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Corneal endothelial cells (CEnCs) regulate corneal hydration and maintain tissue transparency through their barrier and pump function. However, these cells exhibit limited regenerative capacity following injury. Currently, corneal transplantation is the only established therapy for restoring endothelial function, and there are no pharmacologic interventions available for restoring endothelial function. This study investigated the efficacy of the neuropeptide α-melanocyte-stimulating hormone (α-MSH) in promoting endothelial regeneration during the critical window between ocular injury and the onset of endothelial decompensation using an established murine model of injury using transcorneal freezing. Local administration of α-MSH following injury prevented corneal edema and opacity, reduced leukocyte infiltration, and limited CEnC apoptosis while promoting their proliferation. These results suggest that α-MSH has a proregenerative and cytoprotective function on CEnCs and shows promise as a therapy for the prevention and management of corneal endothelial dysfunction.
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Córnea , Edema Corneal , alfa-MSH , Femenino , Embarazo , Animales , Ratones , Ratones Endogámicos BALB C , Humanos , Línea Celular , Córnea/citología , Células Endoteliales , Edema Corneal/tratamiento farmacológico , Edema Corneal/patología , Conservación de Tejido , alfa-MSH/uso terapéutico , Citoprotección , Infiltración Neutrófila , Monocitos/metabolismo , Macrófagos/metabolismo , Cicatrización de Heridas/efectos de los fármacosRESUMEN
Highly inflamed and neovascularized corneal graft beds are known as high-risk (HR) environments for transplant survival. One of the primary factors leading to this rejection is reduction in the suppressive function of regulatory T cells (Treg). Our results show that myeloid-derived suppressor cells (MDSC) counteract interleukin-6-mediated Treg dysfunction by expressing interleukin-10. Additionally, MDSC maintain forkhead box P3 stability and their ability to suppress IFN-γ+ Th1 cells. Administering MDSC to HR corneal transplant recipients demonstrates prolonged graft survival via promotion of Treg while concurrently suppressing IFN-γ+ Th1 cells. Moreover, MDSC-mediated donor-specific immune tolerance leads to long-term corneal graft survival as evidenced by the higher survival rate or delayed survival of a second-party C57BL/7 (B6) graft compared to those of third-party C3H grafts observed in contralateral low-risk or HR corneal transplantation of BALB/c recipient mice, respectively. Our study provides compelling preliminary evidence demonstrating the effectiveness of MDSC in preventing Treg dysfunction, significantly improving graft survival in HR corneal transplantation, and showing promising potential for immune tolerance induction.
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PURPOSE: Vision loss associated with opacification of the cornea is one of the leading causes of blindness globally. However, the epidemiological data pertaining to the demographics, associated etiological causes and reduced vision in corneal opacity patients continue to be sparse. This study assesses the case frequencies, underlying etiologies, and vision outcomes in patients diagnosed with corneal opacity, in the United States. DESIGN: Retrospective cohort study PARTICIPANTS: Patients in the IRIS® Registry (Intelligent Research in Sight) who were diagnosed with corneal opacity between January 1st, 2013, and November 30th, 2020. METHODS: The IRIS Registry contains demographic and clinical data of 79,887,324 patients who presented to eye clinics during the study period. We identified patients with corneal opacity using International Classification of Disease (ICD) codes (ICD-9, and -10) of "371" (corneal scar) and "H17" (corneal opacity), respectively. The analyzed data included demographic parameters included age, sex, race, ethnicity, and geographical location. We evaluated clinical data including laterality, etiology, disease descriptors, and best-corrected visual acuity (VA) up to 1 year before the onset (± 30 days), at the time of diagnosis, and at one year following diagnosis (± 30 days). MAIN OUTCOME MEASURES: Case frequencies, etiology, and vision outcomes in patients diagnosed with corneal opacity. RESULTS: We identified 5,220,382 patients who were diagnosed with corneal opacity and scars using H17 (ICD-10) and 371.0 (ICD-9) codes over seven years. The case frequency of corneal opacity during the study period was 6,535 cases per 100,000 patients (6.5%). The mean age of the patients was 63.36±18.14 years and the majority were female (57.6%). In the cohort, 38.39% and 30.00% of patients had bilateral and unilateral corneal opacity, respectively. Most of the patients were White (69.13%), followed by Black or African American (6.84%), Asian (2.45%), American Indian or Alaska Native(0.34%), Native Hawaii or other Pacific Islander(0.19%). Among the patients with corneal opacity, 7.34% had Hispanic or Latino ethnicity. The primary etiologies associated with corneal opacity included corneal dystrophies (64.66%) followed by edema (18.25%), ulcer (7.78%), keratoconjunctivitis (7.18%), degeneration (5.62%), neovascularization (6.27%), and trauma (5.28%). Visual acuity of the patients significantly worsened due to corneal opacity (0.46±0.74 logMAR; â¼20/58 in Snellen) and did not improve to the baseline (0.37±0.68 logMAR, â¼20/46 in Snellen) post-management (0.43±0.77 logMAR, â¼20/54 in Snellen). The multiple linear regression analysis showed worse vision outcomes in females (compared to males), and Asian, Black or African American, and American Indian or Alaska Native (compared to White) patients. Additionally, worse vision outcomes were observed in patients with opacity associated with corneal malformation, degenerative disorders, edema, injury, and ulcer compared to those with hereditary corneal dystrophy. CONCLUSIONS: Our study shows that the corneal opacity was diagnosed in 6.5% of the patients in the IRIS Registry and it was primarily associated with corneal dystrophies. The final vision outcomes in corneal opacity patients were significantly worse compared to baseline. The worse vision outcomes were associated with sociodemographic differences that might be associated with disparities in access, utilization, and care patterns.
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Regulatory T cells (Tregs) play a critical role in maintaining immune homeostasis, and their dysfunction is implicated in the pathogenesis of various autoimmune disorders, including dry eye disease (DED). Treg dysfunction in DED allows T-helper cell 17 (Th17) mediated chronic inflammation at the ocular surface. In this study, the factors causing Treg dysfunction in DED were investigated. We observed reduced expression of Treg functional markers - FoxP3, CD25, and CTLA-4 in the cells isolated from DED mice (DED Tregs). Additionally, DED Tregs showed increased expression levels of receptors for pro-inflammatory cytokine receptors, namely IL-6R, IL-17RA, and IL-23R. An increased expression level of pro-inflammatory cytokine receptors was observed on exposing Tregs isolated from naïve mice (NTregs) to IL-6 or IL-17, but not IL-23, with a concomitant downregulation of FoxP3, CD25, and CTLA-4 in these cells. Furthermore, among these cytokines, IL-6 induced the most pronounced loss of Treg mediated suppression of Th17 proliferation and IL-10 secretion. In vitro and in vivo blockade of IL-6 effectively restored function in DED Tregs, leading to enhanced suppressive function against proliferating Th17 cells and ameliorating disease severity. In conclusion, this study provides insights into mechanisms of Treg dysregulation in DED, specifically delineating the effect of Th17-associated cytokines, with IL-6 emerging as the critical factor inducing Treg dysfunctionality. These findings highlight the potential for developing novel therapeutic interventions for DED through restoration of immunosuppressive function of Tregs.
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Modelos Animales de Enfermedad , Síndromes de Ojo Seco , Factores de Transcripción Forkhead , Interleucina-6 , Ratones Endogámicos C57BL , Linfocitos T Reguladores , Animales , Linfocitos T Reguladores/inmunología , Síndromes de Ojo Seco/metabolismo , Síndromes de Ojo Seco/inmunología , Ratones , Interleucina-6/metabolismo , Factores de Transcripción Forkhead/metabolismo , Células Th17/inmunología , Antígeno CTLA-4/metabolismo , Femenino , Citometría de Flujo , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Desecación , Células CultivadasRESUMEN
Myeloid derived suppressor cells (MDSCs) are a heterogenous population of immature hematopoietic precursors with known immunoregulatory functions. The immunosuppressive role of MDSCs has been highlighted in several inflammatory ophthalmic disorders; however, their therapeutic application in suppressing the immune-mediated changes in dry eye disease (DED) has not been studied. We observed significant reduction in antigen presenting cell (APC) frequencies and their maturation in the presence of MDSCs. Moreover, co-culturing MDSCs with T helper 17 cells (Th17) resulted in reduced Th17 frequencies and their IL-17 expression. On the contrary, MDSCs maintained regulatory T cell frequencies and enhanced their function in-vitro. Furthermore, we delineated the role of interleukin-10 (IL-10) secreted by MDSCs in their immunoregulatory functions. We confirmed these results by flow cytometry analysis and observed that treatment with MDSCs in DED mice effectively suppressed the maturation of APCs, pathogenic Th17 response, and maintained Treg function and significantly ameliorated the disease. The results in this study highlight the potential therapeutic application of MDSCs in treating refractory DED.
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Modelos Animales de Enfermedad , Síndromes de Ojo Seco , Citometría de Flujo , Ratones Endogámicos C57BL , Células Supresoras de Origen Mieloide , Linfocitos T Reguladores , Células Th17 , Animales , Células Supresoras de Origen Mieloide/inmunología , Síndromes de Ojo Seco/inmunología , Síndromes de Ojo Seco/metabolismo , Ratones , Células Th17/inmunología , Linfocitos T Reguladores/inmunología , Células Presentadoras de Antígenos/inmunología , Femenino , Progresión de la Enfermedad , Interleucina-10/metabolismo , Células Cultivadas , Técnicas de CocultivoRESUMEN
Corneal transplantation is the most common form of solid tissue grafting, with an approximately 80% to 90% success rate. However, success rates may decline when donor tissues are derived from patients with a history of diabetes mellitus (DM). To evaluate the underlying immunopathologic processes that cause graft rejection, we used streptozotocin-induced type 1 DM (DM1) and transgenic Lepob/ob type 2 DM (DM2) diabetic murine models as donors and nondiabetic BALB/c as recipients. DM resulted in an increased frequency of corneal antigen-presenting cells (APCs) with an acquired immunostimulatory phenotype. Following transplantation, recipients that received either type of diabetic graft showed increased APC migration and T helper type 1 alloreactive cells, impaired functional regulatory T cells, and graft survival. Insulin treatment in streptozotocin-induced diabetic mice led to an increased tolerogenic profile of graft APC, lower T helper type 1 sensitization, and a higher frequency of functional regulatory T cells with high suppressive capacity, reflected in increased graft survival. We conclude that both DM1 and DM2 in donors can impact corneal APC functional phenotype, rendering the tissue more immunogenic and thereby increasing the risk of graft failure.
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Trasplante de Córnea , Diabetes Mellitus Experimental , Animales , Ratones , Diabetes Mellitus Experimental/cirugía , Diabetes Mellitus Experimental/patología , Estreptozocina , Córnea , Células Presentadoras de AntígenosRESUMEN
Corneal transplantation is the most common form of tissue transplantation. The success of corneal transplantation mainly relies on the integrity of corneal endothelial cells (CEnCs), which maintain tissue transparency by pumping out excess water from the cornea. After transplantation, the rate of CEnC loss far exceeds that seen with normal aging, which can threaten sight. The underlying mechanisms are poorly understood. Alpha-melanocyte-stimulating hormone (α-MSH) is a neuropeptide that is constitutively found in the aqueous humor with both cytoprotective and immunomodulatory effects. The curent study found high expression of melanocortin 1 receptor (MC1R), the receptor for α-MSH, on CEnCs. The effect of α-MSH/MC1R signaling on endothelial function and allograft survival in vitro and in vivo was investigated using MC1R signaling-deficient mice (Mc1re/e mice with a nonfunctional MC1R). Herein, the results indicate that in addition to its well-known immunomodulatory effect, α-MSH has cytoprotective effects on CEnCs after corneal transplantation, and the loss of MC1R signaling significantly decreases long-term graft survival in vivo. In conclusion, α-MSH/MC1R signaling is critical for CEnC function and graft survival after corneal transplantation.
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Córnea/inmunología , Trasplante de Córnea , Células Endoteliales/inmunología , Supervivencia de Injerto/inmunología , Transducción de Señal/inmunología , alfa-MSH/inmunología , Animales , Línea Celular Transformada , Córnea/patología , Femenino , Supervivencia de Injerto/genética , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Receptor de Melanocortina Tipo 1/genética , Receptor de Melanocortina Tipo 1/inmunología , Transducción de Señal/genética , alfa-MSH/genéticaRESUMEN
Exposure to mustard agents, such as sulfur mustard (SM) and nitrogen mustard (NM), often results in ocular surface damage. This can lead to the emergence of various corneal disorders that are collectively referred to as mustard gas keratopathy (MGK). In this study, we aimed to develop a mouse model of MGK by using ocular NM exposure, and describe the subsequent structural changes analyzed across the different layers of the cornea. A 3 µL solution of 0.25 mg/mL or 5 mg/mL NM was applied to the center of the cornea via a 2-mm filter paper for 5 min. Mice were evaluated prior to and after exposure on days 1, 3, 7, 14, and 28 for 4 weeks using slit lamp examination with fluorescein staining. Anterior segment optical coherence tomography (AS-OCT) and in vivo confocal microscopy (IVCM) tracked changes in the epithelium, stroma, and endothelium of the cornea. Histologic evaluation was used to examine corneal cross-sections collected at the completion of follow-up. Following exposure, mice experienced central corneal epithelial erosion and thinning, accompanied by a decreased number of nerve branches in the subbasal plexus and increased activated keratocytes in the stroma in both dosages. The epithelium was recovered by day 3 in the low dose group, followed by exacerbated punctuate erosions alongside persistent corneal edema that arose and continued onward to four weeks post-exposure. The high dose group showed persistent epitheliopathy throughout the study. The endothelial cell density was reduced, more prominent in the high dose group, early after NM exposure, which persisted until the end of follow-up, along with increased polymegethism and pleomorphism. Microstructural changes in the central cornea at 4 weeks post-exposure included dysmorphic basal epithelial cells and reduced epithelial thickness, and in the limbal cornea included decreased cellular layers. We present a mouse model of MGK using NM that successfully replicates ocular injury caused by SM in humans who have been exposed to mustard gas.
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Enfermedades de la Córnea , Edema Corneal , Úlcera de la Córnea , Gas Mostaza , Humanos , Animales , Ratones , Gas Mostaza/toxicidad , Mecloretamina/toxicidad , Córnea/patología , Enfermedades de la Córnea/inducido químicamente , Enfermedades de la Córnea/patología , Úlcera de la Córnea/patología , Trastornos de la Visión/patología , Microscopía ConfocalRESUMEN
Exposure to mustard agents, such as sulfur mustard (SM) and nitrogen mustard (NM), often results in ocular surface damage. This can lead to the emergence of various corneal disorders that are collectively referred to as mustard gas keratopathy (MGK). In this study, we aimed to develop a mouse model of MGK by using ocular NM exposure, and describe the subsequent structural changes analyzed across the different layers of the cornea. A 3⯵L solution of 0.25â¯mg/mL NM was applied to the center of the cornea via a 2-mm filter paper for 5â¯min. Mice were evaluated prior to and after exposure on days 1 and 3, and weekly for 4 weeks using slit lamp examination with fluorescein staining. Anterior segment optical coherence tomography (AS-OCT) and in vivo confocal microscopy (IVCM) tracked changes in the epithelium, stroma, and endothelium of the cornea. Histologic evaluation and immunostaining were used to examine corneal cross-sections collected at the completion of follow-up. A biphasic ocular injury was observed in mice exposed to NM, most prominent in the corneal epithelium and anterior stroma. Following exposure, mice experienced central corneal epithelial erosions and thinning, accompanied by a decreased number of nerve branches in the subbasal plexus and increased activated keratocytes in the stroma. The epithelium was recovered by day 3, followed by exacerbated punctuate erosions alongside persistent stromal edema that arose and continued onward to four weeks post-exposure. The endothelial cell density was reduced on the first day after NM exposure, which persisted until the end of follow-up, along with increased polymegethism and pleomorphism. Microstructural changes in the central cornea at this time included dysmorphic basal epithelial cells, and in the limbal cornea included decreased cellular layers and p63+ area, along with increased DNA oxidization. We present a mouse model of MGK using NM that successfully replicates ocular injury caused by SM in humans who have been exposed to mustard gas. Our research suggests DNA oxidation contributes to the long-term effects of nitrogen mustard on limbal stem cells.
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Pigment epithelium-derived factor (PEDF) is a widely expressed 50-kDa glycoprotein belonging to the serine protease inhibitor family, with well-established anti-inflammatory functions. Recently, we demonstrated the immunoregulatory role played by PEDF in dry eye disease (DED) by suppressing the maturation of antigen-presenting cells at the ocular surface following exposure to the desiccating stress. In this study, we evaluated the effect of PEDF on the immunosuppressive characteristics of regulatory T cells (Tregs), which are functionally impaired in DED. In the presence of PEDF, the in vitro cultures prevented proinflammatory cytokine (associated with type 17 helper T cells)-induced loss of frequency and suppressive phenotype of Tregs derived from normal mice. Similarly, PEDF maintained the in vitro frequency and enhanced the suppressive phenotype of Tregs derived from DED mice. On systemically treating DED mice with PEDF, moderately higher frequencies and significantly enhanced suppressive function of Tregs were observed in the draining lymphoid tissues, leading to the efficacious amelioration of the disease. Our results demonstrate that PEDF promotes the suppressive capability of Tregs and attenuates their type 17 helper T-cell-mediated dysfunction in DED, thereby playing a role in the suppression of DED.
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Antiinflamatorios/farmacología , Síndromes de Ojo Seco/tratamiento farmacológico , Proteínas del Ojo/farmacología , Factores de Crecimiento Nervioso/farmacología , Serpinas/farmacología , Linfocitos T Reguladores/efectos de los fármacos , Células Th17/efectos de los fármacos , Animales , Células Presentadoras de Antígenos/efectos de los fármacos , Citocinas/genética , Modelos Animales de Enfermedad , Proteínas del Ojo/metabolismo , Femenino , Ratones Endogámicos C57BL , Factores de Crecimiento Nervioso/metabolismo , Fenotipo , Serpinas/metabolismoRESUMEN
Effector Th17 cells, including IFN-γ-IL-17+ (eTh17) and IFN-γ+IL-17+ (eTh17/1) subsets, play critical pathogenic functions in the induction of autoimmunity. As acute inflammation subsides, a small proportion of the effectors survive and convert to memory Th17 cells (mTh17), which sustain chronic inflammation in autoimmune diseases. Herein, we investigated the differential contributions of eTh17 versus eTh17/1 to the memory pool using an experimental model of ocular autoimmune disease. Our results show that adoptive transfer of Tbx21-/- CD4+ T cells or conditional deletion of Tbx21 in Th17 cells leads to diminished eTh17/1 in acute phase and functionally compromised mTh17 in chronic phase. Further, adoptive transfer of disease-specific eTh17/1, but not eTh17, leads to generation of mTh17 and sustained ocular inflammation. Collectively, our data demonstrate that T-bet-dependent eTh17/1 cells generated during the acute inflammation are the principal effector precursors of pathogenic mTh17 cells that sustain the chronicity of autoimmune inflammation.
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Enfermedades Autoinmunes , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares , Enfermedades Autoinmunes/patología , Humanos , Inflamación/patología , Interferón gamma , Interleucina-17/genética , Células TH1 , Células Th17RESUMEN
PURPOSE: To describe the characteristics of neurotrophic keratopathy (NK) in the United States. DESIGN: Retrospective database study. PARTICIPANTS: Thirty-one thousand nine hundred fifteen eyes of 27 483 patients with a diagnosis of NK. METHODS: Retrospective analysis of visits associated with a diagnosis of NK between 2013 and 2018 using the American Academy of Ophthalmology Intelligent Research in Sight (IRIS®) Registry. MAIN OUTCOME MEASURES: Demographic information, prevalence, visual acuity (VA), concomitant diagnosis and procedure codes, and risk factors impacting VA most closely after NK onset date. RESULTS: Mean ± standard deviation (SD) age at initial diagnosis of NK was 68.0 ± 16.0 years, and 58.91% of patients were women (P < 0.0001). Presentation was unilateral in 58.14%, bilateral in 16.13%, and unspecified in 25.73%. Average 6-year prevalence of NK in the IRIS Registry was 21.34 cases per 100 000 patients. Mean ± SD VA was 0.60 ± 0.79 logMAR before diagnosis and 0.88 ± 0.94 logMAR after diagnosis (P < 0.0001). Most common concomitant diagnoses included herpetic keratitis (33.70%), diabetes (31.59%), and corneal dystrophy (14.28%). Common procedures for NK management included the use of amniotic membrane (29.90%), punctal plugs (29.65%), and bandage contact lenses (22.67%). Age, male sex, Black race, Hispanic or Latino ethnicity, unilateral involvement, concomitant diagnoses of diabetes, corneal transplantation, and herpetic keratitis were associated significantly with worse VA. CONCLUSIONS: Based on the IRIS Registry, the prevalence of NK is 21.34 cases per 100 000 patients. Visual acuity was significantly worse after NK diagnosis compared with other time points. Neurotrophic keratopathy was associated most commonly with herpetic keratitis and diabetes. Worse VA in patients with NK was associated with several demographic characteristics, history of diabetes, corneal transplantation, and herpetic keratitis.
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Distrofias Hereditarias de la Córnea , Queratitis Herpética , Enfermedades del Nervio Trigémino , Humanos , Masculino , Femenino , Estados Unidos/epidemiología , Estudios Retrospectivos , Sistema de RegistrosRESUMEN
PURPOSE: To determine the efficacy of local (subconjunctival and topical) bevacizumab (Avastin) treatment in patients undergoing vascularized high-risk corneal transplantation. DESIGN: Pilot, prospective, randomized, double-blind, placebo-controlled clinical trial conducted at 5 clinical centers in the United States, India, and Brazil. PARTICIPANTS: Patients aged > 18 years undergoing high-risk penetrating keratoplasty, defined as corneal neovascularization (NV) in 1 or more quadrants ≥2 mm from the limbus or extension of corneal NV to the graft-host junction in a previously failed graft. METHODS: Patients were randomized to receive subconjunctival bevacizumab (2.5 mg/0.1 ml) or placebo at the time of surgery, followed by topical bevacizumab (10 mg/ml) or topical placebo, administered 4 times per day for 4 weeks. MAIN OUTCOME MEASURE: The 52-week endothelial immune rejection rate. RESULTS: Ninety-two patients were randomized to receive bevacizumab (n = 48) or control (n = 44). The 52-week endothelial rejection rate was 10% in the bevacizumab group and 19% in the control group (P = 0.20). Post hoc, extended follow-up at the lead study site showed an endothelial rejection rate of 3% in the bevacizumab group and 38% in the control group (P = 0.003). Treatment with bevacizumab was found to have a hazard ratio of 0.15 (95% confidence interval, 0.03-0.65, P = 0.01) in a post hoc Cox regression analysis. CONCLUSIONS: In patients undergoing vascularized high-risk corneal transplantation, there was no statistically significant difference in the rate of endothelial rejection at 1 year in the bevacizumab treatment group compared with the control group. This study may have been underpowered to detect a difference between treatment groups, and taken together, our data suggest that, in the current trial design, bevacizumab has a positive but not (yet) significant effect on endothelial rejection.
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Neovascularización de la Córnea , Trasplante de Córnea , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Bevacizumab/uso terapéutico , Neovascularización de la Córnea/tratamiento farmacológico , Neovascularización de la Córnea/cirugía , Humanos , Estudios Prospectivos , Factor A de Crecimiento Endotelial VascularRESUMEN
Despite constant exposure to various environmental stimuli, the ocular surface remains intact and uninflamed while maintaining the transparency of the cornea and its visual function. This 'immune privilege' of the ocular surface is not simply a result of the physical barrier function of the mucosal lining but, more importantly, is actively maintained through a variety of immunoregulatory mechanisms that prevent the disruption of immune homeostasis. In this review, we focus on essential molecular and cellular players that promote immune quiescence in steady-state conditions and suppress inflammation in disease-states. Specifically, we examine the interactions between the ocular surface and its local draining lymphoid compartment, by encompassing the corneal epithelium, corneal nerves and cornea-resident myeloid cells, conjunctival goblet cells, and regulatory T cells (Treg) in the context of ocular surface autoimmune inflammation (dry eye disease) and alloimmunity (corneal transplantation). A better understanding of the immunoregulatory mechanisms will facilitate the development of novel, targeted immunomodulatory strategies for a broad range of ocular surface inflammatory disorders.
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Trasplante de Córnea , Síndromes de Ojo Seco , Conjuntiva , Córnea , Humanos , InflamaciónRESUMEN
Regulatory T cells (Tregs) are crucial mediators of immune homeostasis. They regulate immune response by suppressing inflammation and promoting self-tolerance. In addition to their immunoregulatory role, a growing body of evidence highlights the dynamic role of Tregs in angiogenesis, the process of forming new blood vessels. Although angiogenesis is critically important for normal tissue regeneration, it is also a hallmark of pathological processes, including malignancy and chronic inflammation. Interestingly, the role of Tregs in angiogenesis has been shown to be highly tissue- and context-specific and as a result can yield either pro- or antiangiogenic effects. For these reasons, there is considerable interest in determining the molecular underpinnings of Treg-mediated modulation of angiogenesis in different disease states. The present review summarizes the role of Tregs in angiogenesis and mechanisms by which Tregs regulate angiogenesis and discusses how these mechanisms differ in homeostatic and pathological settings.
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Neoplasias/inmunología , Neovascularización Patológica/inmunología , Neovascularización Fisiológica/inmunología , Linfocitos T Reguladores/inmunología , Animales , Humanos , Inflamación/inmunología , Modelos Animales , Neoplasias/irrigación sanguínea , Transducción de Señal/inmunología , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Autoimmune uveitis is a sight-threatening ocular inflammatory condition in which the retina and uveal tissues become a target of autoreactive immune cells. While microglia have been studied extensively in autoimmune uveitis, their exact function remains uncertain. The objective of the current study was to determine whether resident microglia are necessary and sufficient to initiate and amplify retinal inflammation in autoimmune uveitis. In this study, we clearly demonstrate that microglia are essential for initiating infiltration of immune cells utilizing a murine model of experimental autoimmune uveoretinitis (EAU) and the recently identified microglia-specific marker P2ry12. Initiating disease is the primary function of microglia in EAU, since eliminating microglia during the later stages of EAU had little effect, indicating that the function of circulating leukocytes is to amplify and sustain destructive inflammation once microglia have triggered disease. In the absence of microglia, uveitis does not develop, since leukocytes cannot gain entry through the blood-retinal barrier, illustrating that microglia play a critical role in regulating infiltration of inflammatory cells into the retina.
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Enfermedades Autoinmunes/etiología , Microglía/fisiología , Enfermedades de la Retina/inmunología , Uveítis/inmunología , Animales , Modelos Animales de Enfermedad , Femenino , Ratones , Compuestos Orgánicos , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidoresRESUMEN
The prevalence as well as the severity of dry eye disease increase with age. Memory T helper 17 (Th17) cells (CD4+IL-17A+CD44+) drive the chronic and relapsing course of dry eye disease. Here, we investigated the contribution of memory Th17 cells to age-related dry eye disease, and evaluated memory Th17 cell depletion with anti-IL-15 antibody as a strategy to abrogate the severe exacerbations of dry eye disease observed in aged mice. After initial exposure to desiccating stress, aged mice maintained higher frequencies of memory Th17 cells in the draining lymph nodes relative to young mice. Upon secondary exposure to desiccating stress, aged mice developed more severe corneal epitheliopathy than young mice, which is associated with increased local frequencies of Th17 cells (CD4+IL-17A+). Treatment with anti-IL-15 antibody decreased the enlarged memory Th17 pool in aged mice to frequencies comparable with young mice. Furthermore, anti-IL-15-treated mice showed significantly reduced conjunctival infiltration of Th17 cells and lower corneal fluorescein staining scores compared with saline-treated control mice. Our data suggest that age-related increases in the memory Th17 compartment predispose aged mice toward the development of severe corneal epithelial disease after exposure to a dry environment. Selectively targeting memory Th17 cells may be a viable therapeutic approach in the treatment of age-related dry eye disease.
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Síndromes de Ojo Seco/inmunología , Memoria Inmunológica/inmunología , Células Th17/inmunología , Envejecimiento/inmunología , Envejecimiento/patología , Animales , Síndromes de Ojo Seco/patología , Femenino , Ratones , Ratones Endogámicos C57BLRESUMEN
Neuroinflammation plays an important role in the pathogenesis of ocular surface disease, including dry eye disease (DED), but little is known about the contribution of substance P (SP) to DED. In this study, we investigated the expression of SP at the ocular surface and evaluated its effect on maturation of antigen-presenting cells (APCs), the key cell component involved in the induction of type 17 helper T-cell (Th17) response in DED. The effect of topical blockade of SP signaling was further investigated using neurokinin-1 receptor (NK1R) inhibitors on APC maturation, Th17 cell activation, and disease severity in a mouse model of DED. The results demonstrate that SP is constitutively expressed at the ocular surface, and trigeminal ganglion neurons are the major source of SP in DED. SP derived from trigeminal ganglion enhanced the expression of major histocompatibility complex class II maturation marker by bone marrow-derived dendritic cells, an effect that is abrogated by blockade of SP signaling using NK1R antagonist spantide. Finally, using a well-established murine model of DED, topical treatment of DED mice with NK1R antagonists CP-99,994 and L-733,060 suppressed APC acquisition of major histocompatibility complex class II, reduced Th17 cell activity, and ameliorated DED severity. These findings are of translational value, as they suggest that antagonizing NK1R-mediated SP signaling may be an effective strategy in suppressing Th17-mediated ocular surface disease.
Asunto(s)
Células Presentadoras de Antígenos/inmunología , Modelos Animales de Enfermedad , Síndromes de Ojo Seco/prevención & control , Antagonistas del Receptor de Neuroquinina-1/farmacología , Receptores de Neuroquinina-1/química , Células Th17/inmunología , Animales , Células Presentadoras de Antígenos/efectos de los fármacos , Córnea/efectos de los fármacos , Córnea/inmunología , Síndromes de Ojo Seco/inmunología , Síndromes de Ojo Seco/metabolismo , Síndromes de Ojo Seco/patología , Femenino , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunología , Ratones , Ratones Endogámicos C57BL , Células Th17/efectos de los fármacosRESUMEN
Substance P (SP) is a tachykinin neuropeptide, implicated in the pathogenesis of various inflammatory conditions and a critical mediator in pain transmission. Recently, the role of SP was described in the pathogenesis of dry eye disease (DED) through its role in the maturation of antigen-presenting cells at the ocular surface after exposure to desiccating stress. However, the effect of SP on regulatory T cells (Tregs), which are functionally impaired in DED, remains unclear. This study examined the phenotypic and functional changes in Tregs in response to SP in DED. The in vitro cultures of normal Tregs in the presence of SP led to a significant reduction in both Treg frequencies and their suppressive function, which was prevented by the addition of an SP receptor (neurokinin-1 receptor) antagonist. Furthermore, in vivo treatment with the neurokinin-1 receptor antagonist in DED mice effectively restored Treg function, suppressed pathogenic T helper 17 response, and significantly ameliorated the disease. Our results show that a significant increase in SP levels promotes Treg dysfunction in DED, and blockade of SP effectively restores Treg function and suppresses DED severity.
Asunto(s)
Síndromes de Ojo Seco/inmunología , Síndromes de Ojo Seco/metabolismo , Receptores de Neuroquinina-1/metabolismo , Linfocitos T Reguladores/inmunología , Animales , Femenino , Ratones , Ratones Endogámicos C57BL , Antagonistas del Receptor de Neuroquinina-1/farmacología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/metabolismoRESUMEN
The cornea actively maintains its own avascular status to preserve its ultimate optical function. This corneal avascular state is also defined as "corneal angiogenic privilege", which results from a critical and sensitive balance between anti-angiogenic and pro-angiogenic mechanisms. In our review, we aim to explore the complex equilibrium among multiple mediators which prevents neovascularization in the resting cornea, as well as to unveil the evolutive process which leads to corneal angiogenesis in response to different injuries.