RESUMEN
PURPOSE: Cancer-associated retinal ON bipolar cell dysfunction (CARBD), which includes melanoma-associated retinopathy (MAR), has been reported to be caused by autoantibodies against the molecules expressed in ON bipolar cells, including TRPM1. The purpose of this study was to determine the antigenic regions of the autoantibodies against TRPM1 in the sera of CARBD patients, in whom we previously detected anti-TRPM1 autoantibodies. METHODS: The antigenic regions against TRPM1 in the sera of eight CARBD patients were examined by Western blots using HEK293T cells transfected with the plasmids expressing FLAG-tagged TRPM1 fragments. The clinical course of these patients was also documented. RESULTS: The clinical course differed among the patients. The electroretinograms (ERGs) and symptoms were improved in three patients, deteriorated in one patient, remained unchanged for a long time in one patient, and were not followable in three patients. Seven of the eight sera possessed multiple antigenic regions: two sera contained at least four antigen recognition regions, and three sera had at least three regions. The antigen regions were spread over the entire TRPM1 protein: five sera in the N-terminal intracellular domain, six sera in the transmembrane-containing region, and six sera in the C-terminal intracellular domain. No significant relationship was observed between the location of the antigen epitope and the patients' clinical course. CONCLUSIONS: The antigenic regions of anti-TRPM1 autoantibodies in CARBD patients were present not only in the N-terminal intracellular domain, which was reported in an earlier report, but also in the transmembrane-containing region and in the C-terminal intracellular domain. In addition, the antigenic regions for TRPM1 were found to vary among the CARBD patients examined, and most of the sera had multiple antigenic regions.
Asunto(s)
Autoanticuerpos/sangre , Síndromes Paraneoplásicos Oculares/inmunología , Células Bipolares de la Retina/metabolismo , Canales Catiónicos TRPM/inmunología , Anciano , Western Blotting , Electrorretinografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes Paraneoplásicos Oculares/metabolismo , Síndromes Paraneoplásicos Oculares/patología , Células Bipolares de la Retina/patología , Estudios Retrospectivos , Células Tumorales CultivadasAsunto(s)
Proteínas del Sistema Complemento/metabolismo , Tumor Mulleriano Mixto/patología , Síndromes Paraneoplásicos Oculares/metabolismo , Retina/metabolismo , Degeneración Retiniana/metabolismo , Neoplasias Uterinas/patología , Autoanticuerpos/sangre , Proteínas del Sistema Complemento/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Síndromes Paraneoplásicos Oculares/patologíaRESUMEN
Importance: Bilateral diffuse uveal melanocytic proliferation is a rare sign of several systemic malignant neoplasms. Observations: A patient presenting with uveal melanocytic proliferation underwent a detailed physical examination and extensive imaging. No systemic malignant neoplasm was found. Chorioretinal biopsy was performed, and its immunohistochemical results revealed the presence of primary vitreoretinal lymphoma. Conclusions and Relevance: This patient's results suggest that diffuse uveal melanocytic proliferation may be associated not just with systemic malignant disease, but also with primary intraocular tumors, in this case a primary vitreoretinal lymphoma.
Asunto(s)
Proliferación Celular , Linfoma de Células B Grandes Difuso/patología , Melanocitos/patología , Síndromes Paraneoplásicos Oculares/patología , Neoplasias de la Retina/patología , Úvea/patología , Cuerpo Vítreo/patología , Antimetabolitos Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/metabolismo , Femenino , Angiografía con Fluoresceína , Humanos , Infusiones Intravenosas , Inyecciones Intravítreas , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/metabolismo , Metotrexato/uso terapéutico , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Síndromes Paraneoplásicos Oculares/tratamiento farmacológico , Síndromes Paraneoplásicos Oculares/metabolismo , Neoplasias de la Retina/tratamiento farmacológico , Neoplasias de la Retina/metabolismo , Tomografía de Coherencia Óptica , Agudeza Visual/fisiología , Cuerpo Vítreo/efectos de los fármacos , Cuerpo Vítreo/metabolismoAsunto(s)
Neoplasias Óseas/metabolismo , Calcáneo/diagnóstico por imagen , Regulación Neoplásica de la Expresión Génica , Péptidos y Proteínas de Señalización Intracelular/genética , Síndromes Paraneoplásicos Oculares/genética , Enfermedades de la Retina/genética , Adolescente , Biomarcadores de Tumor/metabolismo , Biopsia , Neoplasias Óseas/complicaciones , Neoplasias Óseas/diagnóstico , Electrorretinografía , Femenino , Estudios de Seguimiento , Humanos , Péptidos y Proteínas de Señalización Intracelular/biosíntesis , Imagen por Resonancia Magnética , Síndromes Paraneoplásicos Oculares/diagnóstico , Síndromes Paraneoplásicos Oculares/metabolismo , Glándula Pineal/metabolismo , ARN Neoplásico/genética , Retina/metabolismo , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/metabolismo , Factores de TiempoRESUMEN
BACKGROUND: Paraneoplastic retinopathy is caused by the cross-reaction of neoplasm-directed autoantibodies against retinal antigens and results in retinal damage. Paraneoplastic vitelliform retinopathy, a presumed paraneoplastic retinopathy with features of atypical melanoma-associated retinopathy, has recently been reported in patients with metastatic melanoma. Ocular ultrastructure and its autoantibody localization of paraneoplastic vitelliform retinopathy are still indefinable. This is the first report of anti-transient receptor potential M1 antibody directly against human retinal bipolar dendritic tips in a melanoma patient with paraneoplastic vitelliform retinopathy. CASE PRESENTATION: We present a pair of postmortem eyes of an 80-year-old male with metastatic cutaneous melanoma, who developed paraneoplastic vitelliform retinopathy. The autopsied eyes were examined with light microscopy, immunohistochemistry, and transmission electron microscopy. Microscopically, the inner nuclear layer and outer plexiform layer were the most affected retinal structures, with local thinning. The lesions extended to the outer nuclear layer, resulting in focal retinal degeneration, edema, and atrophy. No active inflammation or melanoma cells were observed. Immunohistochemistry showed tightly compact bipolar cell nuclei (protein kinase C alpha/calbindin positive) with blur/loss of ON bipolar cell dendritic tips (transient receptor potential M1 positive) in diffusely condensed outer plexiform layer. The metastatic melanoma cells in his lung also showed immunoreactivity against transient receptor potential M1 antibody. Transmission electron microscopy illustrated degenerated inner nuclear layer with disintegration of cells and loss of cytoplasmic organelles. These cells contained many lysosomal and autophagous bodies and damaged mitochondria. Their nuclei appeared pyknotic and fragmentary. The synapses in the outer plexiform layer were extensively degenerated and replaced with empty vacuoles and disintegrated organelles. CONCLUSION: This case provides a convincing histological evidence of melanoma-associated autoantibodies directly against transient receptor potential M1 channels that target the ON bipolar cell structures in the inner nuclear and outer plexiform layers in paraneoplastic vitelliform retinopathy.