Akiko Iwata

Jagged1 Suppresses Collagen-Induced Arthritis by Indirectly Providing a Negative Signal in CD8+ T Cells

Distinct Notch ligands possess a characteristic ability in terms of functional T cell differentiation. However, the precise role or the therapeutic potential of each Notch ligand in autoimmune diseases is largely unknown. In this study, we examined whether Jagged1 modulates a collagen-induced rheumatoid arthritis (CIA) model by altering T cell responses. The injection of a soluble Jagged1-encoding plasmid, sJag1-P, before or even after initial type II collagen (CII) immunization suppressed the disease severity of CIA. However, this treatment did not suppress CII-specific CD4+ T cell proliferation and CII-specific Ab production. Depletion of either CD4+ or CD8+ T cells ameliorated CIA severity and sJag1-P further improved CIA in CD4+ but not CD8+ T cell-depleted mice. Injection of OVA and Jagged1-encoding plasmids inhibited proliferation of OVA-specific granzyme B-producing CD8+ T cells, although Jagged1 could not directly inhibit CD8+ T cell proliferation in vitro. The blockade of Jagged1 by an anti-Jagged1 Ab exacerbated CIA, whereas this effect was not observed in the absence of CD8+ T cells. These data indicate that Jagged1 is able to deliver an indirect negative signal into CD8+ T cells in vivo, which suggests its therapeutic potential in the treatment of CD8+ T cell-mediated diseases, including rheumatoid arthritis.

Diurnal variations in luminal and stromal areas of choroid in normal eyes

Aims To determine the diurnal variations of the luminal and stromal areas of the choroid in normal eyes. Methods This was a prospective observational study of 38 eyes of 38 normal subjects. The blood pressure, heart rate, intraocular pressure and enhanced depth imaging optical coherence tomographic (EDI-OCT) images were recorded every 3u2005hours between 6:00 and 21:00u2005hours. The horizontal EDI-OCT images of the subfoveal choroid were converted to binary images. The central choroidal thickness (CCT), total cross-sectional choroidal area, the luminal areas, stromal areas and the ratio of luminal area to total choroidal area (L/C ratio) were determined. Results There were significant diurnal variations in the CCT, total choroidal area, luminal area and L/C ratio with the maximum values at 6:00u2005hours and the minimum values at 15:00u2005hours (p<0.001 for the CCT, p=0.011 for the total choroidal area, p<0.001 for the luminal area and p=0.014 for the L/C ratio). There was no significant variation in the stromal area (p=0.216). The range of fluctuation in the CCT was significantly correlated with that in the luminal area and the total choroidal area (p<0.001). However, there was no significant correlation between the fluctuation range in the CCT and that in the stromal area (p=0.095). There was no statistical relationship between the systemic parameters and the choroidal parameters. Conclusions The changes in the luminal area are most likely responsible for the diurnal change in the CCT and subfoveal choroidal area. Trial registration number UMIN000019060, Pre-results.

Binarization of enhanced depth imaging optical coherence tomographic images of an eye with Wyburn-Mason syndrome: a case report

BackgroundTo report a thicker choroid and larger choroidal luminal area in an eye with Wyburn-Mason syndrome. To the best of our knowledge, this is the first report demonstrating an increase in the choroidal thickness and the luminal area in a case of Wyburn-Mason syndrome. In addition, we report the changing appearance of retinal arteriovenous malformations over a 16-year period.Case presentationA 27-year-old woman, who was diagnosed with Wyburn-Mason syndrome at age 11xa0years, visited our clinic. Her best-corrected visual acuity was 20/12.5 in the right eye and light perception in the left eye. Severely dilated, tortuous vascular loops were distributed from the optic disc over all four quadrants of the left fundus. The vascular loops in some areas were more dilated and tortuous than 16xa0years earlier. Optical coherence tomography (OCT) showed retinal edema with cystic changes and enlarged choroidal vessel lumens in the left eye. The subfoveal choroidal thickness was manually measured by the caliper function in the enhanced depth imaging OCT (EDI-OCT) images. Binarization of the EDI-OCT images was performed with publicly accessible ImageJ software. The examined area of the subfoveal choroid was 1,500xa0μm wide, and the dark areas representing the luminal areas were traced by the Niblack method. After determining the distance of each pixel, the luminal area was automatically calculated. The subfoveal choroidal thickness was 250xa0μm in the right eye and 462xa0μm in the left eye. The luminal area of the 1,500-μm-wide subfoveal choroid was computed to be 307,165.6xa0μm2 in the right eye and 545,780.7xa0μm2 in the left eye.ConclusionsThe EDI-OCT images showed a thicker choroid, and binarization of the EDI-OCT images showed that the luminal areas were significantly larger in the affected eye, suggesting a dilatation of the choroidal vessels. The results demonstrated that conversion of EDI-OCT images to binary images was a useful method to quantify the choroidal structure.

Abrogation of Rbpj Attenuates Experimental Autoimmune Uveoretinitis by Inhibiting IL-22-Producing CD4(+) T Cells

Experimental autoimmune uveoretinitis (EAU) is an organ-specific T cell-mediated disease induced by immunizing mice with interphotoreceptor retinoid binding protein (IRBP). Autoaggressive CD4+ T cells are the major pathogenic population for EAU. We investigated the contribution of Notch signaling in T cells to EAU pathogenesis because Notch signaling regulates various aspects of CD4+ T cell functions. Rbpj is required for Notch signaling, and Rbpj deficiency in T cells inhibited EAU disease severity. The amelioration of EAU in T cell-specific Rbpj-deficient mice correlated with low levels of IL-22 production from CD4+ T cells, although IRBP-specific CD4+ T cell proliferation and Th17 differentiation were unaffected. Administration of recombinant IL-22 during the late phase, but not the early phase, of EAU increased EAU clinical scores in T cell-specific Rbpj-deficient mice. Notch inhibition in mice immunized with IRBP with a γ-secretase inhibitor (GSI) suppressed EAU progression, even when GSI was administered as late as 13 days after IRBP immunization. Our data demonstrate that Rbpj/Notch-mediated IL-22 production in T cells has a key pathological role in the late phase of EAU, and suggest that Notch blockade might be a useful therapeutic approach for treating EAU.

Selenide Targets to Reperfusing Tissue and Protects It From Injury.

Objectives:Since blood selenium levels decrease after ischemia and reperfusion injury, and low blood selenium correlates with negative outcome, we designed and performed experiments to determine how selenium distribution is affected by ischemia reperfusion injury. Furthermore, we tested whether different chemical forms of selenium would affect outcome after ischemia and reperfusion injury. We also examined the metabolic effects of selenide administration. Design:Laboratory investigation. Setting:Animal research laboratory. Subjects:Adult male C57BL/6 mice. Interventions:To determine selenium localization, we administered tracer doses of radioactive selenium 75 in the form of selenite or selenide and measured blood and tissue selenium levels after ischemia and reperfusion injury. Anesthetized mice were subjected to myocardial ischemia reperfusion injury (coronary artery occlusion for 60u2009min followed by 5u2009min of reperfusion after occlusion was removed) or hindlimb ischemia reperfusion injury (left leg tourniquet for 90u2009min followed by 5u2009min reperfusion after tourniquet removal). To determine whether exogenous selenium administration could reduce ischemia reperfusion injury, we synthesized and administered sodium hydroselenide and sodium selenite solutions (0.05–2.4u2009mg/kg). Solutions were administered at the end of coronary artery occlusion but before reperfusion. In order to determine the metabolic effects of selenide administration, we exposed mice to hydrogen selenide gas (0–5 ppm) mixed into air (20.95% oxygen) for up to 3 hours. Measurements and Main Results:In targeting assays, we measured blood and tissue selenium levels. We observed that blood selenium decreases after myocardial ischemia reperfusion and displays an inverse correlation with injury severity; selenium accumulation in heart correlates directly with injury severity. We also measured whether oxidized selenium, selenite, and reduced selenium, selenide, would target to injured heart tissue in myocardial ischemia reperfusion and injured leg muscle in a hindlimb model of ischemia reperfusion. Only selenide targets to injured tissue. We also measured damage after myocardial ischemia reperfusion injury using morphometry, neutrophil accumulation, blood cardiac troponin levels, and echocardiography and observed in all assays that selenide reduced damage to the heart; selenite was not effective. And finally, to assay metabolism, we measured oxygen consumption, carbon dioxide production, and body core temperature before, during, and after hydrogen selenide administration. All measurements indicate that selenide decreases metabolism. Conclusions:Selenide targets to reperfusing tissue and reduces reperfusion injury perhaps by affecting oxygen metabolism.

Correction: Iodide Protects Heart Tissue from Reperfusion Injury.

The authors wish to amend the Competing Interests statement for this article, which should have included additional information in relation to potential competing interests relevant to this work. The authors apologize for this omission and revise the Competing Interests statement to read as below. n nThe authors have read PLOS ONEs competing interests policy, and they have the following to declare: Dr. Roth is President, Founder, and a member of the Board of Directors for Faraday Pharmaceuticals, a company dedicated to promoting iodide therapy for ischemic injury. Dr. Roth and his co-authors, Drs. Iwata and Morrison, own stock in the company. Additionally, the authors are named on pending patent applications for iodide therapy (Use of Halogen Compounds For the Treatment and Prevention of Heart Attack and Ischemic Injury). This does not affect or alter our adherence to all of PLOS ONEs policies on sharing data and materials.

A case of secondary glaucoma studied by optical coherence tomography of the anterior ocular segment

PURPOSEnTo compare slit lamp biomicroscopy or gonioscopy with optical coherence tomography (OCT) and to assess the efficacy of OCT in a case of anterior segment disease.nnnCASEnA 74-year-old male who had bilateral keratoconus. The left eye was aphakic, and a penetrating keratoplasty was performed on it, as well as Nd:YAG laser capsulotomy. The prognosis was good in the early postoperative stage. But 6 months postoperatively, we could not control the intraocular pressure and judged that a second operation might be needed. Before the operation, we tried to get images of the anterior segment of this eye using slit lamp biomicroscopy, gonioscopy, and OCT.nnnRESULTSnFindings obtained by OCT were more useful than those obtained by slit lamp biomicroscopy or gonioscopy to determine the method of operation.nnnDISCUSSIONnThis case substantiates the view that observation of the anterior ocular segment by OCT is useful for such cases, because in cases of corneal disease we can not get much information about the deep and endothelial side of the cornea from slit lamp biomicroscopy.