Down‐regulation of pigment epithelium‐derived factor in uveitic lesion associates with focal vascular endothelial growth factor expression and breakdown of the blood‐retinal barrier

Abstract

Spontaneous equine recurrent uveitis (ERU) is an incurable autoimmune disease affecting the eye. Identifying biological markers or pathways associated with this disease may allow the understanding of its pathogenesis at a molecular level. The vitreous is the body fluid closest to the disease-affected tissue and possibly also an effector of pathological processes relevant for ERU. Surgical removal of vitreous leads to cessation of relapses in spontaneous uveitis of both man and horse, therefore vitreous composites are likely to contribute to disease progression. Uveitic vitreous is likely to contain potential biomarkers in relatively undiluted quantities. With the goal to identify these markers, we systematically compared vitreous from healthy and disease-affected eyes by proteomic profiling. Nine differentially expressed proteins were identified, that are functionally related to immune response, inflammation, and maintenance of the blood-retinal barrier. One of these, pigment epithelium-derived factor, a protein involved in maintaining a proper blood-retina barrier as well as protecting from neoangiogenesis was additionally found to be down-regulated within uveitic retinal lesions whereas, conversely, vascular endothelial growth factor was found to be up-regulated at these sites. Together, these changes point to as of yet undiscovered biological pathways involved in the pathogenesis of this autoimmune disease.

Deciphering Membrane-Associated Molecular Processes in Target Tissue of Autoimmune Uveitis by Label-Free Quantitative Mass Spectrometry

“…Simultaneous binding of the pro-angiogenic growth factor VEGF and alpha5beta1 integrin to FN greatly enhances the pro-angiogenic effect of VEGF by increasing endothelial cell proliferation (35,36). Since we have previously reported upregulation of VEGF by retinal Mü ller cells in the context of ERU pathology (37), the upregulation of VEGF-receptive ECM proteins in the retina may suggest a synergistic pathomechanism for VEGF in ERU.…”

Label-free LC-MSMS analysis of vitreous from autoimmune uveitis reveals a significant decrease in secreted Wnt signalling inhibitors DKK3 and SFRP2

“…In an earlier study, we used 2D gels to identify differentially regulated proteins in ERU vitreous [5]. With this approach, we identified a total of 42 proteins in vitreous with 9 of these differentially expressed in ERU [5].…”

“…Furthermore, the vitreous is routinely removed in cases of ERU by therapeutic vitrectomy and is therefore available as fresh sample material from early disease stages in horses [4]. Consequently, vitreous has proven to be a very valuable sample when studying vitreo-retinal diseases like ERU [5].…”

Equine Recurrent Uveitis – A Spontaneous Horse Model of Uveitis

“…Major retinal autoantigens, IRBP, S-Ag and CRALBP, were clearly detectable in retinal proteomes of normal equine retina and in retinas with different stages of uveitis. Although the composition of retinal proteomes differs considerably between healthy and diseased states [12] , the IRBP, S-Ag and CRALBP amounts remained unchanged [24] . Substantial photoreceptor damage in uveitic retinas tested in this study was evident by measuring rhodopsin expression levels that were reduced to 27% of the original expression.…”

“…Systematic exploration of the intraocular proteomes of spontaneous uveitis cases and healthy controls enabled the identification of several differentially regulated proteins that belong to pathways involved in immune response [12,13] . The respective upregulated proteins are complement component C3, carboxylesterase D1 and histone deacetylase complex subunit SAP18, which merit further exploration in the context of spontaneous uveitis.…”