RESUMEN
PURPOSE: Bothnia dystrophy is a variant of recessive retinitis punctata albescens (RPA) and is caused by a homozygous R234W mutation in the RLBP1 gene. We report the clinical features of a Japanese patient with the homozygous R234W mutation in the RLBP1 gene. METHODS: An affected woman with RPA has been examined clinically for 25 years. Her DNA was obtained with informed consent, and the exons and surrounding areas of RDH5, rhodopsin, and RLBP1 were amplified by PCR and directly sequenced. RESULTS: Our patient was first examined in our hospital in 1986 when she was 6 years old. Ophthalmoscopy showed numerous small white dots in the posterior pole of both eyes. Although the a- and b-waves of the single flash ERGs were severely reduced after a standard 30 min of dark-adaptation, the amplitudes of both waves increased markedly after 24 hr of dark-adaptation. The visual disturbances and visual field scotomas became more evident in her twenties, and her BCVAs were 0.2 OD and 0.5 OS when she was 31 years old in 2010. Fundus examinations showed macular degeneration in both eyes. A homozygous R234W mutation was detected in RLBP1, and no mutations were detected in RDH5 and rhodopsin. CONCLUSIONS: The clinical characteristics of a Japanese patient with a homozygous R234W mutation in RLBP1 are very similar to that of Swedish patients with Bothnia dystrophy. The origin of the Japanese R234W mutation is probably not the same as that of the Swedish patients, but more likely due to the high incidence of C to T transitions.
Asunto(s)
Proteínas Portadoras/genética , Ceguera Nocturna/diagnóstico , Distrofias Retinianas/diagnóstico , Adulto , Oxidorreductasas de Alcohol/genética , Pueblo Asiatico/genética , Análisis Mutacional de ADN , Adaptación a la Oscuridad , Electrorretinografía , Exones/genética , Femenino , Angiografía con Fluoresceína , Humanos , Japón , Mutación Missense , Ceguera Nocturna/genética , Reacción en Cadena de la Polimerasa , Distrofias Retinianas/genética , Rodopsina/genética , Tomografía de Coherencia Óptica , Agudeza Visual/fisiología , Campos Visuales/fisiologíaRESUMEN
PURPOSE: To define the role of endogenous 4-1BB (an important T-cell costimulatory molecule) in the regulation of ocular disease, MRL-Fas(lpr) mice deficient in 4-1BB were generated, and their lacrimal gland function was studied. METHODS: 4-1BB(-/-)MRL/MpJ-Tnfrs(lpr)/Tnfrs(lpr) (lpr/4-1BB(-/-)) mice were generated and used at the ninth backcross. Mice were killed at various times, and lacrimal gland cellularity was analyzed by flow cytometry. Tear and tissue samples were analyzed by Western blotting for the presence of aquaporin 5 (AQP5) and 120-kDa fragments of alpha-fodrin. Cytokine expression of lacrimal glands was assessed by flow cytometry and RT-PCR analysis. RESULTS: Absence of the 4-1BB gene function in lpr mice resulted in early and increased infiltration of mononuclear cells into lacrimal glands compared with 4-1BB intact lpr mice. The severity of lesions in lpr/4-1BB(-/-) mice was closely associated with enhanced accumulation of primarily CD4(+) T cells within the lacrimal glands and with increased expression of IL-4. Elevated levels of AQP5 and cleaved 120-kDa fragments of alpha-fodrin were found in tears and lacrimal gland lysates, respectively, of lpr/4-1BB(-/-) but not lpr/4-1BB(+/+) mice. CONCLUSIONS: Deletion of 4-1BB in lpr mice accelerates lacrimal gland lesions through increased CD4(+) T-cell infiltration and their production of immune modulators.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Dacriocistitis/inmunología , Silenciador del Gen/fisiología , Aparato Lagrimal/inmunología , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Animales , Linfocitos T CD8-positivos/inmunología , Dacriocistitis/patología , Femenino , Citometría de Flujo , Técnica del Anticuerpo Fluorescente Indirecta , Immunoblotting , Técnicas para Inmunoenzimas , Etiquetado Corte-Fin in Situ , Interferón gamma/metabolismo , Interleucina-4/metabolismo , Aparato Lagrimal/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos MRL lpr , Ratones Noqueados , Regulación hacia ArribaRESUMEN
To explore the roles of 4-1BB (CD137) and CD28 in corneal transplantation, we examined the effect of 4-1BB/4-1BB ligand (4-1BBL) and/or CD28/CD80/CD86 blockade on corneal allograft survival in mice. Allogeneic corneal transplantation was performed between two strains of wild-type (WT) mice, BALB/c and C57BL/6 (B6), and between BALB/c and B6 WT donors and various gene knockout (KO) recipients. Some of the WT graft recipients were treated intraperitoneally with agonistic anti-4-1BB or blocking anti-4-1BBL monoclonal antibody (mAb) on days 0, 2, 4 and 6 after transplantation. Transplanted eyes were observed over a 13-week period. Allogeneic grafts in control WT B6 and BALB/c mice treated with rat immunoglobulin G showed median survival times (MST) of 12 and 14 days, respectively. Allogeneic grafts in B6 WT recipients treated with anti-4-1BB mAb showed accelerated rejection, with an MST of 8 days. In contrast, allogeneic grafts in BALB/c 4-1BB/CD28 KO and B6 CD80/CD86 KO recipients had significantly prolonged graft survival times (MST, 52.5 days and 36 days, respectively). Treatment of WT recipients with anti-4-1BB mAb resulted in enhanced cellular proliferation in the mixed lymphocyte reaction and increased the numbers of CD4(+) CD8(+) T cells, and macrophages in the grafts, which correlated with decreased graft survival time, whereas transplant recipients with costimulatory receptor deletion showed longer graft survival times. These results suggest that the absence of receptors for the 4-1BB/4-1BBL and/or CD28/CD80/CD86 costimulatory pathways promotes corneal allograft survival, whereas triggering 4-1BB with an agonistic mAb enhances the rejection of corneal allografts.
Asunto(s)
Trasplante de Córnea/inmunología , Supervivencia de Injerto/inmunología , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología , Ligando 4-1BB/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Antígeno B7-1/inmunología , Antígeno B7-2/inmunología , Antígenos CD28/inmunología , Quimiocinas/biosíntesis , Quimiocinas/genética , Quimiotaxis de Leucocito , Trasplante de Córnea/métodos , Trasplante de Córnea/patología , Citocinas/biosíntesis , Citocinas/genética , Femenino , Expresión Génica , Rechazo de Injerto/genética , Rechazo de Injerto/inmunología , Rechazo de Injerto/patología , Prueba de Cultivo Mixto de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , ARN Mensajero/genética , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/antagonistas & inhibidores , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/biosíntesisRESUMEN
Interphotoreceptor retinoid binding protein (IRBP)-induced experimental autoimmune uveoretinitis (EAU) is a CD4+ T cell-mediated autoimmune disease. Development of EAU is inhibited by treatment with an agonistic anti-4-1BB mAb. Even established EAU was alleviated by anti-4-1BB mAb. However, inhibition of 4-1BB/4-1BB ligand (4-1BBL) interaction does not suppress the development of EAU. It appears that cross-linking of 4-1BB evokes an active antigen-specific suppression mechanism rather than merely blocking 4-1BB/4-1BBL interaction. We found that administration of anti-4-1BB mAb induced massive clonal expansion of CD11c+CD8+ T cells that produced IFN-gamma, resulting in accumulation of a high level of indoleamine 2,3-dioxygenase (IDO) in CD11c+ dendritic cells. 4-1BB-mediated suppression of EAU was reversed by the pharmacological IDO inhibitor, 1-methyl-tryptophan (1-MT). These studies demonstrate that suppression of EAU results from antigen-driven, 4-1BB-mediated expansion of novel CD11c+CD8+ T cells that suppress antigen-specific CD4+ T cells via an IDO-dependent mechanism.
Asunto(s)
Enfermedades Autoinmunes/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Retina/metabolismo , Retina/patología , Factores de Necrosis Tumoral/metabolismo , Úvea/metabolismo , Úvea/patología , Ligando 4-1BB , Animales , Enfermedades Autoinmunes/enzimología , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Antígenos CD11/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/metabolismo , Proliferación Celular , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Interferón gamma/biosíntesis , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II/metabolismo , Factores de Necrosis Tumoral/deficiencia , Factores de Necrosis Tumoral/genética , Factores de Necrosis Tumoral/inmunologíaRESUMEN
PURPOSE: Three cases of corneal melting caused by a new nonsteroidal anti-inflammatory drug (NSAID), bromfenac sodium, are reported. CASE REPORTS: Case 1: A 58-year-old man with a history of bullous keratopathy caused by Fuchs' corneal dystrophy was treated for episcleritis with topical bromfenac sodium. After 15 days of treatment, melting (80% depth) was observed inferiorly in the paracentral cornea. Case 2: A 71-year-old man underwent uncomplicated pterygium surgery, followed by treatment with topical bromfenac sodium. After 40 days of treatment, a 60%-depth corneal melt occurred in the nasal limbus. Case 3: A 76-year-old woman had a suspected bacterial corneal ulcer that resolved with topical ofloxacin; however, after 5 days of treatment with topical bromfenac sodium, a perforation occurred in the inferonasal cornea. RESULTS: In all three cases, severe corneal melting was characterized by mild hyperemia, very faint infiltration, and mild pain. Conservative treatment, including the use of a bandage soft contact lens and/or antibiotics and lubrication, led to resolution in all cases. CONCLUSIONS: A new NSAID, bromfenac sodium, can lead to severe corneal melting. These findings, together with similar previous reports concerning diclofenac sodium and ketorolac, suggest that careful observation is required when using topical NSAIDs in the treatment of corneal disease.