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D. J. Ramsey, G. A. Fishman, K. R. Alexander, H. Ying, H. Qian; Melanoma-Associated Retinopathy (MAR) Immunoglobins Target Both Rod and Cone ON Bipolar Cells. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4756.
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© ARVO (1962-2015); The Authors (2016-present)
Melanoma-associated retinopathy (MAR) is a paraneoplastic syndrome that is most often associated with a diagnosis of cutaneous metastatic melanoma. Although the pathological mechanism for MAR is not well understood, it is generally accepted that MAR is mediated by an autoimmune reaction. The hallmarks of MAR include a sudden onset of night blindness, the perception of shimmering lights, and a selective reduction in the b-wave of both the scotopic and photopic ERG. In this study, we used immunohistochemical techniques to extend our understanding of the specific retinal cell types targeted by MAR antibodies.
Serum was isolated from two patients with MAR syndrome and from two healthy controls. Rat and baboon retinas were fixed with 4% paraformaldehyde, cryosectioned, and stained with various antisera. Indirect immunofluorescence was performed by incubating retinal tissue first with the appropriate human serum (1:100) and then with FITC-conjugated antibodies against human IgG or IgM. For double- and triple-labeling experiments, primary antibodies directed against PKC, Go, or recoverin were co-applied to the tissue and detected by Cy3- and Cy5-conjugated secondary antibodies.
Cells in the distal portion of the inner nuclear layer in both the rat and baboon retinas were strongly labeled with serum from both MAR patients, detected by anti-IgG, but not anti-IgM, secondary antibodies. No specific staining was observed with human sera derived from normal controls. The subcellular distribution of this interaction was confined to the cell soma with a pronounced absence of staining in the bipolar cell axons (IPL) and dendrites (OPL). Co-localization experiments demonstrated that all MAR-positive cells in the inner nuclear layer co-labeled with Go, a marker for ON bipolar cells, indicating MAR serum reacted specifically with cells of the retinal ON pathway. A majority of MAR-positive cells were also positive for PKC, a specific marker for rod ON bipolar cells. In addition, a subset of MAR-positive cells also co-localized with recoverin, a cone bipolar cell marker.
Antibodies present in the serum of MAR patients label rod bipolar cells and at least one subset of cone ON bipolar cells. Restriction of the reaction to the cell body suggests that the ability of MAR autoantibodies to interrupt the visual signal, as evidenced by the selective reduction in the b-wave of the ERG in these patients, may not occur at the synaptic level, but rather downstream of the G-protein-mediated cascade that regulates light-induced depolarization.
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