Induction of antibodies against oxidized elastin exacerbates structural and functional damage in mouse models of age-related macular degeneration.

Abstract

Purpose : Age-related macular degeneration (AMD) is the leading cause of blindness in Western populations. Morphological and genetic evidence suggests that an overactive complement system may be causative. However, potential ligands involved in complement activation are unknown. In the aged human eye, the elastin layer (EL) of Bruch’s membrane (BrM) is reduced, and a weakened EL might be a risk factor for wet AMD. In mouse eyes, we showed a loss of the EL in the smoke-induced ocular pathology (SIOP) model. Antibody (Ab) profiling in AMD subjects revealed a set of natural Abs that correlate with AMD diagnoses, including IgG/IgM recognizing elastin. Here we tested a potential role for α-elastin Abs in mouse models.

Methods : An immune-response was elicited by immunizing C57BL/6J mice with cigarette-smoke modified (oxidized) or control mouse lung elastin peptide in Freud’s adjuvant. Subsequently, mice were exposed to either cigarette smoke or filtered air, or choroidal neovascularization (CNV) was induced in room air raised mice. Contrast sensitivity was assessed by Optomotry and retinal morphology by spectral-domain optical coherence tomography and electron microscopy.

Results : Mice immunized with ox-elastin generated IgG/IgMs, whereas elastin had only a small effect. Ox-elastin immunization increased CNV size when compared to elastin immunization or PBS controls, and immunization altered the time course of CNV repair. Ox-elastin immunized mice exhibited exacerbated smoke-induced vision loss, with mice exhibiting thicker BrM and more damaged retinal pigment epithelium (RPE) mitochondria when compared to elastin immunized mice. In both models, the observed changes correlated with increased levels of IgM/IgG and C3d in the RPE/choroid, and differential levels of IgG subclasses were identified. Serum-derived IgGs, generated in response to immunization, recognized the main ox-elastin peptide.

Conclusions : Our findings suggest that α-elastin Abs might initiate complement activation leading to structural alterations in mouse models of dry and wet AMD. Antibodies binding to ox-elastin might directly activate complement via the classical or lectin pathway leading to complement-dependent cytotoxicity, or target-bound Abs by binding to their specific receptors might trigger Ab-dependent cell-mediated cytotoxicity.

This is a 2020 ARVO Annual Meeting abstract.