Human melanoma-associated retinopathy (MAR) antibodies alter the retinal ON-response of the monkey ERG in vivo.
OBJECTIVE
Melanoma-associated retinopathy (MAR) is a paraneoplastic condition that causes visual symptoms of night-blindness and photopsias. The electroretinogram (ERG) of MAR patients is characteristically abnormal in a way that implicates retinal depolarizing bipolar cell (DBC) dysfunction. Whether an injection of IgG from MAR patients into the vitreous of monkeys would alter the ERG acutely as a demonstration of a functional basis for patients' visual symptoms was explored.


METHODS
MAR IgG was isolated from three visually symptomatic melanoma patients. Control IgG was from melanoma patients with no vision problems. The ERG was monitored after intravitreal injections into monkey eyes. One eye was injected with 2-amino-4-phosphonobutyric acid (APB), which is known to block DBC ON-pathway responses. Retinal immunocytochemistry was performed using fluorescein isothiocyanate-labeled goat anti-human IgG.


RESULTS
Within 1 to 3 hours after MAR IgG injection, the ERG photopic b-wave was diminished, with far less effect on the a- and d-waves. These changes are characteristic of DBC dysfunction and were similar to the effects of APB. The scotopic ERG b-wave, which reflects activity of rod-driven DBCs, showed a loss of amplitude and threshold sensitivity after MAR IgG. Retinal immunocytochemistry with anti-IgG antibody showed IgG penetration throughout the retinal layers, but staining was not specific for a single type of retinal neuron.


CONCLUSIONS
Intravitreal injection of human MAR IgG altered the monkey ERG acutely in ways that implicate functional disruption of retinal DBC signaling. These results support the hypothesis that MAR IgG circulating antibodies are responsible for the reported visual symptoms. Bipolar cells in the ON-pathway appear to be affected more than OFF-pathway bipolar cells of the cone pathway in this acute preparation.
Lei
B
B
Department of Ophthalmology and Neuroscience Program, the W.K. Kellogg Eye Center, University of Michigan, Ann Arbor 48105, USA.
Bush
R A
RA
Milam
A H
AH
Sieving
P A
PA
D000613:Aminobutyrates / Q000494:pharmacology; D000818:Animals; D000912:Antibodies, Neoplasm / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D002135:Calcium-Binding Proteins / Q000276:immunology*; D004596:Electroretinography / Q000187:drug effects*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005136:Eye Proteins; D051597:Hippocalcin; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007395:Interneurons / Q000187:drug effects; D008074:Lipoproteins; D008253:Macaca mulatta; D008545:Melanoma / Q000276:immunology*; D009419:Nerve Tissue Proteins; D010257:Paraneoplastic Syndromes / Q000503:physiopathology*; D051603:Recoverin; D012160:Retina / Q000187:drug effects / Q000503:physiopathology*
D000613:Aminobutyrates; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D002135:Calcium-Binding Proteins; D018690:Excitatory Amino Acid Agonists; D005136:Eye Proteins; D007074:Immunoglobulin G; D008074:Lipoproteins; D009419:Nerve Tissue Proteins; C496731:RCVRN protein, human; D051603:Recoverin; D051597:Hippocalcin; C012729:2-amino-4-phosphonobutyric acid