Systemic changes in neovascular age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of visual impairment in the aged population worldwide. The mechanisms underlying this multifactorial and heterogenic disease are complex and incompletely understood. There is increasing evidence to suggest that regulatory differences in the immune system are involved in the development of the various subtypes of AMD. The purpose of this thesis was to identify some of these potential differences in patients with early or late (wet, dry, or fibrotic) AMD. Specifically, we sought to determine differences in 1) expression of regulators of the complement pathway (CD46, CD55, and CD59) on circulating leukocytes; 2) expression of microglia-inhibitory proteins (CD200 and CD200R) on circulating leukocytes; and 3) plasma concentrations of 25-hydroxyvitamin D, a factor known to inhibit angiogenesis, fibrosis, inflammation, and oxidation. All participants underwent a semi-structured interview and detailed retinal imaging. Fresh venous blood was obtained and the frequency of cells expressing the proteins in question was determined using flow cytometry. Plasma 25-hydroxyvitamin D was measured using liquid chromatography-tandem mass spectrometry. Also, genotyping as performed in order to determine the frequency of certain single-nucleotide polymorphisms in the vitamin D metabolism. Patients with wet AMD were found to have statistically significant lower frequencies of CD46 and CD59 on CD14+monocytes and higher frequencies of CD200 on CD11b+ monocytes compared to control individuals without AMD (p = 0.0070 and p = 0.047, respectively). Moreover, we found a lower frequency of CD46 on CD45+lymphocytes in patients with wet AMD and subretinal fibrosis compared to patients with wet AMD without fibrosis (p = 0.010). Vitamin D status was not different across AMD subgroups; however, the presence of subretinal fibrosis in patients with wet AMD was associated with a statistically significant lower concentration of 25-hydroxyvitamin D (p < 0.001). Our results suggest that inadequate systemic immune modulation is an important pathogenic mechanism in the aetiology of AMD. Moreover, some differences in protein expression and vitamin D status appear to be related to the phenotypical diversity of AMD, proposing that different mechanisms may underlie the different subtypes of AMD.