Yuri Seo

Dry Eye-Induced CCR7+CD11b+ Cell Lymph Node Homing Is Induced by COX-2 Activities

PURPOSE We aimed to determine the role of CCR7+CD11b+ cell lymph node (LN) homing and T-cell differentiation in dry eye (DE)-induced immunopathogenesis and investigate the therapeutic effects of cyclooxygenase-2 (COX-2) and prostaglandin E2/eicosanoid-prostanoid (PGE2/EP) inhibitors against DE. METHODS Six-week-old female C57BL/6 mice were housed in a controlled-environment chamber and administered topical selective COX-2 inhibitors or EP2 antagonists. Expression of major histocompatibility complex (MHC)-IIhigh, CD11b+, CCR7+, IFN-γ+, IL-17+, and CD4+ in the corneas and draining LNs was evaluated using flow cytometry. Mixed lymphocyte reactions (MLRs) with carboxyfluorescein diacetate succinimidyl ester labeling and intracellular cytokine staining were used to verify DE-induced corneal dendritic cell function. mRNA expression of COX-2, EPs, and proinflammatory cytokines in ocular surface was evaluated using quantitative RT-PCR and immunohistochemical staining. RESULTS Dry eye significantly increased MHC-IIhighCD11b+ and CCR7+CD11b+ cells in the cornea and LNs, and MLR revealed CCR7+CD11b+ cells from DE corneas stimulated IL-17+CD4+ cell proliferation. mRNA levels of COX-2, EP2, IFN-γ, TNF-α, IL-6, and IL-17 were significantly higher in DE ocular surface but were suppressed by topical COX-2 inhibitors and EP2-specific blockers. Immunohistochemical staining showed COX-2 and matrix metalloproteinase expression in DE corneal epithelia that was diminished by both topical treatments. Furthermore, both topical treatments significantly reduced frequencies of MHC-IIhigh, CD11b+, and CCR7+CD11b+ cells in the corneas and LNs, but also IL-17+CD4+ cells in LNs. CONCLUSIONS Topical COX-2/EP2 treatment reduces CCR7+CD11b+ cells on the ocular surface with inhibition of cellular LN homing and suppresses Th17 immune response, suggesting the COX-2/PGE2/EP axis contributes to immuno-inflammatory pathogenesis on the ocular surface and may be a novel therapeutic target in DE.

Intravitreal Bevacizumab for Traumatic Choroidal Rupture.

Purpose To report a case of visual loss associated with traumatic choroidal rupture after blunt ocular trauma that was successfully treated with an early intravitreal bevacizumab injection despite the absence of choroidal neovascularization (CNV). Case Report A 14-year-old boy presented with visual disturbance in his left eye after sustaining an ocular contusion 4 weeks earlier. The best-corrected visual acuity (BCVA) in the left eye was 20/50. Funduscopic examination revealed macular choroidal rupture accompanied by subretinal hemorrhage. Optical coherence tomography (OCT) showed accumulation of subretinal fluid around a disrupted retinal pigment epithelium/Bruch membrane complex extending into the juxtafoveolar area, but there was no active leakage suggestive of CNV on fluorescein angiography. Intravitreal bevacizumab (1.25 mg) injection was performed to treat persistent serous retinal detachment at macula causing visual loss. There was a reduction of subretinal fluid and concomitant improvement of BCVA to 20/30 within 1 week after intravitreal bevacizumab injection. The BCVA recovered to 20/25 in the left eye after 4 weeks, and only a minimal amount of residual fluid remained according to OCT. Complete resolution of subretinal fluid was observed by OCT at the 6-week follow-up examination, and BCVA improved to 20/20. Good visual acuity (20/20) and stable macula were maintained in the left eye at 1 year of follow-up without recurrence of subretinal fluid accumulation or hemorrhage and CNV. There were no ocular or systemic complications associated with intravitreal bevacizumab injection. Conclusions Early intravitreal bevacizumab injection could be an effective treatment option for patients with vision loss associated with traumatic choroidal rupture and subretinal fluid within the posterior pole before development of CNV.

Expression of Lymphangiogenic Markers in Rejected Human Corneal Buttons after Penetrating Keratoplasty

Abstract Purpose: To investigate the extent and distribution of lymphangiogenesis in the rejected corneal graft, we determined the expression of several lymphangiogenic markers in rejected human corneal buttons. Material and methods: Thirty-four corneal buttons were obtained from patients who underwent re-keratoplasty for graft rejection after penetrating keratoplasty. All corneas showed signs of rejection, such as, sudden mutton-fat keratic precipitates (KPs) or lines before re-keratoplasty. The corneas were halved, and one half was used for immunostaining and the other half was used for RT-PCR. Expression of vascular endothelial growth factor (VEGF)-A, VEGF-C, VEGF-D, VEGFR-2, VEGFR-3, LYVE-1 and podoplanin were measured as lymphangiogenic markers. Four non-operated normal corneas were used as controls. Results: Numerous podoplanin positive cells were found in the anterior and posterior stroma. However, LYVE-1 positive mature lymphatics were found only in herpetic keratitis (HK)-induced graft rejection, and not in pseudophakic bullous keratopathy (PBK). RT-PCR showed that levels of VEGF-A, VEGF-C, VEGFR-2, and VEGFR-3 mRNAs were elevated in rejected corneal buttons versus the non-operated control corneas. Based upon the pre-keratoplasty pathologic conditions, HK cases showed higher levels of VEGF-A and VEGFR-2 than PBK. The mRNA ratios (keratoplastic cornea/normal cornea) for VEGF-A and VEGFR-2 were 8.9 and 5.8, respectively. Conclusions: The results suggested that the VEGF-A and the VEGFR-2 may be a more important pathway for lymphangiogenesis in rejected corneal grafts than the VEGFR-3. In addition, organized lymphangiogenesis is more prominent in HK than PBK.

YAG Laser Membranotomy for Subinternal Limiting Membrane Hemorrhage.

PurposeTo report the use of neodymium:yttrium-aluminum-garnet (Nd:YAG) laser internal limiting membranotomy to successfully treat the first reported case of subinternal limiting membrane (sub-ILM) hemorrhage that developed after coil embolization of a cerebral aneurysm. Case ReportA 59-year-old Korean woman visited our clinic complaining of central scotoma in her left eye, which developed shortly after stent-assisted coil embolization of an unruptured internal carotid artery aneurysm. Fundus examination revealed a sub-ILM hemorrhage in her left eye, and after 2 days, a Nd:YAG laser membranotomy was performed with a single 4.5-mJ burst. There was a marked reduction in the sub-ILM hemorrhage 1 day after Nd:YAG laser membranotomy, and after 1 month, her best-corrected visual acuity improved to 20/20, with complete resolution of the sub-ILM hemorrhage. ConclusionsSub-ILM hemorrhage can develop after coil embolization of a cerebral aneurysm, and Nd:YAG laser internal limiting membranotomy can be a useful noninvasive treatment alternative to surgical intervention.

Sphingosine-1-phosphate is involved in inflammatory reactions in patients with Graves’ orbitopathy

ObjectiveGraves’ orbitopathy (GO) is initiated by excessive amount of various inflammatory mediators produced by orbital fibroblasts. This study aimed to assess the crucial role of sphingosine-1-phosphate (S1P) in the inflammatory process of GO.MethodsOrbital adipose/connective tissue samples were obtained from 10 GO patients and 10 normal control individuals during surgery. Primary orbital fibroblast culture was done. After the expression of S1P receptors and sphingosine kinase (SphK) was assessed with the treatment of interleukin (IL)-1β, we evaluated the expression of pro-inflammatory factors [intercellular adhesion molecule-1 (ICAM-1), cyclooxygenase-2 (COX-2) and IL-6] after treating S1P. S1P receptor antagonists and SphK 1 inhibitor were pretreated and the expression of the pro-inflammatory factors was assessed.ResultsIL-1β exacerbated the inflammatory process by enhancing the expression of S1P receptors and SphK in GO orbital fibroblasts. IL-1β also induced the expressions of ICAM-1, COX-2, and IL-6 in GO orbital fibroblasts, and these expressions were effectively inhibited by S1P receptor antagonists and SphK1 inhibitor.ConclusionS1P has an important role in the pathological inflammatory process of GO, which is mediated through the SphK1-S1P- S1P receptor pathway. SphK1 inhibitors and S1P receptors or antagonists could be potential approaches for controlling the inflammatory process of GO.

Central Retinal Vein Occlusion Associated with Ulcerative Colitis.

Purpose To report a case of central retinal vein occlusion without macular edema associated with ulcerative colitis and its novel treatment with intravitreal dexamethasone. Case Report A 40-year-old man with ulcerative colitis presented with sudden visual disturbances. An initial fundus examination showed subtle yellow-to-white patches within the inner retina of the right eye superotemporal to the fovea. There were intraretinal hemorrhages and cotton-wool spots within the superior vascular arcade and nasal to the optic disc. Despite initiation of systemic corticosteroids, 2 weeks later there was an increase in retinal hemorrhages, formation of cotton wool spots, and development of optic disc swelling in the right eye. The patient was eventually diagnosed with nonischemic central retinal vein occlusion associated with ulcerative colitis. He received sustained-release intravitreal dexamethasone, which led to the resolution of retinal hemorrhage, optic disc swelling, and cotton-wool spots. Three months after the injection, retinal hemorrhages were not detectable. However, ocular coherence imaging showed marked thinning of the inner retina at the locations that were previously hyper-reflective. Conclusions Central retinal vein occlusion is an uncommon ophthalmologic manifestation associated with ulcerative colitis. Injection of intravitreal dexamethasone could be a viable treatment option in these patients even without the presence of macular edema.

Reply to a letter to the editor: Diabetic Retinal Pigment Epitheliopathy: Fundus Autofluorescence and Spectral-Domain Optical Coherence Tomography Findings.

We thank Uzun et al. for their valuable comments on our article [1]. We reported that eyes with diabetic retinal pigment epitheliopathy (DRPE) showed decreased visual acuity, thinning of the outer retina, and thickened choroid than did eyes with proliferative diabetic retinopathy (PDR). Choroidal thickness (CT), which was one of the clinical parameters evaluated in our study, could be influenced by many factors, as Uzun et al. have pointed out [2]. As our study was limited by its retrospective design, local/systemic and environmental factors affecting CT could not be evaluated owing to limited data availability. Axial length is highly correlated with the spherical equivalent [3]; however, we did not evaluate the axial lengths in the DRPE and PDR groups. As we mentioned in the Results section of the manuscript, there were no differences in the baseline characteristics, including the spherical equivalent, presence of hypertension, and insulin use, between the DRPE and PDR groups. Therefore, we speculated that the axial lengths would not be different between the groups. Moreover, the body mass index values were not statistically different between the DRPE and PDR groups (21.92 ± 1.45 vs. 21.79 ± 2.59 kg/m, P = 0.902); however, this result was not presented in our manuscript. To minimize the effect of diurnal variation in CT, the CT must be measured at the same time of the day. However, information regarding the time of measurement was not available because of our retrospective study design. A previous prospective study showed that the difference in mean CT did not exceed 10 μm from 9:00 AM to 6:00 PM [4]. As our retrospective study showed a relatively large difference in CT between the DRPE and PDR groups (94.68 ∼ 113.56 μm), it may be appropriate to assume that CT was larger in the DRPE group than in the PDR group. Compliance with ethical standards