Plasma Levels of Matrix Metalloprotease MMP-9 and Tissue Inhibitor TIMP-1 in Caucasian Patients with Polypoidal Choroidal Vasculopathy.

BACKGROUND: Matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinases 1 (TIMP-1) are regulating enzymes of the extracellular matrix. A systemic imbalance of MMP-9 and TIMP-1, thought to reflect an imbalance of the extracellular matrix homeostasis, is previously associated with polypoidal choroidal vasculopathy (PCV) in Asian patients. Previous studies suggest inter-ethnical differences in the genetic background and etiology of PCV. To further explore this issue, we studied the plasma levels of MMP-9 and TIMP-1 in Caucasian patients with PCV and compared to healthy age-matched controls. METHODS: For this prospective case-control study, 60 participants were recruited who were either patients with PCV (n = 26) or healthy controls (n = 34). All participants underwent detailed clinical examination. We sampled fresh venous blood, isolated plasma, and quantified plasma concentrations of the extracellular matrix regulators MMP-9 and TIMP-1 using electrochemiluminescence immunoassays. RESULTS: Plasma levels of MMP-9 (p = 0.4), TIMP-1 (p = 0.9), and MMP-9/TIMP-1 ratio (p = 0.4) did not differ significantly between patients with PCV and healthy controls. No differences appeared after adjusting for influencing co-variates in multivariate analyses. CONCLUSION: We demonstrate that Caucasian patients with PCV do not have altered levels of plasma MMP-9 or plasma TIMP-1. These findings suggest no strong evidence of a systemic imbalance of the extracellular matrix homeostasis in Caucasian patients with PCV. Our findings are in line with studies of other aspects of PCV that are also subject to significant inter-ethnical differences.

Plasma levels of inflammatory chemokines in patients with polypoidal choroidal vasculopathy.

PURPOSE: Chemokines are a group of cytokines that guide immune cell migration. We studied plasma levels of inflammatory chemokines in patients with polypoidal choroidal vasculopathy (PCV) and compared with healthy age-matched control individuals. METHODS: This was a clinic-based prospective case-control study of participants (n = 60) with either PCV (n = 26) or age-matched healthy controls (n = 34). We sampled fresh venous blood and isolated plasma for analysis. We used U-PLEX Human Assays to quantify concentrations of the inflammatory chemokines MCP-1/CCL2, RANTES/CCL5, eotaxin/CCL11, IP-10/CXCL10 and fractalkine/CX3CL1. RESULTS: Plasma levels of fractalkine was significantly higher in patients with PCV when compared to healthy controls (mean ± SD: 7291 ± 2461 pg/ml versus 5879 ± 2001 pg/ml; p = 0.021). Plasma levels of MCP-1 (p = 0.846), RANTES (p = 0.288), eotaxin (p = 0.496) and IP-10 (p = 0.352) did not differ significantly between the groups. To evaluate possible biomarker quality of fractalkine, we used a ROC analysis and found a positive but weak discriminatory ability (AUC = 0.68). CONCLUSION: Patients with PCV have a higher plasma level of fractalkine. Although the differences do not possess strong biomarker qualities, they inform on disease processes of a poorly understood disease and suggest that the fractalkine-CX3CR1 axis may be involved. As this study did not investigate local chemokine concentrations, we are unable to confirm or disprove any local chorioretinal interaction, and our findings should be interpreted with such caution.

Patients with a fast progression profile in geographic atrophy have increased CD200 expression on circulating monocytes.

IMPORTANCE: Geographic atrophy (GA) is a progressing atrophy of the neuroretina with no treatment option. BACKGROUND: Age-related malfunction of retinal microglia amplifies response towards age-related tissue stress in age-related macular degeneration. Here, we investigated monocyte CD200 expression - the circulating middleman negotiating retinal microglial activity - in a poorly understood subtype of age-related macular degeneration. DESIGN: Prospective case-control study. PARTICIPANTS: Forty-six patients with GA and 26 healthy controls were included. METHODS: All participants were subjected to a structured interview and detailed retinal examination. Controls were recruited from patient's spouses accompanying them in the clinic to match the groups best possibly. Participants had no history of immune disorders or cancer, and did not receive any immune-modulating medication. Patients did not have any history or sign of choroidal neovascularization in either eye. Fresh drawn blood was stained with monoclonal antibodies and prepared for flow cytometry to evaluate CD200 expression in monocytes and their functional subsets. MAIN OUTCOME MEASURES: The percentage of CD200+ monocytes in patients and controls. RESULTS: We found that monocytes were more CD200 positive in patients with GA compared to healthy age-matched controls. Then, we explored the potential relationship between CD200 expression and important fundus autofluorescence patterns that predict disease progression. Patients with a high risk of progression (patients with high degree of hyperautofluorescence) had distinctly increased CD200 expression compared to other patients with GA. CONCLUSIONS AND RELEVANCE: Our data reveals that abnormal monocytic CD200 expression is present in GA, and in particular among those identified as fast progressors.

Altered proportion of CCR2+ and CX3CR1+ circulating monocytes in neovascular age-related macular degeneration and polypoidal choroidal vasculopathy.

BACKGROUND: We investigated the expression of chemokine receptors CCR2 (C-C chemokine receptor) 2 and CX3CR1 (C-X3-C receptor 1) on circulating monocyte subsets in patients with neovascular age-related macular degeneration (AMD) and patients with polypoidal choroidal vasculopathy (PCV). METHODS: We recruited patients with neovascular AMD, patients with PCV and age-matched healthy controls for this prospective case-control study. All participants underwent comprehensive clinical examination and imaging. Freshly sampled venous blood was prepared for flow cytometry, where we determined the proportion of CCR2+ - and CX3CR1+ -positive cells in monocyte subsets identified using monocyte identification and subgrouping surface markers CD14, CD16 and HLA-DR. RESULTS: Patients with neovascular AMD had significantly increased proportion of CCR2+ and CX3CR1+ non-classical monocytes. PCV type 1 was associated with significantly increased CCR2+ and CX3CR1+ in all monocyte subsets when compared to PCV type 2. CONCLUSIONS: Neovascular AMD is associated with increased expression of angiogenesis-associated chemokine receptors in the pro-inflammatory non-classical monocytes. PCV differs from neovascular AMD immunologically and show immunological heterogeneity across angiographic subtypes.