The role of inflammation in the pathogenesis of age-related macular degeneration

Abstract

Age-related macular degeneration (AMD), the leading cause of blindness in the elderly, is a complex disease to study because of the potential role of demographic, environmental, and other systemic risk factors, such as age, sex, race, light exposure, diet, smoking, and underlying cardiovascular disease which may contribute to the pathogenesis of this disease. Recently, single nucleotide polymorphisms, DNA sequence variations found within the complement Factor H gene, have been found to be strongly associated with the development of AMD in Caucasians. One single nucleotide polymorphism, Tyr402His, was associated with approximately 50% of AMD cases. We review recent developments in the molecular biology of AMD, including single nucleotide polymorphisms within the Factor H gene, which may predispose individuals to the susceptibility of AMD as well as single nucleotide polymorphisms that may confer a protective effect. Taken together these findings help to provide new insights into the central issues surrounding the pathogenesis of AMD.

Fig. 1

Fundus photographs from patients with juvenile macular dystrophies and corresponding DNA sequence variation associated with the condition. From top to bottom: autosomal dominant macular dystrophy (RDS gene), autosomal dominant Stargardt-like macular dystrophy, X-linked retinoschisis, and autosomal dominant pattern dystrophy.

Fig. 2

Fundus photographs illustrating various stages of dry and wet stage AMD with numerous drusen (upper left); neovascular membrane (upper right); more extensive macular changes (lower left); and minimal geographic atrophy (lower right).

Fig. 3

Drusen. Conventional hematoxlyn-eosin stain of drusen. (Courtesy of Dr. Ralph Eagle of Wills Eye Hospital.)

Fig. 4

Radial drusen in a patient with malattia levintense. Note radial pattern of drusen and neovascular membrane reminiscent of AMD (see Pager et al).

Fig. 5

The tree branches of the complement pathway and the interaction Factor H. (Modified from Levinson and Jawetz and Rodríguez de Cordoba et al.)

Fig. 6

Schematic diagram depicting Factor H and the effects of time, arenetics, and environment on retinal aging and AMD. (Modified from Zarbin.)

Fig. 7

Pedigree of 14-generation family with history of AMD, and a DNA sequence trace of affected family member (top) and known AMD patient (bottom) who shows heterozygous state at exon 9 (*) for the Y402H DNA sequence change.

Fig. 8

Inflammatory process related to cardiovascular disease. This figure depicts the role of macrophages in arterial inflammatory processes. In this example the monocyte can be activated by microbial molecules (as well as other molecules) to induce activation. (Modified from Seddon et al.)