RESUMO
Early stages of geographic atrophy (GA) age-related macular degeneration is characterised by the demise of photoreceptors, which precedes the loss of underlying retinal pigment epithelial (RPE) cells. Sight-loss due to GA has no effective treatment; reflecting both the complexity of the disease and the lack of suitable animal models for testing potential therapies. We report the development and characterisation of a laser-induced mouse model with early GA-like pathology. Retinas were lasered at adjacent sites using a 810 nm laser (1.9 J/spot), resulting in the development of confluent, hypopigmented central lesions with well-defined borders. Optical Coherence Tomography over 2-months showed progressive obliteration of photoreceptors with hyper-reflective outer plexiform and RPE/Bruch's membrane (BrM) layers within lesions, but an unaffected inner retina. Light/electron microscopy after 3-months revealed lesions without photoreceptors, leaving the outer plexiform layer apposed to the RPE. We observed outer segment debris, hypo/hyperpigmented RPE, abnormal apical-basal RPE surfaces and BrM thickening. Lesions had wedge-shaped margins, extended zones of damage, activated Müller cells, microglial recruitment and functional retinal deficits. mRNA studies showed complement and inflammasome activation, microglial/macrophage phagocytosis and oxidative stress providing mechanistic insights into GA. We propose this mouse model as an attractive tool for early GA studies and drug-discovery.
Assuntos
Modelos Animais de Doenças , Atrofia Geográfica/patologia , Raios Infravermelhos/efeitos adversos , Retina/patologia , Animais , Feminino , Atrofia Geográfica/etiologia , Lasers , Camundongos , Camundongos Endogâmicos C57BL , Retina/diagnóstico por imagem , Retina/efeitos da radiação , Tomografia de Coerência ÓpticaRESUMO
PURPOSE: To determine the association of human leukocyte antigen (HLA) C and its cognate killer cell immunoglobulin-like receptor (KIR) ligands with age-related macular degeneration (AMD). METHODS: HLA class I allele groups including the HLA-C principal alleles were genotyped in a cohort of 104 AMD cases and 93 controls by using the PCR-SSP (sequence-specific primers) METHOD: This cohort was then genotyped for 16 KIR genes by PCR-SSP. Frequencies of the tested HLA/KIR alleles were then compared between patients with AMD and normal control subjects. HLA-C1, -Cw*07, and -Cw*0701 genotypes and their combinations with KIR genotypes/haplotypes were tested for association with AMD. Probabilities were obtained with a two-tailed chi(2) test and Bonferroni correction applied for multiple testing (P(c)). RESULTS: The HLA-Cw*0701 allele, in combination with the inhibitory KIR AA haplotype was associated with AMD after logistic regression analysis (P = 0.006, P(c) = 0.036, OR = 4.35, 95% CI = 1.41-13.44). CONCLUSIONS: The HLA-Cw*0701 allele and KIR haplotype AA are associated with AMD. This genotype combination suggests that natural killer cells have a role in the pathogenesis of AMD. Replication studies are needed to confirm these novel HLA-KIR associations with AMD.