From the outcome of these studies, a new working model for AMD generation has emerged that integrates the idea of a tissue-specific inflammatory signal with the recent findings that polymorphisms/mutations in complement pathway genes are linked to AMD. This model is built on the concept of an interplay between the rate of inflammatory signal generation in the outer retina, the immune systems response to the inflammatory signal and the regulation of complement pathway activation in the tissue where the inflammatory signal is generated. In
Figure 4a, the left ordinate indicates the progressive increase in oxidative damage and autoantibody production during aging, as shown on a double-ordinate plot. The right ordinate reflects the efficiency of complement regulation, which establishes a disease threshold (shown as the shaded background). The conditions depicted in
Figure 4a reflect the interaction of these two processes in a normal individual without AMD. Although the inflammatory signal generated in the outer retina and autoantibody levels increase during aging, the level of these signals do not reach the disease threshold during the lifetime of the individual. In
Figure 4b, the rate of inflammatory signal from the outer retina and autoantibody levels progress at the same rate as in
Figure 4a, but polymorphisms/mutations in complement genes lower the disease threshold and allow these two lines to intersect and AMD to be manifest. For simplicity,
Figure 4b depicts complement polymorphisms as having an effect on reducing the disease threshold. Several complement polymorphisms are described that reduce the risk for AMD, which in this model would elevate the disease threshold. In
Figure 4c, changes in the systemic protection in oxidative damage, or environmental conditions that are permissive of oxidative damage result in an increase in the rate of inflammatory signal generation, changing the slope of the dashed line and allowing an early intersect with the disease threshold. Changes in the right and left ordinates should be expected to vary independently. Higher rates of inflammatory signal generation coupled with a lower disease threshold would result in an early onset of AMD. Conversely, a lower rate of inflammatory signal generation in an individual with efficient complement regulation would be reflected in the graph in
Figure 4a.
Figure 4d shows how the immunization of the mouse with CEP fits with this AMD disease model. Normally, CEP would be generated in the outer retina and slowly evoke an immune response that would not reach the disease threshold (similar to that shown in
Fig. 4a). Systemic immunization in the mouse changes the slope of the dashed line (through the generation of the CEP antibody), which rapidly reaches the disease threshold. Complement mediated attack is directed toward the RPE in the outer retina because of the specific generation of CEP adducts in this tissue.