Autoimmune Uveitis

Autoimmune Uveitis is an inflammatory disease of the eye which is caused by autoimmune processes and occurs in recurrent relapses resulting in irreversible blindness. The molecular targets as well as the destructive mechanisms and factors triggering the relapses have remained largely unknown.

In order to study disease mechanisms with molecular and proteomics methods, we use the only spontaneous animal model of this disease: the horse. Horses develop equine recurrent uveitis (ERU) with a very high incidence and the disease progression closely resembles the human form since it also occurs in remitting-relapsing episodes (Deeg et al., Ophthalmic Res 2008).

Autoreactive T-cells (CD4) transgress the blood-retinal barrier and enter the inner eye where they destroy the normal tissue structures. In order to identify the target molecules of autoagressive T-cells, we used a proteomic profiling approach, where retinal tissue is separated by 2D-gel electrophoresis and probed with serum from ERU cases and controls.

Mass spectrometric identification of target proteins revealed CRALBP as a novel autoantigen, which was then confirmed as disease-causative in two different animal models (Lewis rats, horses: EAU) (Deeg et al., MCP 2006). Additionally, CRALBP was shown to be an important auto-antigen in human patients (Deeg et al., Clin Dev Immunol 2007). Since tissue material from healthy and ERU-diseased horses is readily available, we perfomed several quantitative proteomics screens (vitreous, retina, serum) in order to elucidate molecular mechanisms participating in disease progression (Deeg et al., Proteomics 2007; Hauck et al., J Prot Res 2007; Deeg et al., Mol Immunol 2007; Zipplies et al., J Prot Res 2009; Zipplies et al., IOVS 2010; Zipplies et al., Immunobiology 2010; Hauck et al., J Proteomics 2012).

Since a serious break-down of the blood-retinal barrier occurs along with disease progression and as a result the retinal tissue is flooded with serum proteins, we recently developed a membrane protein enrichment method and combined that with an in-depth LC-MSMS based label-free quantitative proteomics comparison (Hauck et al., MCP 2010).

This enabled us to overcome the bias of serum-influxed proteins and we could confirm the previously observed participation of retinal Müller glial cells in the pathology. Additionally, we found significant differential expression of several cellular pathways which have not yet been linked to the molecular events in ERU target tissue, such as metalloproteinases and their inhibitors (Hofmaier et al., IOVS 2011), water and potassium channels (Eberhardt et al., Glia 2011) and signalling molecules of the extracellular matrix (Deeg et al., PLoS One 2011).

 

 

Healthy and uveitic retina

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