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H Xu, JV Forrester, J Liversidge, IJ Crane; Leukocyte Trafficking in Experimental Autoimmune Uveitis: Breakdown of Blood-retinal-barrier and Up-regulation of Cellular Adhesion Molecules . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1565.
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Purpose: To clarify the order of events occurring in the breakdown of the blood-retina barrier (BRB) in experimental autoimmune uveitis (EAU) and to study the relationships between increased vascular permeability, up-regulation of endothelial cell adhesion molecules, and leukocyte adhesion and infiltration during EAU. Methods: B10.RIII mice were immunized with human IRBP peptide 161-180. Changes in the retinal vasculature were examined at different days post-immunization (pi). Evans blue was administered intravenously to assess vascular permeability. Expression of adhesion molecules ICAM-1, VCAM-1, P-selectin, E-selectin, and PECAM-1 were evaluated by in vivo antibody administration. Lymphocytes from inguinal lymph nodes of normal and peptide-immunized mice were labelled in vitro with calcein-AM, infused intravenously into similarly treated syngeneic mice. Retinal flat mounts were observed 24 hours later by confocal microscopy to determine lymphocyte adhesion and infiltration. Results: The first observation of an increase in vascular permeability occurred at day 7 pi and was restricted to focal areas of the retinal venules of the inner vascular plexus. This progressively extended to the outer vascular plexus at day 9 pi. Specific adhesion of leukocytes to the endothelium of retinal venules was first observed at day 6 pi. Leukocyte extravasation into the retinal parenchyma from these vessels began at day 8 pi and extended to the outer vascular plexus at day 9 pi. The expression of adhesion molecules increased progressively during the development of EAU. ICAM-1, P-selectin and E-selectin were expressed predominately in retinal venules, the sites of BRB breakdown, cell adhesion and extravasation. The increase in ICAM-1 and P-selectin expression was associated both spatially and temporally with BRB breakdown, cell adhesion and extravasation. No increase in expression of P-selectin and ICAM-1 was observed either in the mesenteric vessels of EAU mice or in the retinal vessels of ovalbumin immunized mice. Conclusion: The sequence of event in EAU appears to be focal adhesion of leukocytes to discrete sites on retinal venules, followed by upregulation of adhesion molecules especially ICAM-1, P-selectin and breakdown of the BRB, leading to transmigration of leukocytes and recruitment of large numbers of cells to the retinal parenchyma. These changes occur over a short period of 6-9 days pi and initiate the process of tissue damage during the following 2-3 weeks.
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