Abstract
Age-related macular degeneration (AMD) has been associated with both systemic and ocular alterations of the immune system. In particular dysfunction of complement factor H (CFH), a soluble regulator of the alternative pathway of the complement system, has been implicated in AMD pathogenesis. One of the ligands for CFH is long pentraxin 3 (PTX3), which is produced locally in the retinal pigment epithelium (RPE). To test the hypothesis that PTX3 is relevant to retinal immunohomeostasis and may be associated with AMD pathogenesis, we measured plasma PTX3 protein concentration and analyzed the RPE/choroid PTX3 gene expression in patients with AMD. To measure the ability of RPE cells to secrete PTX3 in vitro, polarized ARPE-19 cells were treated with activated T cells or cytokines (interferon (IFN)-gamma and/or tumor necrosis factor (TNF)-alpha) from the basolateral side; then PTX3 protein concentration in supernatants and PTX3 gene expression in tissue lysates were quantified. Plasma levels of PTX3 were generally low and did not significantly differ between patients and controls (P=0.307). No statistically significant difference was observed between dry and exudative AMD nor was there any correlation with hsCRP or CFH genotype. The gene expression of PTX3 increased in RPE/choroid with age (P=0.0098 macular; P=0.003 extramacular), but did not differ between aged controls and AMD patients. In vitro, ARPE-19 cells increased expression of the PTX3 gene as well PTX3 apical secretions after stimulation with TNF-alpha or activated T cells (P<0.01). These findings indicate that PTX3 expressed in the eye cannot be detected systemically and systemic PTX3 may have little or no impact on disease progression, but our findings do not exclude that locally produced PTX3 produced in the posterior segment of the eye may be part of the AMD immunopathogenesis.
Highlights
Age-related macular degeneration (AMD) is the most common cause of vision loss for persons above 50 years of age in Western countries [1,2]
There was a tendency towards slightly lower plasma pentraxin 3 (PTX3) in patients with exudative AMD compared with controls, but this was not statistically significant
There was no statistical correlation between CFHY402H genotype and plasma PTX3 (P = 0.055, data not shown), or between plasma levels of C-reactive protein (CRP) and PTX3
Summary
Age-related macular degeneration (AMD) is the most common cause of vision loss for persons above 50 years of age in Western countries [1,2]. It is hypothesized that the accumulating drusen can trigger local production of inflammatory mediators and attraction of leukocytes, which would lead to an increase in inflammation and retinal stress [6]. The complement system is the first line of defense against microbial intruders, and important for endogenous tissue homeostasis through the opsonization of apoptotic cells and debris It is under tight regulation by soluble and membrane-bound inhibitors, and many complement factors are expressed in the normal human retina. While CRP and SAP are primarily produced in the liver and released to the blood, PTX3 is produced by local tissues at sites of inflammation. This includes the RPE, where PTX3 expression is induced by inflammatory stimuli [19]. Based on the retinal expression of PTX3, the known interaction between PTX3 and CFH and the strong association between CFH polymorphisms and AMD, we hypothesized that retinal PTX3 production could be important for the local immunohomeostasis and that aberrant expression of PTX3 could be associated with the pathophysiology of AMD
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