Purpose: Ageing is the strongest predictor of neovascular age-related macular degeneration (AMD), where neuroinflammation is known to play a major role. Less is known about polypoidal choroidal vasculopathy (PCV), which is an important differential diagnosis to neovascular AMD. Here, we report plasma markers of inflammation with age (inflammaging) in patients with PCV, patients with neovascular AMD and a healthy age-matched control group. Methods: We isolated plasma from fresh venous blood obtained from participants (n = 90) with either PCV, neovascular AMD, or healthy maculae. Interleukin(IL)-1b, IL-6, IL-8, IL-10 and tumour necrosis factor receptor 2 (TNF-R2) were measured using U-PLEX Human Assays. Routine plasma Creactive protein (CRP) was measured using Dimension Vista 1500. Results: Patients with PCV had plasma levels of IL-1b, IL-6, IL-8, IL-10 and TNF-R2 similar to that in healthy controls. Patients with neovascular AMD had significantly higher plasma IL-1b, IL-6 and IL-10 than healthy controls, whereas no significant differences were observed for plasma IL-8 and TNF-R2. Differences between plasma IL-1b, IL-6 and IL-10 possessed a positive but weak ability in discriminating neovascular AMD from PCV. Both patients with PCV and patients with neovascular AMD had significantly higher levels of routine plasma CRP. Conclusion: Patients with PCV differ from patients with neovascular AMD in terms of plasma inflammaging profile. Apart from increased CRP, no signs of inflammaging were observed in patients with PCV. In patients with neovascular AMD, we find a specific angiogenesis-twisted inflammaging profile.
Age-related macular degeneration (AMD) is a degenerative disease of the retina and a leading cause of irreversible vision loss. We investigated the systemic differences in the frequency of T helper (Th) 1 and Th17 cells in patients with non-exudative and exudative AMD and compared to age-matched controls. Flow cytometry was used to determine the systemic frequency of Th1 (CD4+CXCR3+IL12RB2+) and Th17 (CD4+CCR6+IL23R+) cells, and percentage of CD4+ T-cells expressing CXCR3, IL12RB2, CCR6, IL23R, and co-expressing CXCR3 and CCR6. The frequency of Th1 cells and CXCR3+ CD4+ T-cells was lower in patients with exudative AMD. A significant age-dependent decrement in Th1 was observed in controls, but not in non-exudative or exudative AMD. This may be related to the CXCR3+ CD4+ T-cells, which showed similar pattern in controls, but not in non-exudative or exudative AMD. No significant group differences were observed for the frequency of Th17 cells. Correlation networks found several differences between controls and AMD. These data suggests the involvement of the adaptive immune system in AMD and supports the notion of AMD as a systemic disease. Our observations warrant further investigation into the role of the adaptive immune system in the pathogenesis of AMD.
Age-related macular degeneration (AMD) is aetiologically linked to immunological ageing and dysfunction. One aspect of this is the altered neutrophil-tolymphocyte ratio (NLR), which in other domains have been associated with inflammation and angiogenesis, and therefore investigated in patients with AMD in several papers. In this systematic review and meta-analysis, we summarize findings in patients with AMD in relation to NLR, both qualitatively and quantitatively. We searched PubMed/MEDLINE, EMBASE, Web of Science, and the Cochrane Central and identified six studies from where we extracted data on 1178 individuals (777 patients with AMD and 401 healthy controls). Patients with AMD had a higher NLR (weighted mean difference: 0.37, CI 95% 0.08 to 0.66, p = 0.013) when compared to healthy controls. In subgroup analyses, we did not find a significant difference between patients with dry AMD and healthy controls (weighted mean difference: 0.34, CI 95% À0.03 to 0.69, p = 0.068), but did find a strong significant difference between patients with neovascular AMD and healthy controls (weighted mean difference: 0.54, CI 95% 0.23 to 0.86, p = 0.00068). Hence, we find that the association between AMD and elevated NLR may have stronger relevance to the neovascular subtype of AMD. However, the clinical value of measuring the NLR remains unclear.
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.
We found that PCV is immunologically heterogeneous with significant differences between angiographic subtypes. Increased CD11b+ and CD200+ monocytes in those with a strong presence of BVN indicate that BVN development may be associated with retinal injury and a VEGF-mediated process that is either reflected or propelled by systemic changes in monocytes.
Background
Peripheral blood mononuclear cells (PBMCs) are implicated in the pathogenesis of age-related macular degeneration (AMD). We here mapped the global gene transcriptome of PBMCs from patients with different clinical subtypes of late AMD.
Results
We sampled fresh venous blood from patients with geographic atrophy (GA) secondary to AMD without choroidal neovascularizations (
n
= 19), patients with neovascular AMD without GA (
n
= 38), patients with polypoidal choroidal vasculopathy (PCV) (
n
= 19), and aged control individuals with healthy retinae (
n
= 20). We isolated PBMCs, extracted RNA, and used microarray to investigate gene expression. Volcano plots identified statistically significant differentially expressed genes (
P
< 0.05) at a high magnitude (≥30% higher/lower) for GA (62 genes), neovascular AMD (41 genes), and PCV (41 genes). These clinical subtypes differed substantially across gene expression and the following pathways identified in enrichment analyses. In a subgroup analysis, we investigated presence vs. absence of subretinal fibrosis and found 826 differentially expressed genes (≥30% higher/lower,
P
< 0.05) with relation to mRNA splicing, endothelial migration, and interleukin-1 signaling.
Conclusions
We here map the global gene transcriptome of PBMCs related to clinical subtypes of late AMD and find evidence of subtype-specific immunological involvement. Our findings provide a transcriptomic insight into the systemic immunity associated with AMD.
Electronic supplementary material
The online version of this article (10.1186/s12979-019-0160-0) contains supplementary material, which is available to authorized users.
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