Mechanism of CAR syndrome: anti-recoverin antibodies are the inducers of retinal cell apoptotic death via the caspase 9- and caspase 3-dependent pathway

Anti-recoverin autoantibodies have been associated with cancer-associated retinopathy (CAR), a paraneoplastic blinding disease. Those antibodies have been shown to induce apoptotic death of photoreceptor cells. The objective was to ascertain the mechanisms of retinal death induced by anti-recoverin...

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Bibliographic Details
Published in:Journal of neuroimmunology 2002-11, Vol.132 (1), p.72-82
Main Authors: Shiraga, Sharon, Adamus, Grazyna
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Apoptotic Protease-Activating Factor 1
Autoantibodies - immunology
Autoimmunity
Calcium-Binding Proteins - immunology
Cancer-associated retinopathy
Caspase 3
Caspase 9
Caspases - physiology
Cytochrome c Group - metabolism
DNA Fragmentation
Endocytosis
Enzyme Activation
Eye Proteins
Hippocalcin
Lipoproteins
Nerve Tissue Proteins
Paraneoplastic Syndromes - etiology
Photoreceptors
Poly(ADP-ribose) Polymerases - metabolism
Proteins - analysis
Proto-Oncogene Proteins c-bcl-2 - biosynthesis
Rats
Recoverin
Retina - pathology
Retinal degeneration
Retinal Degeneration - etiology
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Summary:Anti-recoverin autoantibodies have been associated with cancer-associated retinopathy (CAR), a paraneoplastic blinding disease. Those antibodies have been shown to induce apoptotic death of photoreceptor cells. The objective was to ascertain the mechanisms of retinal death induced by anti-recoverin antibody in vitro by examining the apoptotic pathway involved in retinal cell death. Internalization of anti-recoverin antibody or its Fab fragments by retinal cells mediated by endocytosis lead to cytotoxicity. Antibody cellular translocation induced the increase of bcl-x s and bax and the decrease in the bcl-x L protein. We detected the release of cytochrome c and down-regulation of the apaf-1 protein. This correlated with the sequential activation of caspase 9 and caspase 3, as well as the degradation of the caspase substrate PARP and the fragmentation of DNA. Our data show that anti-recoverin antibodies are inducers of apoptosis through the mitochondrial pathway involving caspases 9 and 3. We propose that a similar mechanism may be in place in patients with CAR syndrome where high levels of circulating antibodies have been associated with retinal degeneration.
ISSN:0165-5728
1872-8421
DOI:10.1016/S0165-5728(02)00314-4