Glaucoma is no longer viewed simply as elevated intraocular pressure that damages the optic nerve. In addition to high intraocular pressure, evidence is rapidly accumulating that suggests damage to the optic nerve may be initiated or sustained by any number of factors including excitotoxicity, neurotrophin insufficiency, peroxynitrite damage or others yet undefined. These different harmful influences then likely act through common final pathways that eventually disturb ion transport and activate the cellular proteases that accompany neuronal programmed cell death. In this application, the investigators provide evidence that one form of glaucoma may be an autoimmune neuropathy. This mechanism, which they believe is operative in a subset of patients most commonly with normal intraocular pressure, thus represents an important and previously unfund3d area of glaucoma investigation. More importantly, they believe the study of the cell death machinery that mediates this form of glaucomatous optic neuropathy has broad relevance to all forms of glaucoma. They have shown that many normal pressure glaucoma patients have aberrant serum autoantibodies to retinal proteins. In particular, they found that these patients have elevated serum antibodies to heat shock proteins (hsp's). Heat shock proteins are a family of cellular proteins of varying molecular weights that are considered neuroprotective since their expression is induced in neurons to ameliorate damage in response to a variety of stress conditions such as ischemia and excitotoxicity. They have further shown that the application of exogenous small hsp antibodies to human retina and retinal cells in culture, can lead to apoptotic cell death. They believe this is an important clue towards discovering the biochemical mechanism that underlies the optic neuropathy in many patients with glaucoma. They therefore propose a series of experiments to study hsp-antibody induced retinal cell death. They will perform biochemical and immunocytochemical studies to investigate the protective effects of retinal hsp's, and the harmful effects induced by antibodies against these hsp's. They will study the effects of hsp's and their antibodies on the viability of retinal cells utilizing several model systems including isolated human retina, isolated embryonal chick retinal (ex vivo), an established retinal cell line (E1A.NR3) and dissociated rat retinal ganglion cells (in vitro). They will also perform experiments to gain insight into the specific role played by """"""""caspases"""""""" in the retinal apoptotic cell death induced by antibodies against hsp's. In addition, they will continue their search for other potential retinal autoantigens in their patients by performing partial amino acid sequencing of proteins that are immuunoprecipitated with retinal hsp's using monoclonal antibodies. They will also perform molecular cloning of putative autoantigen genes from a human retina cDNA expression library probed with nucleotide sequences based on candidate proteins; or alternatively, with purified antibodies from sera of patients with normal pressure glaucoma. Finally, they will utilize a yeast """"""""two-hydrid"""""""" system to identify genes encoding potentially novel proteins that bind and interact with retinal heat shock proteins.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Visual Sciences A Study Section (VISA)
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Liberman, Ellen S
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Washington University
Schools of Medicine
Saint Louis
United States
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Wax, Martin B; Tezel, Gulgun; Yang, Junjie et al. (2008) Induced autoimmunity to heat shock proteins elicits glaucomatous loss of retinal ganglion cell neurons via activated T-cell-derived fas-ligand. J Neurosci 28:12085-96
Tezel, Gulgun; Yang, Junjie; Wax, Martin B (2004) Heat shock proteins, immunity and glaucoma. Brain Res Bull 62:473-80
Tezel, Gulgun; Wax, Martin B (2003) Glial modulation of retinal ganglion cell death in glaucoma. J Glaucoma 12:63-8
Wax, Martin; Yang, Junjie; Tezel, Gulgun (2002) Autoantibodies in glaucoma. Curr Eye Res 25:113-6
Tezel, G; Li, L Y; Patil, R V et al. (2001) TNF-alpha and TNF-alpha receptor-1 in the retina of normal and glaucomatous eyes. Invest Ophthalmol Vis Sci 42:1787-94
Yang, J; Yang, P; Tezel, G et al. (2001) Induction of HLA-DR expression in human lamina cribrosa astrocytes by cytokines and simulated ischemia. Invest Ophthalmol Vis Sci 42:365-71
Tezel, G; Hernandez, M R; Wax, M B (2001) In vitro evaluation of reactive astrocyte migration, a component of tissue remodeling in glaucomatous optic nerve head. Glia 34:178-89
Tezel, G; Siegmund, K D; Trinkaus, K et al. (2001) Clinical factors associated with progression of glaucomatous optic disc damage in treated patients. Arch Ophthalmol 119:813-8
Yang, J; Patil, R V; Yu, H et al. (2001) T cell subsets and sIL-2R/IL-2 levels in patients with glaucoma. Am J Ophthalmol 131:421-6
Yang, J; Tezel, G; Patil, R V et al. (2001) Serum autoantibody against glutathione S-transferase in patients with glaucoma. Invest Ophthalmol Vis Sci 42:1273-6

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