Multimodal evaluation of an interphotoreceptor retinoid-binding protein-induced mouse model of experimental autoimmune uveitis

Abstract

Eye disease: Understanding autoimmune eye inflammation Studying a mouse model of autoimmune uveitis, a damaging form of eye inflammation affecting the retina and choroid of the eye, reveals new cellular and molecular details of how blood vessel inflammation can damage the retina. Researchers in South Korea and Japan led by Joo Yong Lee at the University of Ulsan, Seoul, initiated autoimmune uveitis in mice by administering retinoid-binding protein, which is known to stimulate autoimmune changes which model aspects of the human disease. Their work revealed that the inflammation caused by the autoimmune response makes the blood vessels supplying the retina more permeable to a variety of large molecules. This increased permeability, due to a membrane transport process called transcytosis, was preceded by specific cellular changes. This deeper understanding of the pathology of uveitis could help research towards new treatments. We aimed to characterize the vascular phenotypes of an experimental autoimmune retinal uveitis (EAU) model induced by interphotoreceptor retinoid-binding protein (IRBP) using multimodal imaging techniques. We systemically administered IRBP or vehicle to adult C57BL/6 mice. Fundus photography, optical coherence tomography (OCT), in vivo live confocal imaging using different tracers, OCT angiography (OCTA), and electroretinography (ERG) were performed after IRBP immunization. Hematoxylin and eosin and immunofluorescence staining were performed to characterize the immune response and vascular permeability. Mice with EAU exhibited perivascular inflammation, vitritis, and superficial retinal inflammation on fundus photography and OCT. H&E revealed immune cell infiltration in the perivascular area of the retina and choroid accompanied by a significant degree of perivasculitis that subsequently damaged photoreceptors 3 weeks postimmunization. Immunofluorescence staining showed subsequent transcytosis induction after local microglial activation followed by neutrophil recruitment in the perivascular area. Transcytosis in the superficial and deep vascular areas was improved by immune cell suppression. Intravital in vivo confocal imaging showed signs of neutrophil infiltration and obstructive vasculitis with perivascular leakage 3 weeks postimmunization. OCTA revealed a significant decrease in vascular flow in the deep capillary layer of the retina. Functional analysis showed that scotopic responses were intact at 2 weeks; however, normal photopic and scotopic responses were hardly detected in mice with EAU mice at 3 weeks postimmunization. Our data suggest that inflammatory cell activation and subsequent transcytosis induction in endothelial cells might be a major pathogenic factor for vascular leakage in uveitis, providing new insights into the pathophysiology of retinal vasculitis in noninfectious uveitis.