Sepideh Faez

Endogenous PMN sialidase activity exposes activation epitope on CD11b/CD18 which enhances its binding interaction with ICAM-1.

Diapedesis is a dynamic, highly regulated process by which leukocytes are recruited to inflammatory sites. We reported previously that removal of sialyl residues from PMNs enables these cells to become more adherent to EC monolayers and that sialidase activity within intracellular compartments of resting PMNs translocates to the plasma membrane following activation. We did not identify which surface adhesion molecules were targeted by endogenous sialidase. Upon activation, β2 integrin (CD11b/CD18) on the PMN surface undergoes conformational change, which allows it to bind more tightly to the ICAM‐1 and ICAM‐2 on the EC surface. Removal of sialyl residues from CD18 and CD11b, by exogenous neuraminidase or mobilization of PMN sialidase, unmasked activation epitopes, as detected by flow cytometry and enhanced binding to ICAM‐1. One sialidase isoform, Neu1, colocalized with CD18 on confocal microscopy. Using an autoperfused microflow chamber, desialylation of immobilized ICAM‐1 enhanced leukocyte arrest in vivo. Further, treatment with a sialidase inhibitor in vivo reversed endotoxin‐induced binding of leukocytes to ICAM‐1, thereby suggesting a role for leukocyte sialidase in the cellular arrest. These data suggest that PMN sialidase could be a physiologic source of the enzymatic activity that removes sialyl residues on β2 integrin and ICAM‐1, resulting in their enhanced interaction. Thus, PMN sialidase may be an important regulator of the recruitment of these cells to inflamed sites.

Treatment of seronegative spondyloarthropathy-associated uveitis with golimumab: retrospective case series.

not have a high resolution. The quality of the images was sufficient to visualize the iris abnormalities in the present cases, however. For cases in which more detailed images might be required, an infrared slit-lamp biomicroscope might prove more appropriate. The flexibility of the mobile camera allowed us to observe an infant and a small child, for whom slit-lamp microscopy and slit-lamp photography are more problematic. This system is also likely to prove beneficial for the observation of pupil shape before keratoplasty in bullous keratopathy patients with an unknown clinical history. Such observation may facilitate identification of a peaked pupil because of vitreous prolapse into the side port or the corneal or sclerocorneal tunnel. On the other hand, we found that although the shape of the pupil of patients with a scarred cornea was visible with the Meibopen camera, it was not as clear as that for individuals with an oedematous cornea (data not shown). Unlike the case of corneal oedema, the corneal opacity associated with a scarred cornea is not due to disorganization of collagen fibres but rather is the result either of abnormal collagen fibres secreted by fibroblasts or myofibroblasts, or of the loss of transparency of corneal stromal cells. The benefits of infrared observation are thus likely to be restricted to oedematous corneas. We have thus demonstrated the novel application of an infrared anterior segment camera to observation of the condition of the iris that is masked by the corneal opacity because of stromal oedema in patients with Peters’ anomaly. This non-invasive approach provides valuable clinical information and should prove applicable to other conditions characterized by corneal stromal oedema.

Discontinuous LYVE-1 expression in corneal limbal lymphatics: dual function as microvalves and immunological hot spots

LYVE‐1+ corneal lymphatics contribute to drainage and immunity. LYVE‐1 is widely accepted as the most reliable lymphatic marker because of its continuous expression in lymphatic endothelium. LYVE‐1 expression in corneal lymphatics has not been examined. In this study, we report intact CD31+ corneal lymphatic capillary endothelial cells that do not express LYVE‐1. The number of LYVE‐1‐ gaps initially increased until 8 wk of age but was significantly reduced in aged mice. C57BL/6 mice showed a notably higher number of the LYVE‐1‐/CD31+ lymphatic regions than BALB/c mice, which suggests a genetic predisposition for this histological feature. The LYVE‐1‐ lymphatic gaps expressed podoplanin and VE‐cadherin but not αSMA or FOXC2. Interestingly, the number of LYVE‐1‐ gaps in FGF‐2, but not VEGF‐A, implanted corneas was significantly lower than in untreated corneas. Over 70% of the CD45+ leukocytes were found in the proximity of the LYVE‐1‐ gaps. Using a novel in vivo imaging technique for visualization of leukocyte migration into and out of corneal stroma, we showed reentry of extravasated leukocytes from angiogenic vessels into newly grown corneal lymphatics. This process was inhibited by VE‐cadherin blockade. To date, existence of lymphatic valves in cornea is unknown. Electron microscopy showed overlapping lymphatic endothelial ends, reminiscent of microvalves in corneal lymphatics. This work introduces a novel corneal endothelial lymphatic phenotype that lacks LYVE‐1. LYVE‐1‐ lymphatic endothelium could serve as microvalves, supporting unidirectional flow, as well as immunological hot spots that facilitate reentry of stromal macropahges.—Nakao, S., Zandi, S., Faez, S., Kohno, R., Hafezi‐Moghadam, A. Discontinuous LYVE‐1 expression in corneal limbal lymphatics: dual function as microvalves and immunological hot spots. FASEB J. 26, 808–817 (2012). www.fasebj.org

Noninvasive molecular imaging reveals role of PAF in leukocyte-endothelial interaction in LPS-induced ocular vascular injury

Uveitis is a systemic immune disease and a common cause of blindness. The eye is an ideal organ for light‐based imaging of molecular events underlying vascular and immune diseases. The phospholipid platelet‐activating factor (PAF) is an important mediator of inflammation, the action of which in endothelial and immune cells in vivo is not well understood. The purpose of this study was to investigate the role of PAF in endothelial injury in uveitis. Here, we use our recently introduced in vivo molecular imaging approach in combination with the PAF inhibitors WEB 2086 (WEB) and ginkgolide B (GB). The differential inhibitory effects of WEB and GB in reducing LPS‐induced endothelial injury in the choroid indicate an important role for PAF‐like lipids, which might not require the PAF receptor for their signaling. P‐selectin glycoprotein ligand‐1‐mediated rolling of mouse leukocytes on immobilized P‐selectin in our autoperfused microflow chamber assay revealed a significant reduction in rolling velocity on the cells’ contact with PAF. Rolling cells that came in contact with PAF rapidly assumed morphological signs of cell activation, indicating that activation during rolling does not require integrins. Our results show a key role for PAF in mediating endothelial and leukocyte activation in acute ocular inflammation. Our in vivo molecular imaging provides a detailed view of cellular and molecular events in the complex physiological setting.—Garland, R. C., Sun, D., Zandi, S., Xie, F., Faez, S., Tayyari, F., Frimmel, S. A. F., Schering, A., Nakao, S., Hafezi‐Moghadam, A. Noninvasive molecular imaging reveals role of PAF in leukocyte‐endothelial interaction in LPS‐induced ocular vascular injury. FASEB J. 25, 1284–1294 (2011). www.fasebj.org

Accuracy of the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) As a Research Tool for Identification of Patients with Uveitis and Scleritis

Abstract Purpose: To report on the accuracy of the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for identifying patients with polymyalgia rheumatica (PMR) and concurrent noninfectious inflammatory ocular conditions in a large healthcare organization database. Methods: Queries for patients with PMR and uveitis or scleritis were executed in two general teaching hospitals’ databases. Patients with ocular infections or other rheumatologic conditions were excluded. Patients with PMR and ocular inflammation were identified, and medical records were reviewed to confirm accuracy. Results: The query identified 10,697 patients with the ICD-9-CM code for PMR and 4154 patients with the codes for noninfectious inflammatory ocular conditions. The number of patients with both PMR and noninfectious uveitis or scleritis by ICD-9-CM codes was 66. On detailed review of the charts of these 66 patients, 31 (47%) had a clinical diagnosis of PMR, 43 (65%) had noninfectious uveitis or scleritis, and only 20 (30%) had PMR with concurrent noninfectious uveitis or scleritis confirmed based on clinical notes. Conclusions: While the use of ICD-9-CM codes has been validated for medical research of common diseases, our results suggest that ICD-9-CM codes may be of limited value for epidemiological investigations of diseases which can be more difficult to diagnose. The ICD-9-CM codes for rarer diseases (PMR, uveitis and scleritis) did not reflect the true clinical problem in a large proportion of our patients. This is particularly true when coding is performed by physicians outside the area of specialty of the diagnosis.