Retinal degeneration is one of the leading causes of visual loss in the world. The mechanism of retinal cell death in different forms of retinal degenerations is not fully understood. There is evidence that a subset of patients with retinopathy may have an autoimmune component to the disease. One possibility is that autoantibodies associated with retinal dysfunction and retinal degeneration could cause retinal damage. Based on clinical and in vitro observations, we propose the hypothesis that autoantibodies may participate in the development of some forms of retinopathies in patients with retinal dysfunction. Some types of human acquired retinopathy may be caused by the action of autoantibodies, functioning through the activation of cell apoptotic responses after prolonged exposure to autoantibodies specific to retinal proteins. When antibodies gain access to the retina through the blood-retinal barrier and penetrate retinal cells, they initiate photoreceptor death by apoptosis. A massive death of retinal cells may lead to significant tissue damage, to visual loss, and finally, to blindness. Antibody penetration into living retinal cells will then constitute a new mechanism of immunologically mediated retinal degeneration. Because the lack of availability of tissue for a direct demonstration of apoptotic cell death in affected retinas of patients, studies using an in vitro model and animal models provide better understanding of the mechanism of cell death induced by immunoglobulins. We propose to use cultured retinal cells and an animal model to study the involvement of autoantibodies in retinal damage. Our long-term goal is to define the mechanism of induction and retinal damage in those autoimmune retinopathies and develop a new in vitro model to analyze the effect of antibody action on retinas. To achieve our goals we propose the following specific aims: (1) Determine whether autoantibodies associated with retinal dysfunction and degeneration are cytotoxic for retinal cells by investigating the relationship between specificity, antibody cell penetration, and cytotoxicity; (2) Define the role of anti-retinal autoantibodies in retinal damage by examining the mechanism of cell entry and the effect of autoantibodies on cell function; (3) Examine the mechanism of cell death in antibody-induced retinal damage by defining the mechanism of antibody-induced apoptosis in retinal cells leading to retinal damage and studying the sensitivity of different retinal cells to antibody-induced apoptosis.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY013053-05
Application #
6652649
Study Section
Special Emphasis Panel (ZAR1-AAA-B (O2))
Program Officer
Shen, Grace L
Project Start
1999-09-30
Project End
2005-07-31
Budget Start
2003-09-30
Budget End
2005-07-31
Support Year
5
Fiscal Year
2003
Total Cost
$203,050
Indirect Cost
Name
Oregon Health and Science University
Department
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Adamus, Grazyna (2015) Latest updates on antiretinal autoantibodies associated with vision loss and breast cancer. Invest Ophthalmol Vis Sci 56:1680-8
Adamus, Grazyna; Chew, Emily Y; Ferris, Frederick L et al. (2014) Prevalence of anti-retinal autoantibodies in different stages of Age-related macular degeneration. BMC Ophthalmol 14:154
Adamus, Grazyna; Bonnah, Robert; Brown, Lori et al. (2013) Detection of autoantibodies against heat shock proteins and collapsin response mediator proteins in autoimmune retinopathy. BMC Ophthalmol 13:48
Adamus, Grazyna; Choi, Dongseak; Raghunath, Anitha et al. (2013) Significance of Anti-retinal Autoantibodies in Cancer-associated Retinopathy with Gynecological Cancers. J Clin Exp Ophthalmol 4:307
Carboni, Giovannella; Forma, Gina; Bond, April D et al. (2012) Bilateral paraneoplastic optic neuropathy and unilateral retinal compromise in association with prostate cancer: a differential diagnostic challenge in a patient with unexplained visual loss. Doc Ophthalmol 125:63-70
Aronow, Mary E; Adamus, Grazyna; Abu-Asab, Mones et al. (2012) Paraneoplastic vitelliform retinopathy: clinicopathologic correlation and review of the literature. Surv Ophthalmol 57:558-64
Abazari, Azin; Allam, Souha S; Adamus, Grazyna et al. (2012) Optical coherence tomography findings in autoimmune retinopathy. Am J Ophthalmol 153:750-6, 756.e1
Adamus, Grazyna; Brown, Lori; Schiffman, Jade et al. (2011) Diversity in autoimmunity against retinal, neuronal, and axonal antigens in acquired neuro-retinopathy. J Ophthalmic Inflamm Infect 1:111-21
Mets, Rebecca B; Golchet, Pamela; Adamus, Grazyna et al. (2011) Bilateral diffuse uveal melanocytic proliferation with a positive ophthalmoscopic and visual response to plasmapheresis. Arch Ophthalmol 129:1235-8
Kruer, M C; Koch, T K; Bourdette, D N et al. (2010) NMDA receptor encephalitis mimicking seronegative neuromyelitis optica. Neurology 74:1473-5

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