AMD-Like Changes in Cfh Transgenic Mice: Can Antigen-Specific Immunity Enhance the Phenotype?

Abstract

Purpose: : The observation that variants of complement factor H (Cfh; a key regulator of complement activation) increase the risk of AMD emphasizes that innate immunity plays a role in the disease. Immunization with carboxyethyl pyrrole (CEP) adducts, subretinal neoantigens derived from oxidative damage to lipids and proteins, can induce an AMD-like phenotype in mice. We hypothesize that an antigen-specific immune response to CEP adducts at the subretinal level can exacerbate the AMD-phenotype seen in the setting of suboptimal complement regulation.

Methods: : We generated transgenic chimeric Cfh lines using two transgenic constructs consisting of the human SCR6-8 sequence flanked by the mouse SCR1-5 and SCR9-20 sequences (under the ApoE promoter). The constructs code for either a tyrosine or a histidine at amino acid position 402. We bred the Cfh transgenic lines with Cfh KO mice to eliminate mouse Cfh. We then immunized young adult (3-4 m old) or middle age (8-10 m old) transgenic and wild type mice using either CEP adducted mouse serum albumin (MSA) or sham-adducted MSA.

Results: : Chimeric Cfh transgenic mice demonstrate an accumulation of basal laminar deposits compared to wild type mice. Moreover, transgenic mice develop a thickening of Bruch’s membrane and complement C3 deposition. Immunization of young or middle aged Cfh transgenic mice with CEP-adducted MSA does not lead to clinical differences compared to sham-adducted MSA 1 month after immunization. We will report further clinical, histopathologic and electron microscopic follows up.

Conclusions: : Cfh transgenic mice develop characteristics consistent with early AMD. Immunization with CEP-adducted MSA does not cause an acute inflammatory process in the retina. Longer observation will determine if a chronic, low grade, subretinal antigen-specific immune response can potentiate the AMD-like changes.

Keywords: age-related macular degeneration • Bruch's membrane • inflammation