The role of Beta-2 Glycoprotein I in age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is a progressive degenerative disorder of the macula of the retina of the human eye. It is considered as the major cause of legal blindness in people older than 50 in western societies. Oxidative stress is believed to play an important role in the pathogenesis of AMD where lipid peroxidation occurs as a result of intense day-to-day exposure to light as well as the oxygen-rich environment of the retina. Consequently, lipid peroxidation by products accumulate within the retina such as malondialdehdye (MDA) and its biologically relevant and relatively more stable form, malondialdehyde acetaldehyde (MAA), which are highly reactive aldehydes that have the ability to react and form adducts with proteins, lipids and DNA of living cells. This may initiate an immune system-mediated inflammatory response which has been reported to cause AMD. Beta-2 glycoprotein I (β2GPI) is an abundant plasma protein with mean serum levels of 200μg/mL which belongs to the complement control protein (CCP) superfamily. It is the major autoantigen in the antiphospholipid syndrome (APS), a disorder characterized by venous and arterial thrombosis, recurrent miscarriages and foetal death. The majority of β2GPI circulates in plasma in its free-thiol form. In this study, it is demonstrated that β2GPI binds MAA-BSA in vitro as determined by a direct ELISA assay. Moreover, β2GPI was able to compete with MAA-BSA for binding apoptotic Jurkat T-cells.

Immunohistochemical analysis of the retina from a 78 years old AMD patient demonstrated that β2GPI is expressed within the retina. Additionally, free-thiol β2GPI was found to protect the human retinal pigment epithelium cell line, ARPE-19, from apoptosis caused by hydrogen peroxide (H2O2) treatment. Finally, levels of total β2GPI were significantly higher in plasma taken from patients with late AMD as compared to those with early AMD and healthy controls. Levels of free-thiol β2GPI in plasma of patients with late AMD were significantly lower than those of healthy controls and early AMD patients. In the light of this study, the redox state of β2GPI may be used as potential biomarker for AMD disease progression.