Anti-recoverin antibodies induce an increase in intracellular calcium, leading to apoptosis in retinal cells

Autoantibodies against recoverin, a Ca 2+-binding protein found in patients with cancer-associated retinopathy (CAR syndrome), penetrate retinal cells and induce their apoptosis via a mitochondrial pathway. The goal of this study was to investigate whether the entry of anti-recoverin antibody into E...

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Veröffentlicht in:Journal of autoimmunity 2006-03, Vol.26 (2), p.146-153
Hauptverfasser: Adamus, Grazyna, Webb, Sarah, Shiraga, Sharon, Duvoisin, Robert M.
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container_end_page 153
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container_start_page 146
container_title Journal of autoimmunity
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creator Adamus, Grazyna
Webb, Sarah
Shiraga, Sharon
Duvoisin, Robert M.
description Autoantibodies against recoverin, a Ca 2+-binding protein found in patients with cancer-associated retinopathy (CAR syndrome), penetrate retinal cells and induce their apoptosis via a mitochondrial pathway. The goal of this study was to investigate whether the entry of anti-recoverin antibody into E1A.NR3 retinal cells causes a change in intracellular Ca 2+. Intracellular Ca 2+ was measured using the Ca 2+-sensitive fluorescent dye Fura-2 AM in living E1A.NR3 retinal cells treated with anti-recoverin antibody Rec-1, patients' autoantibodies, and control rat and human IgG. The exposure of retinal cells to Rec-1 antibody and to the CAR patients' autoantibodies in vitro caused a significant increase in intracellular Ca 2+, while non-specific antibodies did not induce such an effect. Co-treatment of the E1A.NR3 cells with Rec-1 in the presence of nifedipine, a L-type Ca 2+ channel blocker, significantly suppressed the increase of Ca 2+. Treatment with nifedipine also blocked changes in the anti-apoptotic protein bcl-xL and in expressions of the pro-apoptotic protein bax. Nifedipine-treated cells also showed a decrease in cytosolic cytochrome c release and a decrease in caspase 3 activation, compared to cells treated only with Rec-1 antibody. The increase in the antibody-induced Ca 2+ is at least in part dependent on extracellular Ca 2+. Nifedipine was found to inhibit the entry of Ca 2+ into the cells and to protect them from Rec-1-induced apoptosis. Increased levels of intracellular Ca 2+ may lead to retinal dysfunction and degeneration in the CAR syndrome. Our results provide a molecular basis for the use of Ca 2+ blockers in the treatment of the CAR syndrome.
doi_str_mv 10.1016/j.jaut.2005.11.007
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The goal of this study was to investigate whether the entry of anti-recoverin antibody into E1A.NR3 retinal cells causes a change in intracellular Ca 2+. Intracellular Ca 2+ was measured using the Ca 2+-sensitive fluorescent dye Fura-2 AM in living E1A.NR3 retinal cells treated with anti-recoverin antibody Rec-1, patients' autoantibodies, and control rat and human IgG. The exposure of retinal cells to Rec-1 antibody and to the CAR patients' autoantibodies in vitro caused a significant increase in intracellular Ca 2+, while non-specific antibodies did not induce such an effect. Co-treatment of the E1A.NR3 cells with Rec-1 in the presence of nifedipine, a L-type Ca 2+ channel blocker, significantly suppressed the increase of Ca 2+. Treatment with nifedipine also blocked changes in the anti-apoptotic protein bcl-xL and in expressions of the pro-apoptotic protein bax. Nifedipine-treated cells also showed a decrease in cytosolic cytochrome c release and a decrease in caspase 3 activation, compared to cells treated only with Rec-1 antibody. The increase in the antibody-induced Ca 2+ is at least in part dependent on extracellular Ca 2+. Nifedipine was found to inhibit the entry of Ca 2+ into the cells and to protect them from Rec-1-induced apoptosis. Increased levels of intracellular Ca 2+ may lead to retinal dysfunction and degeneration in the CAR syndrome. 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subjects Animals
Antibodies, Monoclonal - pharmacology
Apoptosis - drug effects
Autoantibodies
Autoantibodies - pharmacology
Autoimmunity
bcl-2-Associated X Protein - metabolism
bcl-X Protein - metabolism
Biological and medical sciences
Calcium
Calcium - metabolism
Calcium Channel Blockers - pharmacology
Calcium Channel Blockers - therapeutic use
Calcium-Binding Proteins - antagonists & inhibitors
Calcium-Binding Proteins - immunology
CAR syndrome
Cell Line
Cytochromes c - metabolism
Fundamental and applied biological sciences. Psychology
Fundamental immunology
General aspects
Humans
Immunopathology
Medical sciences
Neoplasms - complications
Neoplasms - immunology
Nifedipine - pharmacology
Nifedipine - therapeutic use
Paraneoplastic syndrome
Rats
Recoverin - antagonists & inhibitors
Recoverin - immunology
Retina
Retina - cytology
Retina - drug effects
Retina - metabolism
Retinal Diseases - drug therapy
Retinal Diseases - immunology
Retinopathy
Syndrome
title Anti-recoverin antibodies induce an increase in intracellular calcium, leading to apoptosis in retinal cells
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