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      Immune response against ocular tissues after immunization with optic nerve antigens in a model of autoimmune glaucoma

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          Abstract

          Purpose

          In recent years, numerous studies have investigated the involvement of immunological mechanisms in glaucoma. Until now, it has not been determined whether the altered antibody pattern detected in patients is harmful to retinal ganglion cells (RGCs) or triggers disease formation in any way. In a model of experimental autoimmune glaucoma, RGC loss can be induced through immunization with certain ocular antigens. In the current study, the time course of the levels of autoreactivity against ocular tissues after immunization was examined.

          Methods

          Intraocular pressure was measured regularly. Ten weeks after immunization with an optic nerve homogenate antigen (ONA), the number of RGCs was determined. Immunoglobulin G levels in aqueous humor were measured via enzyme-linked immunosorbent assay at the same time point. Serum from different time points was used to analyze the possible occurrence of autoreactive antibodies against the retina or optic nerve in this autoimmune glaucoma model. Additionally, optic nerve and brain sections were evaluated for possible pathological findings.

          Results

          Intraocular pressure stayed within the normal range throughout this study. A continuous increase of autoreactive antibodies against the optic nerve and retina sections was observed. At 4, 6, and 10 weeks, antibody reactivity was significantly higher in ONA animals (p<0.01). Aqueous humor immunoglobulin G levels were also significantly higher in the ONA group (p=0.006). Ten weeks after immunization, significantly fewer RGCs were noted in the ONA group (p=0.00003). The optic nerves from ONA animals exhibited damaged axons. No pathological findings appeared in any brain sections.

          Conclusions

          Our findings suggest that these modified antibodies play a substantial role in mechanisms leading to RGC death. The slow dissolution of RGCs observed in animals with autoimmune glaucoma is comparable to the slow progressive RGC loss in glaucoma patients, thus making this a useful model to develop neuroprotective therapies in the future.

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          Molecular basis of the inner blood-retinal barrier and its breakdown in diabetic macular edema and other pathological conditions.

          Ingeborg Klaassen, Cornelis Van Noorden, Reinier Schlingemann (2013)
          Breakdown of the inner endothelial blood-retinal barrier (BRB), as occurs in diabetic retinopathy, age-related macular degeneration, retinal vein occlusions, uveitis and other chronic retinal diseases, results in vasogenic edema and neural tissue damage, causing loss of vision. The central mechanism of altered BRB function is a change in the permeability characteristics of retinal endothelial cells caused by elevated levels of growth factors, cytokines, advanced glycation end products, inflammation, hyperglycemia and loss of pericytes. Subsequently, paracellular but also transcellular transport across the retinal vascular wall increases via opening of endothelial intercellular junctions and qualitative and quantitative changes in endothelial caveolar transcellular transport, respectively. Functional changes in pericytes and astrocytes, as well as structural changes in the composition of the endothelial glycocalyx and the basal lamina around BRB endothelium further facilitate BRB leakage. As Starling's rules apply, active transcellular transport of plasma proteins by the BRB endothelial cells causing increased interstitial osmotic pressure is probably the main factor in the formation of macular edema. The understanding of the complex cellular and molecular processes involved in BRB leakage has grown rapidly in recent years. Although appropriate animal models for human conditions like diabetic macular edema are lacking, these insights have provided tools for rational design of drugs aimed at restoring the BRB as well as for design of effective transport of drugs across the BRB, to treat the chronic retinal diseases such as diabetic macular edema that affect the quality-of-life of millions of patients. 2013 Elsevier Ltd. All rights reserved.
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            Retinal ganglion cells downregulate gene expression and lose their axons within the optic nerve head in a mouse glaucoma model.

            Ileana Soto, Ericka N. Oglesby, Brian Buckingham … (2008)
            Little is known about molecular changes occurring within retinal ganglion cells (RGCs) before their death in glaucoma. Taking advantage of the fact that gamma-synuclein (Sncg) mRNA is expressed specifically and highly in adult mouse RGCs, we show in the DBA/2J mouse model of glaucoma that there is not only a loss of cells expressing this gene, but also a downregulation of gene expression of Sncg and many other genes within large numbers of RGCs. This downregulation of gene expression within RGCs occurs together with reductions in FluoroGold (FG) retrograde transport. Surprisingly, there are also large numbers of Sncg-expressing cells without any FG labeling, and among these many that have a marker previously associated with disconnected RGCs, accumulation of phosphorylated neurofilaments in their somas. These same diseased retinas also have large numbers of RGCs that maintain the intraocular portion while losing the optic nerve portion of their axons, and these disconnected axons terminate within the optic nerve head. Our data support the view that RGC degeneration in glaucoma has two separable stages: the first involves atrophy of RGCs, whereas the second involves an insult to axons, which causes the degeneration of axon portions distal to the optic nerve head but does not cause the immediate degeneration of intraretinal portions of axons or the immediate death of RGCs.
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              Induced autoimmunity to heat shock proteins elicits glaucomatous loss of retinal ganglion cell neurons via activated T-cell-derived fas-ligand.

              Guanghua Peng, Güler G Tezel, Satish V Patil … (2008)
              Glaucomatous optic neuropathy causes blindness through the degeneration of retinal ganglion cells (RGCs) and their axons, which comprise the optic nerve. Glaucoma traditionally is associated with elevated intraocular pressure, but often occurs or may progress with intraocular pressure in the normal range. Like other diseases of the CNS, a subset of glaucoma has been proposed to involve an autoimmune component to help explain the loss of RGCs in the absence of elevated intraocular pressure. One hypothesis involves heat shock proteins (HSPs), because increased serum levels of HSP autoantibodies are prominent in some glaucoma patients with normal pressures. In the first direct support of this hypothesis, we found that HSP27 and HSP60 immunization in the Lewis rat induced RGC degeneration and axon loss 1-4 months later in vivo in a pattern with similarities to human glaucoma, including topographic specificity of cell loss. Infiltration of increased numbers of T-cells in the retina occurred much earlier, 14-21 d after HSP immunization, and appeared to be transient. In vitro studies found that T-cells activated by HSP immunization induced RGC apoptosis via the release of the inflammatory cytokine FasL, whereas HSP immunization induced activation of microglia cells and upregulation of the FasL receptor in RGCs. In summary, our results suggest that RGC degeneration in glaucoma for selected individuals likely involves failed immunoregulation of the T-cell-RGC axis and is thus a disturbance of both proapoptotic and protective pathways.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mol Vis
                Journal ID (iso-abbrev): Mol. Vis
                Journal ID (publisher-id): MV
                Title: Molecular Vision
                Publisher: Molecular Vision
                ISSN (Electronic): 1090-0535
                Publication date Collection: 2013
                Publication date (Electronic): 06 August 2013
                Volume: 19
                Pages: 1804-1814
                Affiliations
                [1 ]Experimental Eye Research Institute, Ruhr University Eye Hospital, Bochum, Germany
                [2 ]Experimental Ophthalmology, Department of Ophthalmology, University Medical Center, Johannes Gutenberg University, Mainz, Germany
                [3 ]Institute of Pathology, Ruhr University, Bochum, Germany
                [4 ]Department of Neuropathology, University Medical Center, Johannes Gutenberg University, Mainz, Germany
                Author notes
                Correspondence to: Stephanie C. Joachim, Experimental Eye Research Institute, Ruhr University Eye Hospital, In der Schornau 23-25, 44892 Bochum, Germany, Phone: +49-234-299-3156, FAX: +49-234-299-3157; email: Stephanie.Joachim@ 123456rub.de
                Article
                Publisher ID: 182 Publisher-manuscript ID: 2013MOLVIS0058
                PMC ID: 3742127
                PubMed ID: 23946635
                SO-VID: aa8f3d5c-61fd-4d70-a9ef-6d119e793a3a
                Copyright © Copyright © 2013 Molecular Vision.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 29 January 2013
                Date accepted : 03 August 2013
                Categories
                Subject: Research Article
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                ScienceOpen disciplines: Vision sciences
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                ScienceOpen disciplines: Vision sciences

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