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1.
Front Endocrinol (Lausanne) ; 13: 1020252, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36465606

RESUMEN

Purpose: To investigate the expression of Glucagon-like peptide-1 receptor (GLP-1R), sodium-glucose co-transporter (SGLT) 1, SGLT2, Glucose transporter type 1 (GLUT1) and GLUT2 in patients with diabetic retinopathy (DR). Methods: We obtained peripheral blood mononuclear cells (PBMCs) and vitreous samples from 26 proliferative DR (PDR) patients, 25 non-proliferative DR (NPDR) patients, 25 non-DR (NDR) patients, and 26 nondiabetic patients with idiopathic epiretinal membranes (ERMs, control). The protein level and mRNA expression level of GLP-1R were quantified by immunoblot and qRT-PCR and the levels of SGLT1, SGLT2, GLUT1, and GLUT2 expression were determined by PCR. Their association with clinical parameters and PBMCs/vitreous cytokine was analyzed. Furthermore, immunofluorescence staining of GLP-1R and SGLT2 was carried out on samples of fibrovascular membranes (FVMs) retrieved from 26 patients with PDR and 26 patients with ERMs. Results: The transcriptional levels of GLP-1R and SGLT2 in PBMCs were significantly more decreased in PDR patients than in patients without DR and controls, which was simultaneously associated with an increased level of expression of tumor necrosis factor (TNF)-α and interferon (IFN)-γ. The expression levels of GLUT1 and GLUT2 were tightly correlated with their SGLT partners, respectively. Further, Immunofluorescence staining showed no positive staining of GLP-1R and SGLT2 was detected in the FVMs from PDR. Conclusions: GLP-1R and SGLT2 were significantly decreased in PDR patients which was associated with an increased level of expression of TNF-α and IFN-γ. These findings implicate that defective GLP-1R and SGLT2 signaling may potentially correlate with immune response cytokines in patients with PDR.


Asunto(s)
Retinopatía Diabética , Receptor del Péptido 1 Similar al Glucagón , Transportador de Glucosa de Tipo 1 , Transportador 2 de Sodio-Glucosa , Humanos , Citocinas/análisis , Citocinas/inmunología , Diabetes Mellitus/genética , Diabetes Mellitus/inmunología , Retinopatía Diabética/genética , Retinopatía Diabética/inmunología , Receptor del Péptido 1 Similar al Glucagón/biosíntesis , Receptor del Péptido 1 Similar al Glucagón/genética , Transportador de Glucosa de Tipo 1/biosíntesis , Transportador de Glucosa de Tipo 1/genética , Leucocitos Mononucleares/inmunología , Transportador 2 de Sodio-Glucosa/biosíntesis , Transportador 2 de Sodio-Glucosa/genética , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genética , Cuerpo Vítreo/química , Cuerpo Vítreo/inmunología
2.
Front Immunol ; 12: 757607, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34795670

RESUMEN

Background: Retinal neovascularization (RNV) membranes can lead to a tractional retinal detachment, the primary reason for severe vision loss in end-stage disease proliferative diabetic retinopathy (PDR). The aim of this study was to characterize the molecular, cellular and immunological features of RNV in order to unravel potential novel drug treatments for PDR. Methods: A total of 43 patients undergoing vitrectomy for PDR, macular pucker or macular hole (control patients) were included in this study. The surgically removed RNV and epiretinal membranes were analyzed by RNA sequencing, single-cell based Imaging Mass Cytometry and conventional immunohistochemistry. Immune cells of the vitreous body, also known as hyalocytes, were isolated from patients with PDR by flow cytometry, cultivated and characterized by immunohistochemistry. A bioinformatical drug repurposing approach was applied in order to identify novel potential drug options for end-stage diabetic retinopathy disease. Results: The in-depth transcriptional and single-cell protein analysis of diabetic RNV tissue samples revealed an accumulation of endothelial cells, macrophages and myofibroblasts as well as an abundance of secreted ECM proteins such as SPARC, FN1 and several types of collagen in RNV tissue. The immunohistochemical staining of cultivated vitreal hyalocytes from patients with PDR showed that hyalocytes express α-SMA (alpha-smooth muscle actin), a classic myofibroblast marker. According to our drug repurposing analysis, imatinib emerged as a potential immunomodulatory drug option for future treatment of PDR. Conclusion: This study delivers the first in-depth transcriptional and single-cell proteomic characterization of RNV tissue samples. Our data suggest an important role of hyalocyte-to-myofibroblast transdifferentiation in the pathogenesis of diabetic vitreoretinal disease and their modulation as a novel possible clinical approach.


Asunto(s)
Transdiferenciación Celular , Retinopatía Diabética/patología , Membrana Epirretinal/patología , Miofibroblastos/patología , Neovascularización Retiniana/patología , Cuerpo Vítreo/inmunología , Adulto , Anciano , Células Cultivadas , Biología Computacional , Retinopatía Diabética/complicaciones , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/metabolismo , Reposicionamiento de Medicamentos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Membrana Epirretinal/metabolismo , Proteínas del Ojo/biosíntesis , Proteínas del Ojo/genética , Femenino , Ontología de Genes , Humanos , Mesilato de Imatinib/uso terapéutico , Factores Inmunológicos/uso terapéutico , Masculino , Persona de Mediana Edad , Neovascularización Retiniana/etiología , Neovascularización Retiniana/metabolismo , Perforaciones de la Retina/patología , Análisis de la Célula Individual , Transcriptoma , Cuerpo Vítreo/patología , Adulto Joven
3.
Front Immunol ; 11: 581288, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33117388

RESUMEN

Pathological angiogenesis of the retina is a key component of irreversible causes of blindness, as observed in proliferative diabetic retinopathy (PDR). The pathogenesis of PDR is complex and involves vascular, inflammatory, and neuronal mechanisms. Several structural and molecular alterations associated to PDR are related to the presence of inflammation that appears to play a non-redundant role in the neovascular response that characterizes the retina of PDR patients. Vascular endothelial growth factor (VEGF) blockers have evolved over time for the treatment of retinal neovascularization. However, several limitations to anti-VEGF interventions exist. Indeed, the production of other angiogenic factors and pro-inflammatory mediators may nullify and/or cause resistance to anti-VEGF therapies. Thus, appropriate experimental models are crucial for dissecting the mechanisms leading to retinal neovascularization and for the discovery of more efficacious anti-angiogenic/anti-inflammatory therapies for PDR patients. This review focuses on the tight cross talk between angiogenesis and inflammation during PDR and describe how the chick embryo chorioallantoic membrane (CAM) assay may represent a cost-effective and rapid in vivo tool for the study of the relationship between neovascular and inflammatory responses elicited by the vitreous humor of PDR patients and for the screening of novel therapeutic agents.


Asunto(s)
Retinopatía Diabética/etiología , Neovascularización Retiniana/etiología , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Embrión de Pollo , Membrana Corioalantoides/irrigación sanguínea , Membrana Corioalantoides/inmunología , Membrana Corioalantoides/patología , Retinopatía Diabética/inmunología , Retinopatía Diabética/patología , Humanos , Inflamación/etiología , Inflamación/inmunología , Inflamación/patología , Modelos Animales , Modelos Biológicos , Neovascularización Retiniana/inmunología , Neovascularización Retiniana/patología , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/fisiología , Cuerpo Vítreo/inmunología , Cuerpo Vítreo/patología
4.
Mol Vis ; 26: 472-482, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32606566

RESUMEN

Purpose: The purpose of this study was to investigate the levels of cytokines in the vitreous, and their correlation with the density of inflammatory cells in fibrovascular membranes (FVMs) in patients with proliferative diabetic retinopathy (PDR) to evaluate intraocular inflammatory conditions with regard to disease activity. Methods: Thirty-three patients (33 eyes) with PDR requiring vitreoretinal surgery because of FVMs and tractional detachment were enrolled in the study, and compared with 20 patients (20 eyes) with macular hole (MH; control group). All patients underwent complete ophthalmological examinations before surgery. The activity of the disease was noted in patients with PDR. Samples of vitreous and blood were taken, and cytokine (MCP-1, IL-8, IL-6, VEGF, IL-1ß, TNF-α, MIP-1α, MIP-1ß, IL-10, and IL-12) levels were measured using cytometric bead array (CBA). Samples of FVMs were analyzed with immunohistochemical methods for the presence of inflammatory cells (CD45+, CD14+, CD3+, CD4+, CD8+, and CD19+ cells), and the numerical areal density was calculated (NA). Spearman's correlation was used to assess the association between variables. The Mann-Whitney test was used to assess the differences between independent groups. The Wilcoxon signed-rank test was used for assessing differences between two related groups. A p value of less than 0.05 was considered statistically significant. Results: Patients with active PDR had statistically significantly higher levels of MCP-1 (p = 0.003), VEGF (p = 0.009), and IL-8 (p = 0.02) in the vitreous in comparison with those with inactive PDR. CD45+, CD14+, CD3+, CD4+, CD8+, and CD19+ cells were identified in FVMs for patients with PDR. Statistically significantly higher numerical areal density of T lymphocytes (CD3+, CD4+, and CD8+) was demonstrated in patients with active PDR in comparison with patients with inactive PDR. Moderate to strong correlations were found between either MCP-1 or IL-8 in the vitreous, and the numerical areal density of cells (CD45+, CD3+, CD4+, and CD8+) in the FVMs, and weaker between either MCP-1 or IL-8 in the vitreous and the numerical areal density of CD14+ cells in the FVMs. Conclusions: The correlation of cytokine (MCP-1 and IL-8) vitreous levels with the density of inflammatory cells in FVMs, and differences in cytokine levels in the vitreous between patients with active and inactive PDR, and between the vitreous and serum in PDR indicate the importance of local intraocular inflammation in patients with PDR.


Asunto(s)
Quimiocina CCL2/inmunología , Retinopatía Diabética/inmunología , Interleucina-8/inmunología , Perforaciones de la Retina/inmunología , Linfocitos T/inmunología , Factor A de Crecimiento Endotelial Vascular/inmunología , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/inmunología , Anciano , Anciano de 80 o más Años , Antígenos CD/genética , Antígenos CD/inmunología , Estudios de Casos y Controles , Quimiocina CCL2/genética , Retinopatía Diabética/genética , Retinopatía Diabética/patología , Retinopatía Diabética/cirugía , Femenino , Expresión Génica , Humanos , Inflamación , Interleucina-10/genética , Interleucina-10/inmunología , Interleucina-12/genética , Interleucina-12/inmunología , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Interleucina-8/genética , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Retina/inmunología , Retina/patología , Retina/cirugía , Perforaciones de la Retina/genética , Perforaciones de la Retina/patología , Linfocitos T/patología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología , Factor A de Crecimiento Endotelial Vascular/genética , Cirugía Vitreorretiniana/métodos , Cuerpo Vítreo/inmunología , Cuerpo Vítreo/patología , Cuerpo Vítreo/cirugía
5.
J Diabetes Res ; 2020: 4631290, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32714992

RESUMEN

AIM: To analyze the levels of B-cell-produced antibodies in the vitreous humor of patients with or without diabetic retinopathy (DR) both qualitatively and quantitatively. METHODS: A total of 52 type 2 diabetes mellitus (T2DM) with DR patients and 52 control subjects without diabetes mellitus or inflammatory diseases were included in this prospective study. The levels of immunoglobulin (Ig)A, IgM, and IgG subtypes were measured using a magnetic color-bead-based multiplex assay. RESULTS: The concentrations of IgA, IgM, and total antibodies in the DR group were significantly higher than those in the control group (all p < 0.001), but there was no significant difference in the 4 IgG subtypes between the two groups after Bonferroni correction. Pearson's correlation analysis revealed low negative correlations between levels of antibodies (IgA, IgM) and estimated glomerular filtration rate (eGFR, r = -0.443, r = -0.377, respectively, both p < 0.05). Furthermore, multiple linear regression analysis yielded three equations to predict the concentrations of IgA, IgM, and total antibodies in the vitreous humor according to eGFR and other clinical variables (r = 0.542, r = 0.461, and r = 0.312, respectively, all p < 0.05). CONCLUSION: Increased levels of IgA, IgM, and total antibodies produced by B cells were observed in the vitreous humor of T2DM patients with DR. There were low negative correlations between levels of antibodies (IgA, IgM) and eGFR.


Asunto(s)
Linfocitos B/inmunología , Diabetes Mellitus Tipo 2/inmunología , Retinopatía Diabética/inmunología , Inmunoglobulina A/análisis , Inmunoglobulina G/análisis , Inmunoglobulina M/análisis , Cuerpo Vítreo/inmunología , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad
6.
Adv Ther ; 37(5): 2550-2559, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32274748

RESUMEN

INTRODUCTION: Proliferative vitreoretinopathy (PVR), which is regulated by growth factors and cytokines, is the leading cause of failure in vitreoretinal surgery. In this study, we aimed to investigate the role of the human serum and vitreous inflammation-related factors in the development of proliferative vitreoretinopathy (PVR). METHODS: Blood and vitreous samples were obtained from patients undergoing pars plana vitrectomy. Inflammation-related factors were detected using an immunology multiplex assay on a Luminex® xMAP® platform. Patients with PVR and rhegmatogenous retinal detachment (RRD) were compared with macular hole (MH) or epiretinal membrane (ERM) patients without any other ocular or systemic disease. RESULTS: Thirty-six serum samples and 34 vitreous samples were obtained. Thirty-one different growth factors and cytokines were detected in serum samples. However, none of the circulating growth factors and cytokines were found to be different from the controls. Ten different growth factors and cytokines were measured in the vitreous samples. The concentration levels of PDGF-AA, TGF-α, VEGF, IL-6, IL-8, and TNFß were found to have significantly increased in the vitreous of PVR patients. CONCLUSION: Our study found that none of the circulating inflammation-related factors were changed in PVR or RRD patients, indicating the absence of a system inflammatory biomarkers to predict the development of proliferative vitreoretinopathy. As a supplement to previous research, the concentrations of PDGF-AA, TGF-α, VEGF, IL-6, IL-8, and TNFß were significantly upregulated in the vitreous of PVR patients. These factors should be considered for preventing PVR.


Asunto(s)
Mediadores de Inflamación/metabolismo , Vitreorretinopatía Proliferativa/inmunología , Cuerpo Vítreo/inmunología , Adulto , Anciano , Ensayo de Inmunoadsorción Enzimática , Membrana Epirretinal/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Desprendimiento de Retina/metabolismo , Desprendimiento de Retina/cirugía , Perforaciones de la Retina/patología , Vitrectomía/métodos
7.
Ophthalmology ; 127(2): 221-229, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31676123

RESUMEN

PURPOSE: Collapsin response-mediator protein 5 (CRMP5) immunoglobulin G (IgG) has been associated with paraneoplastic optic neuritis, vitritis, retinitis, or a combination thereof, but few reports of these findings exist in the literature. We reviewed the neuro-ophthalmic findings and visual outcomes in a large series of CRMP5 IgG-positive patients to characterize further its clinical phenotype and response to treatment. DESIGN: Retrospective case series. PARTICIPANTS: Seventy-six patients with CRMP5 autoimmunity examined at the Mayo Clinic, Rochester, Minnesota. METHODS: Single academic medical center chart review of all CRMP5 IgG-positive (serum titer, >1:240) patients seen between 2001 and 2017. MAIN OUTCOME MEASURES: Neuro-ophthalmic manifestations and outcomes of CRMP5 autoimmunity, coexisting neural autoantibody presence and paraneoplastic associations, and the impact of immunosuppressant therapy. RESULTS: Twenty-nine of 76 patients (38%) demonstrated neuro-ophthalmic manifestations. Of the 29 patients with neuro-ophthalmic findings, the median age was 67 years (range, 33-88 years) and 20 (69%) were women. Cancer was diagnosed in 62% of the patients (small-cell carcinoma in 83%). Neuro-ophthalmic symptoms occurred before the diagnosis of cancer in 72%. Seventeen of 29 patients (59%) showed ocular (i.e., anterior visual pathway or intraocular) manifestations; presenting median visual acuity was 20/50 (range, 20/20-counting fingers) and the final median visual acuity was 20/40 (range, 20/20-hand movements). Fourteen of 17 patients (82%) demonstrated optic neuropathy, with 12 of these patients also showing retinitis or uveitis. Three of 17 patients (18%) showed retinitis or uveitis without optic neuropathy. All 12 patients with optic neuropathy and a documented fundus examination at visual symptom onset demonstrated optic disc edema. No patients showed optic nerve enhancement on magnetic resonance imaging. Twelve of 29 patients (41%) demonstrated ocular motility dysfunction consisting of central nystagmus and diplopia. Among those receiving immunosuppressive therapy, visual function improved in 50%. CONCLUSIONS: In our cohort of 29 CRMP5 IgG-positive patients with neuro-ophthalmic manifestations, optic neuropathy presented with optic disc edema, often associated with uveitis, retinitis, or both. The combination of retinitis, vitritis, and optic disc edema without optic nerve enhancement should prompt serologic testing for CRMP5 IgG to expedite vision-sparing immunosuppressant therapy and a targeted search for a systemic cancer.


Asunto(s)
Autoanticuerpos/sangre , Oftalmopatías/inmunología , Hidrolasas/inmunología , Proteínas Asociadas a Microtúbulos/inmunología , Papiledema/inmunología , Síndromes Paraneoplásicos Oculares/inmunología , Retinitis/inmunología , Cuerpo Vítreo/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Oftalmopatías/diagnóstico , Oftalmopatías/tratamiento farmacológico , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Glucocorticoides/uso terapéutico , Humanos , Inmunoglobulina G/sangre , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Papiledema/diagnóstico , Papiledema/tratamiento farmacológico , Síndromes Paraneoplásicos Oculares/diagnóstico , Síndromes Paraneoplásicos Oculares/tratamiento farmacológico , Retinitis/diagnóstico , Retinitis/tratamiento farmacológico , Estudios Retrospectivos , Agudeza Visual/fisiología , Campos Visuales/fisiología , Cuerpo Vítreo/efectos de los fármacos , Cuerpo Vítreo/patología
8.
Cells ; 8(12)2019 11 27.
Artículo en Inglés | MEDLINE | ID: mdl-31783639

RESUMEN

Equine recurrent uveitis (ERU) is considered one of the most important eye diseases in horses and typically appears with relapsing inflammatory episodes without systemic effects. Various disorders have been described as an initial trigger, including infections. Independent of the initiating cause, there are numerous indications that ERU is an immune-mediated disease. We investigated whether neutrophil extracellular traps (NETs) are part of the ERU pathogenesis. Therefore, vitreous body fluids (VBF), sera, and histological sections of the eye from ERU-diseased horses were analyzed for the presence of NET markers and compared with horses with healthy eyes. In addition, NET formation by blood derived neutrophils was investigated in the presence of VBF derived from horses with healthy eyes versus ERU-diseased horses using immunofluorescence microscopy. Interestingly, NET markers like free DNA, histone-complexes, and myeloperoxidase were detected in higher amounts in samples from ERU-diseased horses. Furthermore, in vitro NET formation was higher in neutrophils incubated with VBF from diseased horses compared with those animals with healthy eyes. Finally, we characterized the ability of equine cathelicidins to induce NETs, as potential NET inducing factors in ERU-diseased horses. In summary, our findings lead to the hypothesis that ERU-diseased horses develop more NETs and that these may contribute to the pathogenesis of ERU.


Asunto(s)
Enfermedad Crónica/veterinaria , Trampas Extracelulares/inmunología , Caballos/inmunología , Uveítis , Cuerpo Vítreo/inmunología , Animales , Péptidos Catiónicos Antimicrobianos/inmunología , Uveítis/inmunología , Uveítis/veterinaria , Cuerpo Vítreo/patología , Catelicidinas
9.
Bioconjug Chem ; 30(11): 2782-2789, 2019 11 20.
Artículo en Inglés | MEDLINE | ID: mdl-31553572

RESUMEN

Treatment of ocular diseases associated with neovascularization currently requires frequent intravitreal injections of antivascular endothelial growth factor (anti-VEGF) therapies. Reducing the required frequency of anti-VEGF injections and associated clinical visits may improve patient adherence to the prescribed treatment regimen and improve outcomes. Herein, we explore conjugation of rabbit and fragment antibodies (Fab) to the biopolymer hyaluronic acid (HA) as a half-life modifying strategy, and assess the impact on Fab biophysical properties and vitreal pharmacokinetics. HA-Fab conjugates of three distinct molecular weights and hydrodynamic radii (RH) were assessed for in vivo pharmacokinetic performance relative to unconjugated Fab after intravitreal injection in rabbits. Covalent conjugation to HA did not significantly alter the thermal stability or secondary or tertiary structure, or diminish the potency of the Fab, thereby preserving its pharmacological properties. Conjugation to HA did significantly slow the in vivo clearance of Fab from the rabbit vitreous in an RH-dependent manner. Compared to free Fab (observed vitreal half-life of 2.8 days), HA-Fab conjugates cleared with observed half-lives of 7.6, 10.2, and 18.3 days for 40 kDa, 200 kDa, and 600 kDa HA conjugates, respectively. This work elucidates a possible strategy for long-acting delivery of proteins intended for the treatment of chronic posterior ocular diseases.


Asunto(s)
Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacocinética , Ácido Hialurónico/inmunología , Fragmentos Fab de Inmunoglobulinas/inmunología , Cuerpo Vítreo/metabolismo , Animales , Anticuerpos Monoclonales/administración & dosificación , Humanos , Inyecciones Intravítreas , Conejos , Distribución Tisular , Cuerpo Vítreo/inmunología
10.
Cutan Ocul Toxicol ; 38(4): 360-369, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31213109

RESUMEN

Purpose: To compare the efficacy of systemic and intravitreal infliximab treatments in an experimental endotoxin-induced uveitis (EIU) model. Methods: Twenty-eight white New Zealand rabbits were equally divided into 4 groups. Group 1 received an intravitreal injection of 0.1 cc saline, group 2 received an intravitreal injection of 2 µg/0.1 cc lipopolysaccharide (LPS), group 3 received an intravitreal injection of 2 µg/0.1 cc LPS and 2 mg/0.1 cc infliximab, and group 4 received intravitreal injection of 2 µg/0.1 cc LPS and intravenous injection of 5 mg/kg infliximab. Clinical, biochemical (aqueous and vitreous humour protein levels and TNF-α concentrations), and histopathological evaluations were performed. Results: The clinical examination score was lower in group 4 than in group 2 (p = 0.006); but there was no significant difference between groups 2 and 3 (Bonferroni correction, p = 0.016). No statistically significant difference was found among groups 2, 3, and 4 for aqueous humour protein levels (p > 0.05). Significantly higher aqueous humour concentrations of TNF-α was measured in group 3 comparing to both group 1 and 4 (p = 0.003 and p = 0.002, respectively). No significant difference was found in vitreous protein levels or TNF-α concentrations among all study groups (Bonferroni correction, p = 0.026 and p = 0.101, respectively). Histopathological evaluation of the uveal tissue and anterior chamber reaction revealed the highest inflammation in group 3 (p < 0.001). In group 4, histopathological evaluation of uveal tissue was lower than in groups 2 and 3 (p < 0.001 and p = 0.001, respectively); whereas there was no difference in anterior chamber inflammation between groups 2 and 4 (p = 1.00). Conclusion: Intravitreal 2 mg/0.1 cc infliximab injection exacerbated inflammation in an EIU model; whereas systemic infliximab treatment at a dose of 5 mg/kg suppressed inflammation effectively and rapidly.


Asunto(s)
Antiinflamatorios/administración & dosificación , Infliximab/administración & dosificación , Uveítis/tratamiento farmacológico , Animales , Cámara Anterior/efectos de los fármacos , Cámara Anterior/inmunología , Antiinflamatorios/efectos adversos , Proteínas del Ojo/metabolismo , Infliximab/efectos adversos , Inyecciones Intravenosas , Inyecciones Intravítreas , Lipopolisacáridos , Conejos , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Úvea/efectos de los fármacos , Úvea/patología , Uveítis/inducido químicamente , Uveítis/inmunología , Uveítis/patología , Cuerpo Vítreo/inmunología
11.
PLoS One ; 13(10): e0205292, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30296277

RESUMEN

PURPOSE: To investigate the immunopathogenesis of endophthalmitis, and determine if cytokine profiles could serve as biomarkers of disease severity in infectious endophthalmitis. MATERIALS AND METHODS: Vitreous samples of 46 patients clinically diagnosed as endophthalmitis (of which 25 were culture positive) and 20 non-infectious controls from patients with Retinal Detachment (RD) or diabetic retinopathy were included in the study. The cytokine and chemokine expression patterns of 40 immune mediators including 6 antiinflammatory cytokines, 15 proinflammatory cytokines, 9 Growth factors and 10 proinflammatory chemokines in the vitreous were were analyzed by multiplex cytokine immunoassay. In addition, significant immune mediators were correlated with initial and final visual acuity (VA). RESULTS: Our results demonstrated elevated expression of 16 mediators such as GCSF, GRO, IFN-γ, IL-1α, IL-1ß, IL-1 RA, IL-6, IL-8, IP-10, MCP-1, MCP-3, MIP-1α, IL-1ß, TGF-α, TNF-α in patients with culture positive endophthalmitis. Cytokine profile expression significantly differed between patients with proven endophthalmitis and the non-infectious controls in heat map analysis. PCoA plot indicated five mediators (IL-1RA, IL-6, IL-8, GRO, G-CSF) as biomarkers that could be Independent Predictors of Disease especially in culture negative cases. Correlation of cytokines with VA revealed strong association between the initial VA and intraocular levels of TGF-α, IL-1ß and IL-8 but there was no correlation with the severity or visual outcome of infection. CONCLUSION: In comparison to non-infectious ocular conditions, the pathogenesis of infectious endophthalmitis correlates with increased expression levels of IL-1RA, IL-6, IL-8, GRO, G-CSF. Understanding cytokine profiles in culture negative endophthalmitis patients could aid in therapy in non-responders to empirical antibiotic therapy.


Asunto(s)
Infecciones Bacterianas/inmunología , Retinopatía Diabética/inmunología , Endoftalmitis/inmunología , Desprendimiento de Retina/inmunología , Cuerpo Vítreo/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Infecciones Bacterianas/diagnóstico , Infecciones Bacterianas/metabolismo , Infecciones Bacterianas/patología , Biomarcadores/metabolismo , Quimiocina CXCL1/genética , Quimiocina CXCL1/inmunología , Niño , Preescolar , Retinopatía Diabética/diagnóstico , Retinopatía Diabética/metabolismo , Retinopatía Diabética/patología , Endoftalmitis/diagnóstico , Endoftalmitis/metabolismo , Endoftalmitis/patología , Femenino , Expresión Génica , Bacterias Gramnegativas/aislamiento & purificación , Bacterias Grampositivas/aislamiento & purificación , Factor Estimulante de Colonias de Granulocitos/genética , Factor Estimulante de Colonias de Granulocitos/inmunología , Humanos , Proteína Antagonista del Receptor de Interleucina 1/genética , Proteína Antagonista del Receptor de Interleucina 1/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Interleucina-8/genética , Interleucina-8/inmunología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Desprendimiento de Retina/diagnóstico , Desprendimiento de Retina/metabolismo , Desprendimiento de Retina/patología , Índice de Severidad de la Enfermedad , Agudeza Visual , Cuerpo Vítreo/metabolismo , Cuerpo Vítreo/patología
12.
Exp Eye Res ; 176: 141-146, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30006272

RESUMEN

A high prevalence of serum antiretinal antibodies (ARAs) in patients with uveitis has been previously described, though their clinical role remains elusive. Assessment of intraocular ARAs may provide further insight into the pathogenesis of diverse uveitis entities. In this study we investigate the prevalence of multiple specific anti-ocular antibodies (AOcAs), including ARAs, in intraocular fluid of patients with uveitis. Autoantibody profiling with 188 different ocular antigens was performed by a multiplex immunoassay with intraocular fluid samples of 76 patients with uveitis. Clinical data from uveitis patients were collected and statistical analyses were executed to evaluate associations between intraocular AOcAs and clinical characteristics. Controls consisted of 19 intraocular fluid samples from cataract patients. A spectrum of 22 different AOcAs was present in higher levels in patients with uveitis than in controls (p < 0.05), but in moderately elevated titers (<2x). High elevations of intraocular AOcAs in uveitis (>5x compared to cataract) were observed in varicella zoster virus-induced uveitis, multiple sclerosis-associated uveitis and patients with unexplained uveitis but positive quantiferon test. Presence of macular edema was associated with increased intraocular levels of tyrosinase antibodies. Our results show that patients with uveitis are characterized by the presence of a broad spectrum of moderately elevated levels of intraocular AOcAs, and high intraocular AOcA levels were found in several specific uveitis entities. This study favors secondary production of AOcAs and not their inciting role.


Asunto(s)
Humor Acuoso/inmunología , Autoanticuerpos/metabolismo , Autoantígenos/inmunología , Proteínas del Ojo/inmunología , Retina/inmunología , Uveítis/inmunología , Cuerpo Vítreo/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
13.
Immunol Invest ; 47(6): 615-631, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29733740

RESUMEN

PURPOSE: To assess cellular composition and local cytokine response in vitreous humor of tubercular uveitis. METHODS: Cells were collected from vitreous cassettes and peripheral blood of 8 tubercular uveitis and 5 control subjects, undergoing vitrectomy and analyzed by flow cytometry for cellular composition, activation status, proinflammatory cytokine expression, and uptake of TLR9 ligand, CpG ODN 2216. RESULTS: CD3 + T cells with equal proportion of CD4+ and CD8 + T cells formed major fraction of infiltrating cells. The vitreous humor showed higher expression of recent activation marker, CD69, and proinflammatory cytokines, IFN-γ and IL-17A, in CD4 + T cells as compared to peripheral blood. Lastly, intraocular CD4 + T cells showed reduced uptake of ODN 2216 than peripheral blood. CONCLUSIONS: Our results indicate that local antigenic stimuli trigger T cell infiltration and activation of CD4 + T cells that are hyporesponsive to TLR9 stimulation. These infiltrating T cells might be responsible in further aggravating ocular inflammation.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Activación de Linfocitos/inmunología , Tuberculosis Ocular/inmunología , Uveítis/inmunología , Cuerpo Vítreo/citología , Cuerpo Vítreo/inmunología , Adulto , Anciano , Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Femenino , Humanos , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Lectinas Tipo C/metabolismo , Masculino , Persona de Mediana Edad , Oligonucleótidos/metabolismo , Receptor Toll-Like 9/inmunología , Tuberculosis Ocular/microbiología , Uveítis/microbiología , Cuerpo Vítreo/microbiología , Adulto Joven
15.
Ocul Immunol Inflamm ; 26(1): 27-36, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-27467093

RESUMEN

PURPOSE: To study the role of regulatory T cells (Tregs) in patients with tubercular uveitis. METHODS: Frequencies of peripheral Tregs, Th1, Th17 cells, and intracellular cytokines were determined in 17 tubercular uveitis patients and 18 disease controls. Function of Tregs, Th1, and Th17 cells was assessed in vitro. Simultaneously, ocular levels of IFN-γ, IL-17A, IL-4, and IL-10 were also measured. RESULTS: Frequencies of peripheral Tregs in tubercular uveitis subjects were significantly lower compared with disease controls. Furthermore, expression of TGF-ß and IL-2Rα, but not CTLA4, was reduced in Tregs of the tubercular uveitis group. The tubercular uveitis group demonstrated heightened Th1, Th17 responses following in vitro stimulation with phorbol myristate acetate (PMA)/ionomycin. Interestingly, Treg suppression assay did not show a significant difference between the two groups. Ocular levels of IFN-γ, IL-17A, and IL-10 were also elevated in tubercular uveitis group. CONCLUSIONS: Low Treg frequency and hyporesponsive function contribute to proinflammatory responses manifesting at ocular level in tubercular uveitis.


Asunto(s)
Linfocitos T Reguladores/fisiología , Tuberculosis Ocular/inmunología , Uveítis/inmunología , Adolescente , Adulto , Anciano , Antígeno CTLA-4/metabolismo , Citocinas/metabolismo , Femenino , Humanos , Inmunofenotipificación , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Masculino , Persona de Mediana Edad , Factor de Crecimiento Transformador beta/metabolismo , Tuberculosis Ocular/cirugía , Uveítis/cirugía , Vitrectomía , Cuerpo Vítreo/inmunología , Adulto Joven
16.
BMJ Open ; 7(11): e014549, 2017 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-29150462

RESUMEN

PURPOSE: To determine the clinical relevance of vitreous biomarkers in patients with uveitis. DESIGN: Multicentre, prospective, observational study. SETTING: Uveitis outpatient clinics of two academic medical centres in Japan. PATIENT POPULATION: This study included 234 eyes of 191 patients with various uveitis aetiologies: definitive sarcoidosis (61 eyes of 46 patients), suspected sarcoidosis (60 eyes of 45 patients), intraocular tumour (34 eyes of 27 patients), viral infection (20 eyes of 18 patients), non-sarcoidosis (16 eyes of 16 patients) and unknown aetiology (43 eyes of 39 patients). OBSERVATION PROCEDURE: Vitreous samples (taken by pars planta vitrectomy) were analysed with flow cytometry, cytology and multiplex PCR analysis. MAIN OUTCOME MEASURES: The primary outcome measures were the diagnostic values of various biomarkers (T cells, B cells and pathogen DNA) in vitreous samples. The secondary outcome was visual acuity after vitrectomy. RESULTS: Sarcoidosis showed higher CD4/CD8 or CD4+ measurements than other aetiologies (p<0.01). In samples with viral infection, pathogen DNA was detected, and CD8+ counts were higher than the other aetiologies (p<0.01). Eyes with tumour had higher CD19+ (p<0.05). Non-sarcoidosis had lower CD4/CD8 than sarcoidosis, higher CD8+ than sarcoidosis and lower CD19+ than tumour (p<0.01). Unknown uveitis had lower CD4/CD8 than sarcoidosis (p<0.01), and higher CD4/CD8 than non-sarcoidosis, viral infection or tumour (p<0.001). Visual acuity improved after vitrectomy (p<0.001). CONCLUSIONS: Uveitis aetiologies had distinct vitreous biomarker profiles, especially of infiltrating lymphocytes. Analyses of CD4/CD8 ratio, T-lymphocyte and B-lymphocyte subset, and pathogen DNA in vitreous samples have good safety profiles and high diagnostic value for uveitis classification. TRIAL REGISTRATION NUMBER: UMIN000004980; Pre-results.


Asunto(s)
Relación CD4-CD8 , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/patología , Sarcoidosis/inmunología , Uveítis/clasificación , Cuerpo Vítreo/inmunología , Antígenos CD19 , Biomarcadores/análisis , Biomarcadores de Tumor/análisis , Neoplasias del Ojo/diagnóstico , Neoplasias del Ojo/inmunología , Citometría de Flujo , Humanos , Estudios Prospectivos , Reacción en Cadena en Tiempo Real de la Polimerasa , Sarcoidosis/diagnóstico , Sarcoidosis/microbiología , Sarcoidosis/virología , Sensibilidad y Especificidad , Vitrectomía , Cuerpo Vítreo/microbiología , Cuerpo Vítreo/patología , Cuerpo Vítreo/virología
17.
Clin Infect Dis ; 65(12): 2122-2125, 2017 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-29020238
18.
Cell Mol Life Sci ; 74(23): 4329-4337, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28913545

RESUMEN

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/patología
19.
Nat Microbiol ; 2: 17113, 2017 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-28715405

RESUMEN

Ebola virus (EBOV) persistence in asymptomatic humans and Ebola virus disease (EVD) sequelae have emerged as significant public health concerns since the 2013-2016 EVD outbreak in Western Africa. Until now, studying how EBOV disseminates into and persists in immune-privileged sites was impossible due to the absence of a suitable animal model. Here, we detect persistent EBOV replication coinciding with systematic inflammatory responses in otherwise asymptomatic rhesus monkeys that had survived infection in the absence of or after treatment with candidate medical countermeasures. We document progressive EBOV dissemination into the eyes, brain and testes through vascular structures, similar to observations in humans. We identify CD68+ cells (macrophages/monocytes) as the cryptic EBOV reservoir cells in the vitreous humour and its immediately adjacent tissue, in the tubular lumina of the epididymides, and in foci of histiocytic inflammation in the brain, but not in organs typically affected during acute infection. In conclusion, our data suggest that persistent EBOV infection in rhesus monkeys could serve as a model for persistent EBOV infection in humans, and we demonstrate that promising candidate medical countermeasures may not completely clear EBOV infection. A rhesus monkey model may lay the foundation to study EVD sequelae and to develop therapies to abolish EBOV persistence.


Asunto(s)
Infecciones Asintomáticas , Ebolavirus/fisiología , Fiebre Hemorrágica Ebola/virología , África Occidental , Animales , Antígenos CD , Antígenos de Diferenciación Mielomonocítica , Encéfalo/citología , Encéfalo/virología , Modelos Animales de Enfermedad , Ebolavirus/aislamiento & purificación , Epidídimo/citología , Epidídimo/virología , Fiebre Hemorrágica Ebola/sangre , Fiebre Hemorrágica Ebola/inmunología , Fiebre Hemorrágica Ebola/patología , Humanos , Macaca mulatta , Macrófagos/virología , Masculino , Replicación Viral , Cuerpo Vítreo/citología , Cuerpo Vítreo/inmunología , Cuerpo Vítreo/virología
20.
BMJ Case Rep ; 20172017 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-28438752

RESUMEN

IgG4-related disease (IgG4-RD) is a rare, chronic inflammatory condition that may involve nearly every organ system. Originally identified as a cause of autoimmune pancreatitis, its characteristic histological and clinical features have been found in a wide variety of inflammatory presentations, including the eye and orbit. Here we describe an example of a case of IgG4-RD initially presenting as scleritis and vitritis, with further progression to multifocal bilateral orbital involvement. Tissue biopsy of an orbital mass was highly characteristic of IgG4-RD histology and a rapid clinical response to corticosteroids was observed. This case highlights IgG4-RD as a rare cause of intraocular inflammation that may progress to involve the orbit.


Asunto(s)
Inmunoglobulina G/inmunología , Enfermedades Orbitales/inmunología , Escleritis/inmunología , Corticoesteroides/uso terapéutico , Anciano de 80 o más Años , Biopsia , Diagnóstico Diferencial , Progresión de la Enfermedad , Femenino , Humanos , Enfermedades Orbitales/diagnóstico , Enfermedades Orbitales/tratamiento farmacológico , Escleritis/diagnóstico , Escleritis/tratamiento farmacológico , Cuerpo Vítreo/inmunología
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