Search Results (5)

The purpose of this project was to define gene expression changes associated with the acquisition and loss of resilience to diabetic retinopathy (RDR) in individual retinal cell types. A non-immune form of type 1 diabetes mellitus (DM) was induced by injecting male C57Bl6J mice with streptozotocin. Single-cell RNA sequencing was performed on retinas from mice that experienced DM for 5 or 15 days, along with retinas from age-matched, non-DM mice. The resulting data sets were analyzed to identify DM-associated differentially expressed genes and pathway enrichments after each duration of DM. We observed that acquisition of RDR, previously shown to arise after 5 days of DM was linked to altered expression of genes in a subset of retinal cells, mainly Müller cells. Pathway analysis indicated enhancement of numerous modes of protection, including reinforced neurovascular and structural homeostasis through phagocytosis, integrin signaling, and interferon-mediated defense. After 15 days of DM, when we previously showed that RDR is waning this pro-protection surge in gene expression subsided. We conclude that a duration of DM that is too short to cause diabetic retinopathy (DR) nonetheless evoked a profound change in the gene expression profile within a subset of retinal cell types. The nature and timing of this molecular shift indicated that it was not the preamble to DM-related damage that eventually develops. Rather, DM engaged numerous defense programs within Müller cells. The temporal alignment between RDR and activation of Müller cell-based defense provides a molecular foundation for the retina’s transient ability to remain healthy in the face of DM. Full article

Diabetic retinopathy (DR) remains the leading cause of blindness in the working-age population. Its progression causes gradual damage to corneal nerves, resulting in decreased corneal sensitivity (CS) and disruption of anterior-eye-surface homeostasis, which is clinically manifested by increased ocular discomfort and dry eye disease (DED). This study included 52 DR patients and 52 sex- and age-matched controls. Ocular Surface Disease Index (OSDI) survey, tear film-related parameters, CS, and in vivo corneal confocal microscopy (IVCM) of the subbasal plexus were performed. Furthermore, all patients underwent tear sampling for neurotrophin and cytokine analysis. OSDI scores were greater in DR patients than in controls (p = 0.00020). No differences in the Schirmer test score, noninvasive tear film-break-up time (NIBUT), tear meniscus or interferometry values, bulbar redness, severity of blepharitis or meibomian gland loss were found. In the DR group, both the CS (p < 0.001), and the scotopic pupil diameter (p = 0.00008) decreased. IVCM revealed reduced corneal nerve parameters in DR patients. The stage of DR was positively correlated with the OSDI (Rs = +0.51, 95% CI: + 0.35–+0.64, p < 0.001) and negatively correlated with IVCM corneal nerve parameters and scotopic pupillometry (Rs = −0.26, 95% CI: −0.44–−0.06, p = 0.0097). We found negative correlations between the OSDI and IVCM corneal innervation parameters. The DR group showed lower tear film-brain-derived neurotrophic factor (BDNF) levels (p = 0.0001) and no differences in nerve growth factor (NGF)-β, neurotrophin (NT)-4, vascular endothelial growth factor (VEGF), interleukin (IL)-1β, IL-4, IL-5, IL-6, or IL-12 concentrations. Tumor necrosis factor (TNF)-α, IL-2, IL-8, IL-10, granulocyte macrophage colony-stimulating factor (GM-CSF), and interferon (IFN)-γ levels were decreased among patients with DR. Corneal innervation defects have a direct impact on patients’ subjective feelings. The evolution of DR appears to be associated with corneal nerve alterations, emphasizing the importance of IVCM. Full article

Various immune mediators identified to date are associated with the development of advanced forms of diabetic retinopathy (DR), such as proliferative DR and diabetic macular edema, although the exact pathophysiological mechanisms of early stages of DR such as simple DR remain unclear. We determined the immune mediator profile in the aqueous humor of eyes with simple DR. Fifteen eyes of fifteen patients with simple DR were studied. Twenty-two eyes of twenty-two patients with cataracts and no DR served as controls. Undiluted aqueous humor samples were collected, and a cytometric bead array was used to determine the aqueous humor concentrations of 32 immune mediators comprising 13 interleukins (IL), interferon-γ, interferon-γ-inducible protein-10 (IP-10), monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-1α, MIP-1β, regulated on activation, normal T cell expressed and secreted (RANTES), monokine induced by interferon-γ, basic fibroblast growth factor (bFGF), Fas ligand, granzyme A, granzyme B, interferon-inducible T-cell alpha chemoattractant (ITAC), fractalkine, granulocyte macrophage colony-stimulating factor, granulocyte colony-stimulating factor (G-CSF), vascular endothelial growth factor (VEGF), angiogenin, tumor necrosis factor-α, and CD40 ligand. Among the 32 immune mediators, 10 immune mediators, including bFGF, CD40 ligand, fractalkine, G-CSF, IL-6, IL-8, MIP-α, MIP-1β, and VEGF, showed significantly higher aqueous humor concentrations and the Fas ligand had significantly lower concentration (p < 0.05) in eyes with simple DR compared with control eyes. Of these 10 cytokines with significant concentration alteration, protein–protein interaction analysis revealed that 8 established an intricate interaction network. Various immune mediators may contribute to the pathogenesis of simple DR. Attention should be given to the concentrations of immune mediators in ocular fluids even in simple DR. Large-scale studies are warranted to assess whether altered aqueous humor concentrations of these 10 immune mediators are associated with an increased risk of progression to advanced stages of DR. Full article

Prevalence of dengue retinopathy varies across epidemics, with the disease linked to circulation of dengue virus serotype 1 (DENV-1). The retinal pigment epithelium has been implicated in the pathology. We investigated infectivity, molecular response, and barrier function of epithelial cells inoculated with DENV strains from different outbreaks in Singapore. Monolayers of human retinal pigment epithelial cells (multiple primary cell isolates and the ARPE-19 cell line) were inoculated with six DENV strains, at multiplicity of infection of 10; uninfected and recombinant strain-infected controls were included where relevant. Infectivity and cell response were assessed primarily by RT-qPCR on total cellular RNA, and barrier function was evaluated as electrical resistance across monolayers. Higher viral RNA loads were measured in human retinal pigment epithelial cells infected with DENV-1 strains from the 2005 Singapore epidemic, when retinopathy was prevalent, versus DENV-1 strains from the 2007 Singapore epidemic, when retinopathy was not observed. Type I interferon (IFN) transcripts (IFN-β and multiple IFN-stimulated genes) were up-regulated, and impact on barrier function was more pronounced, for cells infected with DENV-1 strains from the 2005 versus the 2007 Singapore epidemics. Aside from serotype, strain of DENV may determine the potential to induce retinal pathology. Identification of molecular markers of disease-associated DENV strains may provide insights into the pathogenesis of dengue retinopathy. Full article

This retrospective cohort study aims to investigate interferon (IFN)-associated retinopathy incidence in patients with chronic hepatitis C virus (HCV) infection treated with pegylated interferon (PegIFN) plus ribavirin (RBV). We selected 1688 patients undergoing PegIFN/RBV therapy for HCV (HCV-treated cohort), 3376 patients not receiving HCV treatment (HCV-untreated cohort) and 16,880 controls without HCV (non-HCV cohort) from the Taiwan Longitudinal Health Insurance Database. The patients were frequency-matched by age, sex, and index date at a 1:2:10 ratio, and followed up until the end of 2013. Cox proportional hazard regression models were used to compare the incidences of any retinal vascular events, including subtypes, among the three cohorts. Compared with the non-HCV cohort, the HCV-treated cohort had a significantly increased risk of retinopathy (hazard ratio (HR) = 4.98, 95% confidence interval (CI): 2.02–12.3). The risk was particularly prominent for retinal hemorrhage (HR = 12.7, 95% CI: 3.78–42.9). When the HCV-untreated cohort was used as the reference, the aforementioned HRs increased to 9.02 (95% CI: 3.04–26.8) and 32.3 (95% CI: 3.94–265), respectively. This study suggested that PegIFN/RBV therapy significantly increased the risk of retinal hemorrhage but not retinal vascular occlusions in the HCV-treated cohort. Full article