review recent findings on the immune processes underlying uveitis and those that have been shown to contribute to AMD, discussing in this context parallels and differences between overt inflammation and para-inflammation in the eye. We propose that mechanisms associated with ocular immune privilege, in combination with paucity of age-related antigen(s) within the target tissue, dampen what could otherwise be overt inflammation and result in the para-inflammation that characterizes age-associated neurodegenerative disease.
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Inmunidad Adaptativa/inmunología , Células Presentadoras de Antígenos/inmunología , Degeneración Macular/inmunología , Subgrupos de Linfocitos T/inmunología , Uveítis/inmunología , Animales , Citocinas/inmunología , Humanos , Mediadores de Inflamación/inmunologíaRESUMEN
Age-related macular degeneration (AMD) is the leading cause of central vision loss worldwide. Loss of retinal pigment epithelium (RPE) is a major pathological hallmark in AMD with or without pathological neovascularization. Although activation of the immune system is implicated in disease progression, pathological pathways remain diverse and unclear. Here, we report an unexpected protective role of a pro-inflammatory cytokine, interleukin-33 (IL-33), in ocular angiogenesis. IL-33 and its receptor (ST2) are expressed constitutively in human and murine retina and choroid. When RPE was activated, IL-33 expression was markedly elevated in vitro. We found that IL-33 regulated tissue remodelling by attenuating wound-healing responses, including reduction in the migration of choroidal fibroblasts and retinal microvascular endothelial cells, and inhibition of collagen gel contraction. In vivo, local administration of recombinant IL-33 inhibited murine choroidal neovascularization (CNV) formation, a surrogate of human neovascular AMD, and this effect was ST2-dependent. Collectively, these data demonstrate IL-33 as a potential immunotherapy and distinguishes pathways for subverting AMD pathology. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Interleucina-33/inmunología , Degeneración Macular/inmunología , Adolescente , Adulto , Anciano , Animales , Células Cultivadas , Coroides/inmunología , Neovascularización Coroidal/tratamiento farmacológico , Neovascularización Coroidal/inmunología , Fibroblastos/inmunología , Humanos , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Interleucina-33/uso terapéutico , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Proteínas Recombinantes/uso terapéutico , Epitelio Pigmentado de la Retina/inmunología , Adulto JovenRESUMEN
Age-related macular degeneration (AMD) is a complex and progressive degenerative eye disease resulting in severe loss of central vision. Recent evidence indicates that immune system dysregulation could contribute to the development of AMD. We hypothesize that defective lysosome-mediated clearance causes accumulation of waste products in the retinal pigmented epithelium (RPE), activating the immune system and leading to retinal tissue injury and AMD. We have generated unique genetically engineered mice in which lysosome-mediated clearance (both by phagocytosis and autophagy) in RPE cells is compromised, causing the development of features of early AMD. Our recent data indicate a link between lipocalin-2 (LCN-2) and the inflammatory responses induced in this mouse model. We show that nuclear factor-κB (NF-κB) and STAT-1 may function as a complex in our animal model system, together controlling the upregulation of LCN-2 expression in the retina and stimulating an inflammatory response. This study revealed increased infiltration of LCN-2-positive neutrophils in the choroid and retina of early AMD patients as compared with age-matched controls. Our results demonstrate that, both in our animal model and in human AMD, the AKT2-NF-κB-LCN-2 signalling axis is involved in activating the inflammatory response, making this pathway a potential target for AMD treatment. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Lipocalina 2/genética , Lisosomas/inmunología , Degeneración Macular/genética , FN-kappa B/genética , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de Señal , Factores de Edad , Animales , Autofagia , Coroides/inmunología , Coroides/metabolismo , Modelos Animales de Enfermedad , Humanos , Inflamación , Lipocalina 2/metabolismo , Lisosomas/metabolismo , Degeneración Macular/inmunología , Degeneración Macular/patología , Ratones , FN-kappa B/metabolismo , Neutrófilos/inmunología , Fagocitosis , Proteínas Proto-Oncogénicas c-akt/metabolismo , Retina/inmunología , Retina/lesiones , Retina/metabolismo , Epitelio Pigmentado de la Retina/inmunología , Epitelio Pigmentado de la Retina/metabolismo , Regulación hacia ArribaRESUMEN
PURPOSE OF REVIEW: The intestinal commensal microbiota are important in shaping immune cell repertoire and are influenced by host genetics. Because of this intricate interaction, an intestinal dysbiosis has been associated with multiple immune-mediated polygenic diseases. This review summarizes the literature on how alterations in the intestinal microbiota contribute to immune-mediated ocular disease, and how to potentially target the gut microbiome for therapeutic benefit. RECENT FINDINGS: Several groups have demonstrated the importance of the intestinal microbiome in uveitis pathogenesis. Two groups showed that altering the microbiota with oral antibiotics results in reduced uveitis severity, and another group demonstrated that a commensal bacterial antigen activates retina-specific autoreactive T cells, potentially indicating a commensal trigger for uveitis. We have found that commensal bacterial metabolites, short chain fatty acids, can suppress autoimmune uveitis. Age-related macular degeneration is associated with an intestinal dysbiosis, which can be influenced by genetic risk alleles and age-related eye disease study (AREDS) supplementation. Strategies that might be effective for targeting the intestinal microbiota might involve several approaches, including the use of antibiotics, drugs that supplement beneficial bacterial components or target inflammatory bacterial strains, dietary strategies or microbial transplantation. SUMMARY: The intestinal microbiota are potentially crucial in propagating inflammatory diseases of the eye, and can be targeted for therapeutic benefit.
Asunto(s)
Disbiosis/inmunología , Microbioma Gastrointestinal/fisiología , Degeneración Macular/inmunología , Uveítis/inmunología , Bacterias/metabolismo , Humanos , Retina/inmunologíaRESUMEN
Proliferative vitreoretinal diseases such as diabetic retinopathy, proliferative vitreoretinopathy (PVR), and age-related macular degeneration are a leading cause of decreased vision and blindness in developed countries. In these diseases, retinal fibro(vascular) membrane (FVM) formation above and beneath the retina plays an important role. Gene expression profiling of human FVMs revealed significant upregulation of periostin. Subsequent analyses demonstrated increased periostin expression in the vitreous of patients with both proliferative diabetic retinopathy and PVR. Immunohistochemical analysis showed co-localization of periostin with α-SMA and M2 macrophage markers in FVMs. In vitro, periostin blockade inhibited migration and adhesion induced by PVR vitreous and transforming growth factor-ß2 (TGF-ß2). In vivo, a novel single-stranded RNAi agent targeting periostin showed the inhibitory effect on experimental retinal and choroidal FVM formation without affecting the viability of retinal cells. These results indicated that periostin is a pivotal molecule for FVM formation and a promising therapeutic target for these proliferative vitreoretinal diseases.
Asunto(s)
Moléculas de Adhesión Celular/genética , Neovascularización Coroidal/genética , Retinopatía Diabética/genética , Degeneración Macular/genética , Vitreorretinopatía Proliferativa/genética , Actinas/genética , Actinas/inmunología , Animales , Moléculas de Adhesión Celular/antagonistas & inhibidores , Moléculas de Adhesión Celular/inmunología , Neovascularización Coroidal/inmunología , Neovascularización Coroidal/patología , Neovascularización Coroidal/terapia , Retinopatía Diabética/inmunología , Retinopatía Diabética/patología , Retinopatía Diabética/terapia , Regulación de la Expresión Génica , Silenciador del Gen , Humanos , Degeneración Macular/inmunología , Degeneración Macular/patología , Degeneración Macular/terapia , Ratones , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Retina/inmunología , Retina/patología , Transducción de Señal , Factor de Crecimiento Transformador beta2/genética , Factor de Crecimiento Transformador beta2/inmunología , Vitreorretinopatía Proliferativa/inmunología , Vitreorretinopatía Proliferativa/patología , Vitreorretinopatía Proliferativa/terapia , Cuerpo Vítreo/inmunología , Cuerpo Vítreo/patologíaRESUMEN
RATIONALE: Age-related macular degeneration (AMD) is one of the leading causes of blindness among the elderly. Due to its complex etiology, current treatments have been insufficient. Previous studies reveal three systems closely involved in AMD pathogenesis: lipid metabolism, oxidation and inflammation. These systems are also involved in Alzheimer's disease, atherosclerosis and glomerulonephritis. Understanding commonalities of these four diseases may provide insight into AMD etiology. OBJECTIVES: To understand AMD pathogenesis by analogy and suggest ideas for future research, this study summarizes main commonalities in disease pathogenesis of AMD, Alzheimer's disease, atherosclerosis and glomerulonephritis. METHODS: Articles were identified through PubMed, Ovid Medline and Google Scholar. We summarized the common findings and synthesized critical differences. RESULTS: Oxidation, lipid deposition, complement activation, and macrophage recruitment are involved in all four diseases shown by genetic, molecular, animal and human studies. Shared genetic variations further strengthen their connection. Potential areas for future research are suggested throughout the review. CONCLUSIONS: The four diseases share many steps of an overall framework of pathogenesis. Various oxidative sources cause oxidative stress. Oxidized lipids and related molecules accumulate and lead to complement activation, macrophage recruitment and pathology. Investigations that arise under this structure may aid us to better understand AMD pathology.
Asunto(s)
Enfermedad de Alzheimer/patología , Aterosclerosis/patología , Glomerulonefritis/patología , Metabolismo de los Lípidos/inmunología , Degeneración Macular/patología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/metabolismo , Animales , Apolipoproteínas/genética , Apolipoproteínas/inmunología , Aterosclerosis/genética , Aterosclerosis/inmunología , Aterosclerosis/metabolismo , Colesterol/metabolismo , Activación de Complemento , Proteínas del Sistema Complemento/genética , Proteínas del Sistema Complemento/inmunología , Expresión Génica , Variación Genética , Glomerulonefritis/genética , Glomerulonefritis/inmunología , Glomerulonefritis/metabolismo , Humanos , Inflamación , Metabolismo de los Lípidos/genética , Macrófagos/inmunología , Macrófagos/patología , Degeneración Macular/genética , Degeneración Macular/inmunología , Degeneración Macular/metabolismo , Estrés OxidativoRESUMEN
Age-related macular degeneration (AMD) is the leading cause of central vision loss in the over 50s worldwide. Activation of the immune system has been implicated in disease progression, but while polymorphisms in genes associated with the immune system have been identified as risk factors for disease, the underlying pathways and mechanisms involved in disease progression remain incompletely characterised. Typically inflammatory responses are mediated by microbial infection; however, in chronic conditions, a form of 'sterile' inflammation exists whereby immune responses occur in areas of the body, in the absence of microbes; 'sterile' inflammation is likely to be central to AMD. In this case the innate immune response is triggered when alarm signals released by stressed cells or damaged tissue are identified by pattern recognition receptors (PRRs). Toll-like receptors (TLRs) are a family of membrane-spanning PRRs for which host-derived ligands have been identified; these include heat shock proteins, extracellular matrix breakdown products, mRNA from necrotic cells and modified lipids. Here we review the evidence for TLR involvement in the pathogenesis of AMD.