The role of the immune response in age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries; with the aging population, the negative health impacts and costs of the disease will increase dramatically over the next decade. Although the exact cause of AMD is unknown, genetic studies have implicated the complement system as well as other immune responses in disease pathogenesis and severity. Furthermore, histologic studies have shown the presence of macrophages, lymphocytes, and mast cells, as well as fibroblasts, in both atrophic lesions and with retinal neovascularization. This review summarizes discussions from the fifth annual conference of the Arnold and Mabel Beckman Initiative for Macular Research by the Inflammation and Immune Response Task Force. These deliberations focused on the role of inflammatory immune responses, including complement, inflammasomes, adaptive immune responses, and para-inflammation, unanswered questions and studies to address these questions, and potential immune-related therapeutic targets for AMD.

Figure 1

Schematic diagram of complement factor H (CFH). The protein consists entirely of 20 repeating homologous units (complement control repeats or CCPs), each ~60 amino acids in length (like beads on a string). The N-terminal portion houses the regulatory domains (repeats 1–4). The surface-binding recognition motifs are located in repeats 6–8, 12–14 and 19 and 20. They are also known as anionic- or heparin-binding sites. Both Y402H in repeat 7, and a rare variant in repeat 20 [12], are associated with AMD; these regions mediate the binding of factor H to cellular debris such as drusen or damaged retinal cells/tissues. Atypical hemolytic uremic syndrome (aHUS) has been compared to AMD because multiple variants leading to haploinsufficiency of factor H allow for excessive complement activation in this thrombomicroangiopathy [–15]. Specifically, about 60% of the mutations in aHUS occur in repeats 19 and 20, which decrease factor H's ability to bind to damaged endothelium. DAA, decay accelerating activity; CA, cofactor activity; Hep, heparin binding; CRP, C-reactive protein. Modified from Richards et al. [13].

Figure 2

An integrated model of immune regulation of AMD.