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The Journal of Neuroscience, November 12, 2008, 28(46):12085-12096; doi:10.1523/JNEUROSCI.3200-08.2008

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Neurobiology of Disease
Induced Autoimmunity to Heat Shock Proteins Elicits Glaucomatous Loss of Retinal Ganglion Cell Neurons via Activated T-Cell-Derived Fas-Ligand

Martin B. Wax,^1,2 Gülgün Tezel,^3,4 Junjie Yang,¹ Guanghua Peng,⁵ Rajkumar V. Patil,¹ Neeraj Agarwal,⁶ Rebecca M. Sappington,⁷ and David J. Calkins⁷

¹Ophthalmology Discovery Research, Alcon Corporation, Fort Worth, Texas 76134, ²Department of Ophthalmology, University of Texas Southwestern Medical School, Dallas, Texas 75390-9057, ³Departments of Ophthalmology and Visual Sciences and ⁴Anatomical Sciences and Neurobiology, University of Louisville, Louisville, Kentucky 40202, ⁵Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri 63110, ⁶Oculomotor Systems and Neuro-Ophthalmology, Division of Extramural Research, National Eye Institute, Bethesda, Maryland 20892; and ⁷The Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, Tennessee 37232

Correspondence should be addressed to Dr. Martin B. Wax, Department of Ophthalmology, University of Texas Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, TX 75390-9057. Email: mbw817{at}yahoo.com

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.

Key words: autoimmunity; glaucoma; microglia; T-cells; FasL; heat shock proteins

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Received July 9, 2008; revised Aug. 25, 2008; accepted Sept. 7, 2008.

Correspondence should be addressed to Dr. Martin B. Wax, Department of Ophthalmology, University of Texas Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, TX 75390-9057. Email: mbw817{at}yahoo.com

This article has been cited by other articles:

				S. C. Joachim, F. H. Grus, D. Kraft, K. White-Farrar, G. Barnes, M. Barbeck, S. Ghanaati, S. Cao, B. Li, and M. B. Wax Complex Antibody Profile Changes in an Experimental Autoimmune Glaucoma Animal Model Invest. Ophthalmol. Vis. Sci., October 1, 2009; 50(10): 4734 - 4742. [Abstract] [Full Text] [PDF]

				G. Tezel and the Fourth ARVO/Pfizer Ophthalmics Research Instit The Role of Glia, Mitochondria, and the Immune System in Glaucoma Invest. Ophthalmol. Vis. Sci., March 1, 2009; 50(3): 1001 - 1012. [Full Text] [PDF]

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