Abstract
Autoimmune uveitis is an intraocular inflammation that arises through autoreactive T-cells attacking the inner eye, eventually leading to blindness. However, the contributing molecular pathomechanisms within the affected tissues remain as yet elusive. The extracellular matrix (ECM) is a highly dynamic structure that varies tremendously and influences the encompassing tissue. In order to assess ECM re-modeling in autoimmune uveitis, we investigated the expression of ECM molecules fibronectin and osteopontin in vitreous and retina samples. This was carried out in the only spontaneous animal model for human autoimmue uveitis, namely equine recurrent uveitis (ERU) that resembles the human disease in clinical as well as in immunopathological aspects. ERU is a naturally occurring autoimmune disease in horses that develops frequently and has already proved its value to study disease-related pathomechanisms. Western blot analysis of fibronectin and osteopontin in healthy and uveitic vitreous revealed significant reduction of both proteins in uveitis. Immunohistochemical expression of fibronectin in healthy retinas was restricted to the inner limiting membrane abutting vimentin positive Müller cell endfeet, while in uveitic sections, a disintegration of the ILM was observed changing the fibronectin expression to a dispersed pattern extending toward the vitreous. Retinal expression of osteopontin in control tissue was found in a characteristic Müller cell pattern illustrated by co-localization with vimentin. In uveitic retinas, the immunoreactivity of osteopontin in gliotic Müller cells was almost absent. The ability of Müller cells to express fibronectin and osteopontin was additionally shown by immunocytochemistry of primary cultured equine Müller cells and the equine Müller cell line eqMC-7. In conclusion, severe ECM re-modeling in autoimmune uveitis reported here, might affect the adhesive function of fibronectin and thus the anchoring of Müller cell endfeet to the ILM. Furthermore, the absence of osteopontin in gliotic Müller cells might represent reduced neuroprotection, an osteopontin attribute that is intensively discussed.
Highlights
Autoimmune uveitis is a sight-threatening intraocular inflammation driven by eye-invading autoreactive T-cells that cross the blood-retinal barrier [1,2]
In order to evaluate this finding and further characterize its role in uveitis pathogenesis, we investigated the expression of fibronectin in vitreous and retina of control and uveitic samples since the vitreous body and the retina have been shown to play a crucial role in the pathogenesis of autoimmune uveitis [3,28,29]
In the present study we demonstrated a significant downregulation of fibronectin in vitreous samples of equine recurrent uveitis (ERU) diseased horses compared to controls by western blotting experiments (Fig. 1A)
Summary
Autoimmune uveitis is a sight-threatening intraocular inflammation driven by eye-invading autoreactive T-cells that cross the blood-retinal barrier [1,2]. The majority of molecular pathomechanisms within the eye contributing to the onset of disease and to the loss of immune-privilege remain as yet unresolved [3]. Equine recurrent uveitis (ERU) is the only spontaneous animal model for autoimmune uveitis, and ERU resembles closely the human disease in many clinical as well as immunopathological aspects [5,6]. In contrast to the human disease, ERU is a frequent pathology in the equine population. Cellular retinaldehyde binding protein (CRALBP) was first discovered in ERU [9] and proved subsequently to be a frequently targeted autoantigen in human autoimmune uveitis [10]. ECM does fill intercellular space, proteins of the ECM are involved in a variety of major functions including cellular signalling, regulation of development and differentiation and mediation of cell-matrix adhesion among others [15,16,17]
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